bluuebunny/crossref_metadata_2025 huggingface dataset:
ORGANIC SOLVENT-ASSISTED TRANSFER PRINTING ON HYDROPHOBIC POLYMER SUBSTRATE WITH HIGH EFFICIENCY
Authors: YANG HAIJUN , WANG PENG , WANG HUABIN , WANG XINYAN , ZHANG FUCHUN , LI BIN , LI HAI
Published: January 2009

Patterning materials on hydrophobic polymer substrates have extensive applications in fabricating flexible devices at low cost, while the low transfer efficiency encumbers its advance. This paper provides a facile route to transfer materials onto hydrophobic polymer substrates with high efficiency by operating in organic solvent atmosphere. Under the assistance of condensed organic solvent layer on the substrate, bovine serum albumin (BSA) are desirably transferred onto untreated hydrophobic polymer substrates, such as poly(dimethylsiloxane) (PDMS), polystyrene (PS), and poly(ethylene terephthalate) (PET) as a proof-of-concept experiment. Moreover, the combination of this method with stepwise contraction and adsorption nanolithography (SCAN) was also demonstrated as an alternative way to further miniaturize patterns prepared by other methods.
EFFECT OF Ce-DOPING ON STRUCTURAL AND ELECTRICAL PROPERTIES OF DIELECTRIC Bi2Ti2O7 THIN FILMS
Authors: JING XIANGYANG , HUANG BAIBIAO , YAO SHUSHAN , ZHANG QI , WANG ZEYAN , WANG PENG , ZHENG LIREN
Published: January 2009

Ce -doped Bi 2 Ti 2 O 7 thin films have been successfully prepared on P-type Si substrates by a chemical solution deposition method. The structural properties of the films were studied by X-ray diffraction. The phase of Ce -doped Bi 2 Ti 2 O 7 was more stable than that of Bi 2 Ti 2 O 7 without Ce substitution. The films exhibited good insulating properties at room temperature. The dielectric constant of the films annealed at 700°C at 100 kHz was 168 and the dissipation factor was 0.038. All these results showed that Ce -doped Bi 2 Ti 2 O 7 thin films could be used as storage capacitors in DRAM and MOS.
π–d INTERACTION BASED MOLECULAR CONDUCTING MAGNETS: HOW TO INCREASE THE EFFECTS OF THE π–d INTERACTION
Authors: MIYAZAKI AKIRA , ENOKI TOSHIAKI
Published: January 2009

The crystal structures and electronic and magnetic properties of conducting molecular magnets developed by our group are reviewed from the viewpoints of our two current strategies for increasing the efficiency of the π–d interaction. (EDTDM)2 FeBr 4 is composed of quasi-one-dimensional donor sheets sandwiched between magnetic anion sheets. The ground state of the donor layer changes from the insulator state to the metallic state by the application of pressure. When it is near to the insulator–metal phase boundary pressure, the magnetic order of the anion spins considerably affects the transport properties of the donor layer. The crystal structure of ( EDO – TTFBr 2)2 FeX 4 ( X = Cl , Br ) is characterized by strong intermolecular halogen–halogen contacts between the organic donor and FeX 4 anion molecules. The presence of the magnetic order of the Fe 3+ spins and relatively high magnetic order transition temperature proves the role of the halogen–halogen contacts as exchange interaction paths.
DIAMOND-LIKE CARBON: A NEW MATERIAL BASE FOR NANO-ARCHITECTURES
Authors: LI XIJUN , CHUA DANIEL H. C.
Published: January 2009

Diamond-like carbon (DLC) is a form of amorphous carbon which has high fraction of sp3 hybridization. Due to its nature of sp3 bonding, diamond-like carbon has been shown to have excellent properties similar to that of diamond. This includes high hardness, excellent wear-resistance, large modulus and chemically inert. Traditional applications include wear resistant coatings and protective film. This article intends to review the synthesis and material properties of diamond-like carbon as well as its potential as a novel material for applications in nano-architecture and nano-mechanical devices. An introduction into metal-dopants in diamond-like carbon film will be briefly mentioned as well as techniques on the design and fabrication of this material.
A UNITARY INVARIANT IN RIEMANNIAN GEOMETRY
Authors: CONNES ALAIN
Published: January 2009

We introduce an invariant of Riemannian geometry which measures the relative position of two von Neumann algebras in Hilbert space, and which, when combined with the spectrum of the Dirac operator, gives a complete invariant of Riemannian geometry. We show that the new invariant plays the same role with respect to the spectral invariant as the Cabibbo–Kobayashi–Maskawa mixing matrix in the Standard Model plays with respect to the list of masses of the quarks.
LIFETIME OF A DE SITTER PARTICLE
Authors: EPSTEIN HENRI
Published: January 2009

