bluuebunny/crossref_metadata_2025 huggingface dataset:
Poincaré Recurrences in a Nonautonomous Chaotic Map
Authors: Boev Yaroslav , Semenova Nadezhda , Strelkova Galina , Anishchenko Vadim
Published: August 2014

The statistics of Poincaré recurrences is studied numerically in a one-dimensional cubic map in the presence of harmonic and noisy excitations. It is shown that the distribution density of Poincaré recurrences is periodically modulated by the harmonic force. It is established that the relationship between the Afraimovich–Pesin dimension and Lyapunov exponents is violated in the nonautonomous system.
On Bifurcations Inducing Glacial Cycle Lengthening During Pliocene/Pleistocene Epoch
Authors: Ivashchenko N. N. , Kotlyakov V. M. , Sonechkin D. M. , Vakulenko N. V.
Published: August 2014

In the Pliocene (about two–five million years ago) global climate fluctuated with a period corresponding well to the 41-thousand-year cycle of changes in the Earth's axis obliquity. Then, this period disappeared, despite the fact that the obliquity cycle even slightly increased its swing and, therefore, the climatic response to this external climate forcing would have only strengthened. By analyzing paleoclimatic records covering the whole Pliocene and Pleistocene epoch, we show that the climatic response to the obliquity cycle simply became unstable, and therefore unobservable. At the same time, through the period-doubling bifurcation, which is well-known in dynamical system theory, new stable, and so observable, climatic fluctuations have been excited with an approximately doubled period. Further, these fluctuations experienced several secondary bifurcations, and, as a result, their periods increased even more.
Normalization of a System with Two Large Delays
Authors: Kashchenko Ilia
Published: August 2014

In this paper, the local dynamics of differential equations is studied with two asymptotically large proportional delays. Depending on the parameters, critical cases in the problem of the stability of the equilibrium state are identified. In all critical cases, special evolutionary equations (quasinormal forms) are built. Their nonlocal dynamics determine the local behavior of solutions of the original equations.
CUBA'S EMERGING SELF-EMPLOYED ENTREPRENEURS: RECENT DEVELOPMENTS AND PROSPECTS FOR THE FUTURE
Authors: GONZÁLEZ-CORZO MARIO A. , JUSTO ORLANDO
Published: August 2014

This paper examines the evolution of Cuba's self-employed entrepreneurs since the sector became an officially-recognized alternative to State sector employment in 2010. Despite the expansion of authorized self-employment activities and the implementation of gradual economic reforms to "update" the country's socialist economic model since 2010, Cuba's emerging self-employed entrepreneurs still face a series of constraints and limitations, such as an onerous tax system, underdeveloped banking and financial sectors, lack of access to organized input markets and a still hostile business climate that hinder their ability to expand and contribute to the country's economic growth.
Iridium complexes of [26]hexaphyrin(1.1.1.1.1.1) and [36]octaphyrin(1.1.1.1.1.1.1.1)
Authors: Naoda Koji , Osuka Atsuhiro
Published: August 2014

Iridium metalation of [26]hexaphyrin 1 and [36]octaphyrin 2 gave Ir ( III ) complex of [26]hexaphyrin 3 and Ir ( I ) complex of [36]octaphyrin 4, respectively. The complex 3 is an aromatic molecule displaying considerably electron-rich nature while the complex 4 shows weak antiaromatic nature with a small HOMO–LUMO gap of 0.82 eV.
Synthesis, reactivity and property of 5,15-dithiaporphyrin copper(II) complex
Authors: Wachi Naruhiko , Kondo Takeshi , Ito Satoru , Hiroto Satoru , Shin Ji-Young , Shinokubo Hiroshi
Published: August 2014

Preparation of 5,15-dithiaporphyrin copper(II) complex was carried out by treatment of 5,15-dithiaporphyrin free-base with copper(II) acetate. X-ray diffraction analysis elucidated its dimeric structure in the solid state, in which the meso-sulfur atom served as an axial ligand to each pentacoordinated Cu ( II ) center. Temperature dependent magnetic susceptibility of the complex was measured to reveal the weak antiferromagnetic interaction between two Cu ( II ) centers in the solid state. 5,15-dithiaporphyrin Cu ( II ) complex was converted into 10-thiacorrole Cu ( II ) complex in good yield upon heating with triphenylphosphine in refluxing toluene.
On skew Hurwitz serieswise Armendariz rings
Authors: Ahmadi M. , Moussavi A. , Nourozi V.
Published: August 2014

For a ring endomorphism α, we introduce and investigate skew Hurwitz serieswise Armendariz (or SHA) rings which are a generalization of α-rigid rings and determine the radicals of the skew Hurwitz series ring (HR, α), in terms of those of R. We prove that several properties transfer between R and the extensions, in case R is an SHA-ring. We also construct various types of nonreduced SHA-rings.
Learning Hurdles for Sleeping Experts
Authors: Kanade Varun , Steinke Thomas
Published: August 2014

We study the online decision problem in which the set of available actions varies over time, also called the
sleeping
experts
problem. We consider the setting in which the performance comparison is made with respect to the
best
ordering
of actions in hindsight. In this article, both the payoff function and the availability of actions are adversarial. Kleinberg et al. [2010] gave a computationally efficient no-regret algorithm in the setting in which payoffs are stochastic. Kanade et al. [2009] gave an efficient no-regret algorithm in the setting in which action availability is stochastic.