The familiar rule which, in Minkowski space-time, forbids the decay of a particle into heavier products, does not hold in de Sitter space-time. We study, in first order of perturbation theory, the decay of a particle of the "principal series" and show that it may decay into two particles of any of the "principal" or "complementary" series (with suitable interaction terms). Spectral conditions reappear in the decay of a "complementary" particle: but its lifetime is 0.
N-COMPLEXES AND HIGHER SPIN GAUGE FIELDS
Authors: HENNEAUX MARC
Published: January 2009

N-complexes have been argued recently to be algebraic structures relevant to the description of higher spin gauge fields. N-complexes involve a linear operator d that fulfills dN = 0 and that defines a generalized cohomology. Some elementary properties of N-complexes and the evidence for their relevance to the description of higher spin gauge fields are briefly reviewed.
THEORETICAL PHYSICS IN REAL LIFE
Authors: ROUET ALAIN
Published: January 2009

The unexpected efficiency of some theoretical physics methods in solving technical problems is illustrated by a few examples. This had been well understood by physicists like Wigner, but slightly forgotten in the last decades.
WiFi exposed
Authors: Bittau Andrea
Published: January 2009

Over the past few years, IEEE 802.11 wireless networks have become increasingly widely deployed. Wireless LANs can be found in coffee shops, airports, hospitals, and all major institutes. However, as for conventional wired networks, the spread of such networks may have been faster than the diffusion of security knowledge about them. As a consequence, 802.11 is the new playground for many hackers, who are attracted to the environment by virtue of its anonymity. Attacks may be traced back to the wireless network, but the intruder could have been anyone driving by within the radius of the network, making it hard, if not impossible, for him/her to be traced. Securing wireless networks is a hard task, because the standard solutions do not work effectively in guaranteeing privacy and authentication, as this article shows; as a consequence, many wireless networks are left open.This article is structured as follows: initially, an overview of the 802.11 protocol is presented. This is followed by an analysis of the steps involved in connection to and use of such a network, first in the absence of encryption and then taking into account WEP. Attacks for these different scenarios are presented and analyzed, leading to the conclusion that WEP is unsuitable as the sole security measure for such links. Finally, attacks on wired networks that are connected to a wireless LAN are analyzed.The article concludes that existing standards for wireless security as applied to the most widely used wireless standard, 802.11, are inadequate in several ways, can be attacked using publicly available tools, and lead to a false sense of security. Some advice about mitigation of threats is offered throughout the article, but the most effective solution is awareness of potential attacks and the maximization of the amount of time and effort needed to break into the network by using defence in depth.
DNA smart card for financial transactions
Authors: Gleni Sofia , Petratos Panagiotis
Published: January 2009

In this paper, a secure environment for electronic commerce is introduced. The environment is formed via a synthesis of biometrics consumer authentication with a security token. Such a token is a smart card containing cryptographic keys and a cryptographic microprocessor for data encryption. The keys are used to further authenticate the possessor of the card as the actual owner and also to facilitate secure electronic financial transactions. New technologies like these bring benefits to society by enhancing the standard of living, however, numerous challenges are introduced [1].Biometrics is a Greek composite word stemming from the synthesis of bio and metric, meaning life measurement. In this context, the science of biometrics is concerned with the accurate measurement of unique biological characteristics of an individual in order to securely identify them to a computer or other electronic system. Biological characteristics measured usually include fingerprints, voice patterns, retinal and iris scans, face patterns, and even the chemical composition of an individual's DNA [9].
A distributed security scheme for ad hoc networks
Authors: Gada Dhaval , Gogri Rajat , Rathod Punit , Dedhia Zalak , Mody Nirali , Sanyal Sugata , Abraham Ajith
Published: January 2009

In an ad hoc wireless network where wired infrastructures are not feasible, energy and bandwidth conservation are the two key elements presenting challenges to researchers. Limited bandwidth makes a network easily congested by the control signals of the routing protocol. Routing schemes developed for wired networks seldom consider restrictions of this type. Instead, they assume that the network is mostly stable and that the overhead for routing messages is negligible. Considering these differences between wired and wireless network, it is necessary to develop a wireless routing protocol that limits congestion in the network [1, 5, 8, 9, 10, 11].This paper proposes minor modifications to the existing Ad hoc On Demand Vector (AODV) routing protocol (RFC 3561) in order to restrict congestion in networks during a particular type of Denial of Service (DoS) attack. In addition to this, it incurs absolutely no additional overhead [4]. We describe the DoS attack caused due to Route Request (RREQ) flooding and its implications on existing AODV-driven Mobile Ad hoc Networks (MANET) [2, 14]. To combat this DoS attack, a proactive scheme [12] is proposed. We present an illustration to describe the implications of RREQ flooding on pure AODV and the modified AODV protocols. To quantify the effectiveness of the proposed scheme, we simulated a DoS [6] attack in a mobile environment and study the performance results.
Architecting trust-enabled peer-to-peer file-sharing applications
Authors: Suryanarayana Girish , Diallo Mamadou H. , Erenkrantz Justin R. , Taylor Richard N.
Published: January 2009

Decentralized peer-to-peer (P2P) resource sharing applications lack a centralized authority that can facilitate peer and resource look-ups and coordinate resource sharing between peers. Instead, peers directly interact and exchange resources with other peers. These systems are often open and do not regulate the entry of peers into the system. Thus, there can be malicious peers in the system who threaten others by offering Trojan horses and viruses disguised as seemingly innocent resources. Several trust-based solutions exist to address such threats; unfortunately there is a lack of design guidance on how these solutions can be integrated into a resource sharing application. In this paper, we describe how two teams of undergraduate students separately integrated XREP, a third-party reputation-based protocol for file-sharing applications, with PACE, our software architecture-based approach for decentralized trust management. This was done in order to construct trust-enabled P2P file-sharing application prototypes. Our observations have revealed that using an architecture-based approach in incorporating trust into P2P resource-sharing applications is not only feasible, but also significantly beneficial. Our efforts also demonstrate both the ease of adoption and ease of use of the PACE-based approach in constructing such trust-enabled decentralized applications.
An approach for detecting prosodic phrase boundaries in spoken english
Authors: Brierley Claire , Atwell Eric
Published: January 2009

Prosodic phrasing is the means by which speakers of any given language break up an utterance into meaningful chunks. The term "prosody" itself refers to the tune or intonation of an utterance, and therefore prosodic phrases literally signal the end of one tune and the beginning of another. This study uses phrase break annotations in the Aix-MARSEC corpus of spoken English as a "gold standard" for measuring the degree of correspondence between prosodic phrases and the discrete syntactic grouping of prepositional phrases, where the latter is defined via a chunk parsing rule using nltk_lite's regular expression chunk parser.

A three-way comparison is also introduced between the "gold standard" chunk parsing rule and human judgment in the form of intuitive predictions about phrasing. Results show that even with a discrete syntactic grouping and a small sample of text, problems may arise for this rule-based method due to uncategorical behavior in parts of speech. Lack of correspondence between intuitive prosodic phrases and corpus annotations highlights the optional nature of certain boundary types. Finally, there are clear indications, supported by corpus annotations, that significant prosodic phrase boundaries occur within sentences and not just at full stops.
Adaptively ranking alerts generated from automated static analysis
Authors: Heckman Sarah Smith
Published: January 2009

Static analysis tools are useful for finding common programming mistakes that often lead to field failures. However, static analysis tools regularly generate a high number of false positive alerts, requiring manual inspection by the developer to determine if an alert is an indication of a fault. The adaptive ranking model presented in this paper utilizes feedback from developers about inspected alerts in order to rank the remaining alerts by the likelihood that an alert is an indication of a fault. Alerts are ranked based on the homogeneity of populations of generated alerts, historical developer feedback in the form of suppressing false positives and fixing true positive alerts, and historical, application-specific data about the alert ranking factors. The ordering of alerts generated by the adaptive ranking model is compared to a baseline of randomly-, optimally-, and static analysis tool-ordered alerts in a small role-based health care application. The adaptive ranking model provides developers with 81% of true positive alerts after investigating only 20% of the alerts whereas an average of 50 random orderings of the same alerts found only 22% of true positive alerts after investigating 20% of the generated alerts.
MultiVizArch
Authors: Sawant Amit Prakash , Bali Naveen
Published: January 2009

This article presents an automated technique for visualizing large software architectures using multiple graphical representations, including multi-dimensional scaling, 2-D grid, and spiral layouts. We describe how our software visualization methods were applied to the Network Appliance operating system known as Data ONTAP 7G (ONTAP). We show how each method can be applied to comprehend a specific aspect of ONTAP. This approach can be used by software engineers, architects, and developers to better understand the architecture of their code.
Geometric and path tracing methods for simulating light transport through volumes of water particles
Authors: Hegarty James
Published: January 2009

The visual appearance of volumes of water particles, such as clouds, waterfalls, and fog, depends both on microscopic interactions between light rays and individual droplets of water, and also on macroscopic interactions between multiple droplets and paths of light rays. This paper presents a model that builds upon a typical single-scattering volume renderer to correctly account for these effects. To accurately simulate the visual appearance of a surface or a volume of particles in a computer-generated image, the properties of the material or particle must be specified using a Bidirectional Reflectance Distribution Function (BRDF), which describes how light reflects off of a material, and the Bidirectional Transmittance Distribution Function (BTDF), which describes how light refracts into a material. This paper describes an optimized BRDF and BTDF for volumes of water droplets, which takes their geometry into account in order to produce well-known effects, such as rainbows and halos. It also describes how a multiple-scattering path tracing volume integrator can be used to more accurately simulate macroscopic light transport through a volume of water, creating a more "cloudlike" appearance than a single-scattered volume integrator. This paper focuses on replicating the visual appearance of volumes of water particles, and although it makes use of physical models, the techniques presented are not intended to be physically accurate.
Prefix compression of sparse binary strings
Authors: Salomon David
Published: January 2009

Note from ACM Crossroads: Due to errors in the layout process for printing on paper, the version of this article in the printed magazine contained several errors (mostly related to superscripts). This HTML version is the accurate version. Please refer to this HTML version instead of the printed version and accept our apologies for any inconvenience.
CMUnited
Authors: Veloso Manuela , Stone Peter , Han Kwun , Achim Sorin
Published: January 2009

Robotic soccer is a challenging research domain involving multiple agents that need to collaborate in an adversarial environment to achieve specific objectives. This article describes CMUnited, the team of small robotic agents that we developed to enter the RoboCup-97 competition. We designed and built the robotic agents, devised the appropriate vision algorithm, and developed and implemented algorithms for strategic collaboration between the robots in an uncertain and dynamic environment. The robots can organize themselves in formations, hold specific roles, and pursue their goals. In game situations, they have demonstrated their collaborative behaviors on multiple occasions. The robots can also switch roles to maximize the overall performance of the team. We present an overview of the vision processing algorithm which successfully tracks multiple moving objects and predicts trajectories. The paper then focuses on the agents' behaviors ranging from low-level individual behaviors to coordinated, strategic team behaviors. CMUnited won the RoboCup-97 small-robot competition at IJCAI-97 in Nagoya, Japan.
Extending Java to support shared resource protection and deadlock detection in threads programming
Authors: Van Engen Anita J. , Bradshaw Michael K. , Oostendorp Nathan
Published: January 2009

Java threads enable programmers to write parallel programs very easily and conveniently. However, the current Java specification does not adequately provide for the protection of shared resources or for deadlock detection, two of the most common problems arising from parallel programs. The ability to solve these problems is crucial for Java concurrent programming. In this paper, we introduce and implement a model that can aid in writing parallel programs by providing shared resource protection and deadlock detection.
Using the Java Native Interface
Authors: Husaini S. Fouzi
Published: January 2009

The Java Native Interface (JNI) comes with the standard Java Development Kit (JDK) from Sun Microsystems. It permits Java programmers to integrate native code (currently C and C++) into their Java applications. This article will focus on how to make use of the JNI and will provide a few examples illustrating the usefulness of this feature. Although a native method system was included with the JDK 1.0 release, this article is concerned with the JDK 1.1 JNI which has several new features, and is much cleaner than the previous release. Also, the examples given will be specific to JDK 1.1 installed on the Solaris Operating System.
Reasoning about computational resource allocation
Authors: Grass Joshua
Published: January 2009

Anytime Algorithms are algorithms that exchange execution time for quality of results. Since many computational tasks are too complicated to be completed at real-time speeds, anytime algorithms allow systems to intelligently allocate computational time resources in the most effective way, depending on the current environment and the system's goals. This article briefly covers the motivations for creating anytime algorithms, the history of their development, a definition of anytime algorithms, and current research involving anytime algorithms.
Mutual authenticating protocol with key distribution in client/server environment
Authors: Cavaiani Charles , Alves-Foss Jim
Published: January 2009

The explosive growth of networked and internetworked computer systems during the past decade has brought about a need for increased protection mechanisms. This paper discusses three authentication protocols that incorporate the use of methods that present effective user authentication. The first two protocols have been previously discussed in the literature; the third protocol draws from the first two and others to produce an authentication scheme that provides both mutual authentication and secure key distribution which is easy to use, is compatible with present operating systems, is transparent across systems, and provides password file protection.
Dependency diagrams
Authors: Ray Mark
Published: January 2009

A method of illustrating program structure by showing how sections depend on each other is presented. This suggests an intuitive metric for program partitioning, which is developed with supporting theory.
A formative evaluation of scenario-based tools for learning object-oriented design
Authors: Harley Hope D. , Seals Cheryl D. , Rosson Mary Beth
Published: January 2009

Advances in computing have awakened a century old teaching philosophy: learner-centered education. This philosophy is founded on the premise that people learn best when engrossed in the topic, participating in activities that motivate learning and help them to synthesize their own understanding. We consider how the object-oriented design (OOD) learning tools developed by Rosson and Carroll [5] facilitate active learning of this sort. We observed sixteen students as they worked through a set of user interaction scenarios about a blackjack game. We discuss how the features of these learning tools influenced the students' efforts to learn the basic constructs of OOD.
OpenMath and MathML: semantic markup for mathematics
Authors: Caprotti O. , Carlisle D.
Published: January 2009

Unambiguous representation of mathematics is crucial for communications among humans or among computer systems. OpenMath is a standard aimed at supporting a semantically rich interchange of mathematics among varied computational software tools such as computer algebra systems, theorem provers, and tools for visualizing or editing mathematical text. MathML is a W3C Recommendation for the encoding of mathematics 'on the web' which also includes mechanisms for encoding mathematical semantics. We introduce each of these two languages and describe their relationships.
Software verification and validation with destiny
Authors: Dykstra Josiah
Published: January 2009

This paper presents an introduction to computer-aided theorem proving and a new approach using parallel processing to increase power and speed of this computation. Automated theorem provers, along with human interpretation, have been shown to be powerful tools in verifying and validating computer software. Destiny is a new tool that provides even greater and more powerful analysis enabling greater ties between software programs and their specifications.
Common mistakes in online and real-time contests
Authors: Manzoor Shahriar
Published: January 2009

Each year the Association for Computing Machinery (ACM) arranges a worldwide programming contest. This contest has two rounds: the regional contests and the World Final. The teams with the best results in the regional contests advance to the World Final. The contest showcases the best programmers in the world to representatives of large companies who are looking for talent. When practicing for programming competitions, remember that all your efforts should be directed at improving your programming skills. No matter what your performance is in a contest, don't be disappointed. Success in programming contests is affected by factors other than skill, most importantly, adrenaline, luck, and the problem set of the contest. One way of getting immediate feedback on your efforts is to join the Valladolid Online Programming Practice/Contest or the online judge hosted by Ural State University (USU). Successfully solving problems increases your online ranking in the respective competitions.This article is for beginning programmers who are new to programming contests. I will discuss the common problems faced in contests, the University of Valladolid online judge, and the USU online judge. The suggestions are divided into three parts: General Suggestions, Online Contest Suggestions, and Valladolid-Specific Suggestions. Throughout this paper, please note that in real-time contests, the judges are human and in online contests, the judges are computer programs, unless otherwise noted.
Blood Monocytes: Development, Heterogeneity, and Relationship with Dendritic Cells
Authors: Auffray Cedric , Sieweke Michael H. , Geissmann Frederic
Published: January 2009

Monocytes are circulating blood leukocytes that play important roles in the inflammatory response, which is essential for the innate response to pathogens. But inflammation and monocytes are also involved in the pathogenesis of inflammatory diseases, including atherosclerosis. In adult mice, monocytes originate in the bone marrow in a Csf-1R (MCSF-R, CD115)-dependent manner from a hematopoietic precursor common for monocytes and several subsets of macrophages and dendritic cells (DCs). Monocyte heterogeneity has long been recognized, but in recent years investigators have identified three functional subsets of human monocytes and two subsets of mouse monocytes that exert specific roles in homeostasis and inflammation in vivo, reminiscent of those of the previously described classically and alternatively activated macrophages. Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation.
IL-17 and Th17 Cells
Authors: Korn Thomas , Bettelli Estelle , Oukka Mohamed , Kuchroo Vijay K.
Published: January 2009

CD4+T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places the Th17 lineage in close relationship with CD4+CD25+Foxp3+regulatory T cells (Tregs), as TGF-β also induces differentiation of naive T cells into Foxp3+Tregs in the peripheral immune compartment. The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation. Furthermore, we now appreciate the importance of Th17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Lessons Learned from the Natural Hosts of HIV-Related Viruses
Authors: Paiardini Mirko , Pandrea Ivona , Apetrei Cristian , Silvestri Guido
Published: January 2009

The fact that human immunodeficiency virus (HIV) causes a deadly disease in humans whereas its simian counterparts, the simian immunodeficiency viruses (SIVs), are virtually nonpathogenic in their natural hosts remains a fundamental mystery of modern medicine. Arguably, the pathogenesis of HIV infection will remain poorly understood until the mechanisms responsible for the AIDS resistance of natural SIV hosts are fully explained. Over the past few years, some key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and have evolved to down-modulate the expression of CCR5 on CD4+T cells. Better elucidation of the mechanisms underlying the lack of disease progression of natural SIV infections holds promise for the design of novel preventive and therapeutic approaches to HIV infection.
The Expanded Biology of Serotonin
Authors: Berger Miles , Gray John A. , Roth Bryan L.
Published: January 2009

Serotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new “expanded serotonin biology” and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.
Advances in Autism
Authors: Geschwind Daniel H.
Published: January 2009

Autism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.
Prospects for Life Span Extension
Authors: Sierra Felipe , Hadley Evan , Suzman Richard , Hodes Richard
Published: January 2009

Life expectancy has increased dramatically in the United States and in much of the world in recent years and decades. The factors underlying this increase are incompletely understood and are undoubtedly complex. A question that drives current research is whether life expectancy can be further extended using current knowledge of modifiable risk factors. A still more challenging research focus is on the possibility that life expectancy might be further increased through knowledge gained from studies of the basic biology of aging and its genetic and environmental modifiers.
The HapMap and Genome-Wide Association Studies in Diagnosis and Therapy
Authors: Manolio Teri A. , Collins Francis S.
Published: January 2009

The International HapMap Project produced a genome-wide database of human genetic variation for use in genetic association studies of common diseases. The initial output of these studies has been overwhelming, with over 150 risk loci identified in studies of more than 60 common diseases and traits. These associations have suggested previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. Here we examine the development and application of the HapMap to genome-wide association (GWA) studies; present and future technologies for GWA research; current major efforts in GWA studies; successes and limitations of the GWA approach in identifying polymorphisms related to complex diseases; data release and privacy polices; use of these findings by clinicians, the public, and academic physicians; and sources of ongoing authoritative information on this rapidly evolving field.
Hypereosinophilic Syndrome: Current Approach to Diagnosis and Treatment
Authors: Klion Amy
Published: January 2009

Hypereosinophilic syndrome is a heterogeneous group of rare disorders characterized by marked blood or tissue eosinophilia resulting in a wide variety of clinical manifestations. Although the existence of clinical subtypes (or variants) of HES has been appreciated for some time, the recent characterization of some of these variants at the molecular and immunologic levels has demonstrated dramatic differences in disease pathogenesis, response to treatment, and prognosis depending on the etiology of the eosinophilia. This, together with the availability of novel targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, has fundamentally altered the approach to the diagnosis and treatment of HES.
Variation in Institutional Strength
Authors: Levitsky Steven , Murillo María Victoria
Published: January 2009

Comparative research on political institutions has begun to turn from issues of formal institutional design to issues of institutional strength. Rather than assuming a tight fit between formal rules and political behavior, these studies examine how variation in the stability and/or enforcement of formal rules shapes actors' expectations and behavior. This article explores the emerging research agenda on institutional strength. It disaggregates the concept of institutional strength into two dimensions—enforcement and stability—and it argues that institutions vary widely on both dimensions. The article then examines the sources of this variation and its implications for comparative research. It shows how recent research on weak institutions may be used to refine existing theories of institutional effects, design, and development, which should broaden the comparative scope of these theories. The conclusion examines ways of developing comparative measures of institutional strength.
Has the Study of Global Politics Found Religion?
Authors: Philpott Daniel
Published: January 2009

The past generation has witnessed a resurgence of religion in global politics, but political science has been slow to catch up with it. The reason lies in the secularism embedded in the field's major theories, one that reflects actual secularism in world politics, beginning with the events surrounding the Peace of Westphalia in 1648 and growing steadily through the middle twentieth century. Today, a small but growing number of political scientists have begun to explore religion, doing so in ways that depart from secular assumptions and embrace religion's distinctiveness to greater and lesser degrees.
TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription
Authors: Schlöndorff Johannes , del Camino Donato , Carrasquillo Robert , Lacey Vanessa , Pollak Martin R.
Published: January 2009

Mutations in the canonical transient receptor potential channel TRPC6 lead to an autosomal dominant form of human kidney disease characterized histologically by focal and segmental glomerulosclerosis. Several of these mutations enhance the amplitude and duration of the channel current. However, the effect of these mutations on the downstream target of TRPC6, the nuclear factor of activated T cell (NFAT) transcription factors, has not been previously examined. Here we demonstrate that all three TRPC6 mutations previously shown to enhance channel activity lead to enhanced basal NFAT-mediated transcription in several cell lines, including cultured podocytes. These effects are dependent on channel activity and are dominant when mutants are coexpressed with wild-type TRPC6. While TRPC6 mutants do not demonstrate an increase in basal channel currents, a subset of cells expressing the R895C and E897K mutants have elevated basal calcium levels as measured by Fura-2 imaging. Activation of NFAT by TRPC6 mutants is blocked by inhibitors of calcineurin, calmodulin-dependent kinase II, and phosphatidylinositol 3-kinase. PP2 partially inhibits NFAT activation by mutant TRPC6 independently of Src, Yes, or Fyn. Differences in channel glycosylation and surface expression do not explain the ability of mutants to enhance NFAT activation. Taken together, these results identify the activation of the calcineurin-NFAT pathway as a potential mediator of focal segmental glomerulosclerosis.
Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters
Authors: Leuthold Simone , Hagenbuch Bruno , Mohebbi Nilufar , Wagner Carsten A. , Meier Peter J. , Stieger Bruno
Published: January 2009

Organic anion transporting polypeptides (humans OATPs, rodents Oatps) are expressed in most mammalian tissues and mediate cellular uptake of a wide variety of amphipathic organic compounds such as bile salts, steroid conjugates, oligopeptides, and a large list of drugs, probably by acting as anion exchangers. In the present study we aimed to investigate the role of the extracellular pH on the transport activity of nine human and four rat OATPs/Oatps. Furthermore, we aimed to test the concept that OATP/Oatp transport activity is accompanied by extrusion of bicarbonate. By using amphibian Xenopus laevis oocytes expressing OATPs/Oatps and mammalian cell lines stably transfected with OATPs/Oatps, we could demonstrate that in all OATPs/Oatps investigated, with the exception of OATP1C1, a low extracellular pH stimulated transport activity. This stimulation was accompanied by an increased substrate affinity as evidenced by lower apparent Michaelis-Menten constant values. OATP1C1 is lacking a highly conserved histidine in the third transmembrane domain, which was shown by site-directed mutagenesis to be critically involved in the pH dependency of OATPs/Oatps. Using online intracellular pH measurements in OATP/Oatp-transfected Chinese Hamster Ovary (CHO)-K1 cells, we could demonstrate the presence of a 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid-sensitive chloride/bicarbonate exchanger in CHO-K1 cells and that OATP/Oatp-mediated substrate transport is paralleled by bicarbonate efflux. We conclude that the pH dependency of OATPs/Oatps may lead to a stimulation of substrate transport in an acidic microenvironment and that the OATP/Oatp-mediated substrate transport into cells is generally compensated or accompanied by bicarbonate efflux.
Gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in a model of postinfective IBS
Authors: Choudhury Barun K. , Shi Xuan-Zheng , Sarna Sushil K.
Published: January 2009

The cellular mechanisms of motility dysfunction in postinfectious irritable bowel syndrome (PI-IBS) are not known. We used a rat model of neonatal inflammation to test the hypothesis that gene plasticity in colonic circular smooth muscle cells underlies motility dysfunction in PI-IBS. Mild/moderate or severe inflammation was induced in neonatal and adult rats. Experiments were performed in tissues obtained at 7 days (short term) and 6–8 wk (long term) after the induction of inflammation. Severe inflammation in neonatal rats induced persistent long-term smooth muscle hyperreactivity to acetylcholine (ACh), whereas that in adult rat caused smooth muscle hyporeactivity that showed partial recovery in the long term. Mild/moderate inflammation had no effect in neonatal rats, but it induced smooth muscle hyporeactivity to ACh in adult rats, which recovered fully in the long term. Smooth muscle hyperreactivity to ACh resulted in accelerated colonic transit and increase in defecation rate, whereas hyporeactivity had opposite effects. Smooth muscle hyperreactivity to ACh was associated with increase in transcription rate of key cell-signaling proteins of the excitation-contraction coupling α1C subunit of Cav1.2 (L-type) calcium channels, Gαq, and 20-kDa myosin light chain (MLC20), whereas hyporeactivity was associated with their suppression. Inflammation in adult rats induced classical inflammatory response, which was absent in neonatal rats. Severe neonatal inflammation enhanced plasma norepinephrine and muscularis propria vasoactive intestinal polypeptide in the long term. We conclude that severe, but not mild/moderate, inflammation in a state of immature or impaired stress and immune response systems alters the transcription rate of key cell-signaling proteins of excitation-contraction coupling in colonic circular smooth muscle cells to enhance their contractility and accelerate colonic transit and defecation rate.
Maternal stress and development of atherosclerosis in the adult apolipoprotein E-deficient mouse offspring
Authors: Andersson Irene J. , Jiang Yan-Yan , Davidge Sandra T.
Published: January 2009

Stress is a risk factor for cardiovascular disease, such as atherosclerosis. Stress during pregnancy (maternal stress) may have long-term consequences for the health of the offspring. However, it is not known whether maternal stress affects the offspring's predisposition to develop atherosclerosis. Atherosclerosis is often related to vascular endothelial dysfunction. We hypothesized that maternal stress affects vascular endothelial function and accelerates development of atherosclerosis in offspring of apolipoprotein E-deficient mice, a model commonly used for atherosclerosis research. Stress was induced by restraining dams in small cylinders for five consecutive days (2 h/day) beginning on gestational day 8 ± 0.5. Vascular function and development of atherosclerosis in the aorta were determined in male and female offspring at 11–15 wk of age (with early lesions) and at 22–26 wk of age (with established lesions). Endothelium-dependent vasorelaxation was determined using methacholine (0.0001–10 μmol/l) in the absence or presence of the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; 100 μmol/l). Male offspring (11–15 wk old) from stressed dams were less dependent on nitric oxide for relaxation compared with controls (l-NAME inhibition: 38 ± 10 vs. 69 ± 6%, P < 0.05). Atherosclerotic lesion area was larger in male and female 25- to 26-wk-old offspring from stressed dams compared with corresponding controls [median (interquartile range): males: 6.8 (5.4–7.7) vs. 5.1 (4.4–5.5), P < 0.05, females: 10.0 (8.9–10.9) vs. 7.0 (4.7–8.7), P < 0.05]. In conclusion, maternal stress renders the apolipoprotein E-deficient offspring more susceptible to develop atherosclerosis.
Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue
Authors: Madden C. J. , Morrison S. F.
Published: January 2009

The paraventricular nucleus of the hypothalamus (PVH) plays an important role in energy homeostasis, regulating neuroendocrine, behavioral, and autonomic functions. However, the role of the PVH in regulating thermogenesis and energy expenditure in brown adipose tissue (BAT) is unclear. The present study investigated the effect of activating neurons within the PVH on BAT thermogenesis. In urethane- and chloralose-anesthetized, artificially ventilated rats maintained at a core body temperature of 37.0–38.0°C, microinjection of N-methyl-d-aspartate (NMDA, 12 pmol in 60 nl) in the PVH did not increase BAT sympathetic nerve activity (SNA) or BAT thermogenesis. In contrast, the increase in BAT SNA evoked by body cooling was completely reversed by microinjection of NMDA in the PVH. Additionally, the increases in BAT SNA evoked by body cooling, by microinjection of prostaglandin E2 (170 pmol in 60 nl) in the medial preoptic area or by microinjection of bicuculline (30 pmol in 60 nl) in the dorsomedial hypothalamus were completely reversed by microinjection of bicuculline (30 pmol in 60 nl) in the PVH. Although the increases in BAT SNA and thermogenesis evoked by microinjection of NMDA (12 pmol in 60 nl) in the raphe pallidus (RPa) was markedly attenuated following microinjection of bicuculline (30 pmol) in the PVH, the increases in BAT SNA and thermogenesis evoked by microinjection of bicuculline (30 pmol in 60 nl) in the RPa were unaffected by microinjection of bicuculline in the PVH. These results demonstrate that disinhibition of neurons in the PVH inhibits BAT SNA likely via activation of a GABAergic input to BAT sympathetic premotor neurons in the RPa.
Regulation of PTH mRNA stability by the calcimimetic R568 and the phosphorus binder lanthanum carbonate in CKD
Authors: Nechama Morris , Ben-Dov Iddo Z. , Silver Justin , Naveh-Many Tally
Published: January 2009

Secondary hyperparathyroidism is characterized by increased parathyroid hormone (PTH) mRNA stability that leads to increased PTH mRNA and serum PTH levels. PTH gene expression is reduced by the calcimimetic R568 and the oral phosphorus binder lanthanum carbonate (La). Changes in PTH mRNA stability are regulated by the binding of trans-acting stabilizing and destabilizing factors to a defined cis element in the PTH mRNA 3′-untranslated region (UTR). Adenosine-uridine (AU)-binding factor 1 (AUF1) is a PTH mRNA-stabilizing protein, and K-homology splicing regulatory protein (KSRP) is a destabilizing protein that targets mRNAs, including PTH mRNA, to degradation by the ribonuclease complex exosome. We now show that KSRP-PTH mRNA binding is decreased in parathyroids from rats with adenine-induced chronic kidney disease (CKD) where PTH mRNA is more stable. KSRP-PTH mRNA binding is increased by treatment with both R568 and La, correlating with decreased PTH gene expression. In vitro degradation assays using transcripts for PTH mRNA and rat parathyroid extracts reproduce the differences in mRNA stability in vivo. Accordingly, PTH mRNA is destabilized in vitro by parathyroid extracts from CKD rats treated with R568 or La compared with parathyroid extracts from untreated CKD rats. This destabilizing effect of R568 and La is dependent on KSRP and the PTH mRNA 3′-UTR. Therefore, the calcimimetic R568 and correction of serum phosphorus by La determine PTH mRNA stability through KSRP-mediated recruitment of a degradation complex to the PTH mRNA, thereby decreasing PTH expression.