However, the question of whether there exists a
computationally
efficient
no-regret algorithm in the adversarial setting was posed as an open problem by Kleinberg et al. [2010]. We show that such an algorithm would imply an algorithm for PAC learning
DNF
, a long-standing important open problem. We also consider the setting in which the number of available actions is restricted and study its relation to agnostic-learning monotone disjunctions over examples with bounded Hamming weight.
MOOCs: Symptom, Not Cause of Disruption
Authors: Perelman Lewis J.
Published: August 2014

Is the MOOCs phenomenon a disruptive innovation or a transient bubble? It may be partly both. Broadcasting lectures and opening up courses via MOOCs by itself poses little change of the academic status quo. But academia is part of a broader academic-bureaucratic complex that provided a core framework for industrial-age institutions. The academic-bureaucratic complex rests on the premise that knowledge and talent must be scarce. Presumed scarcity justifies filtering access to information, to diplomas, and to jobs. But a wave of post-industrial technical, economic, and social innovations is making knowledge and talent rapidly more abundant and access more "open." This mega-trend is driving the academic-bureaucratic complex toward bankruptcy. It is being replaced by new, radically different arrangements of learning and work. The embrace of MOOCs is a symptom, not a cause of academia's obsolescence.
Multicore Processors and Database Systems
Authors: Ross Kenneth A.
Published: August 2014

Database management systems are necessary for transaction processing and query processing. Today, parallel database systems can be run on multicore platforms. Presented within is an overview of how multicore machines have impacted the design and implementation of database management systems.
Exploration in Interactive Personalized Music Recommendation
Authors: Wang Xinxi , Wang Yi , Hsu David , Wang Ye
Published: August 2014

Current music recommender systems typically act in a greedy manner by recommending songs with the highest user ratings. Greedy recommendation, however, is suboptimal over the long term: it does not actively gather information on user preferences and fails to recommend
novel
songs that are potentially interesting. A successful recommender system must balance the needs to
explore
user preferences and to
exploit
this information for recommendation. This article presents a new approach to music recommendation by formulating this exploration-exploitation trade-off as a reinforcement learning task. To learn user preferences, it uses a Bayesian model that accounts for both audio content and the novelty of recommendations. A piecewise-linear approximation to the model and a variational inference algorithm help to speed up Bayesian inference. One additional benefit of our approach is a single unified model for both music recommendation and playlist generation. We demonstrate the strong potential of the proposed approach with simulation results and a user study.
CAMA
Authors: Dezfouli Behnam , Radi Marjan , Whitehouse Kamin , Razak Shukor Abd , Tan Hwee-Pink
Published: August 2014

Network simulation is an essential tool for the design and evaluation of wireless network protocols, and realistic channel modeling is essential for meaningful analysis. Recently, several network protocols have demonstrated substantial network performance improvements by exploiting the capture effect, but existing models of the capture effect are still not adequate for protocol simulation and analysis. Physical-level models that calculate the signal-to-interference-plus-noise ratio (SINR) for every incoming bit are too slow to be used for large-scale or long-term networking experiments, and link-level models such as those currently used by the NS2 simulator do not accurately predict protocol performance. In this article, we propose a new technique called the
capture modeling algorithm
(CAMA) that provides the simulation fidelity of physical-level models while achieving the simulation time of link-level models. We confirm the validity of CAMA through comparison with the empirical traces of the experiments conducted by various numbers of CC1000 and CC2420-based nodes in different scenarios. Our results indicate that CAMA can accurately predict the packet reception, corruption, and collision detection rates of real radios, while existing models currently used by the NS2 simulator produce substantial prediction error.
The iDEA DSP Block-Based Soft Processor for FPGAs
Authors: Cheah Hui Yan , Brosser Fredrik , Fahmy Suhaib A. , Maskell Douglas L.
Published: August 2014

DSP blocks in modern FPGAs can be used for a wide range of arithmetic functions, offering increased performance while saving logic resources for other uses. They have evolved to better support a plethora of signal processing tasks, meaning that in other application domains they may be underutilised. The DSP48E1 primitives in new Xilinx devices support dynamic programmability that can help extend their usefulness; the specific function of a DSP block can be modified on a cycle-by-cycle basis. However, the standard synthesis flow does not leverage this flexibility in the vast majority of cases. The lean DSP Extension Architecture (iDEA) presented in this article builds around the dynamic programmability of a single DSP48E1 primitive, with minimal additional logic to create a general-purpose processor supporting a full instruction-set architecture. The result is a very compact, fast processor that can execute a full gamut of general machine instructions. We show a number of simple applications compiled using an MIPS compiler and translated to the iDEA instruction set, comparing with a Xilinx MicroBlaze to show estimated performance figures. Being based on the DSP48E1, this processor can be deployed across next-generation Xilinx Artix-7, Kintex-7, Virtex-7, and Zynq families.
Benefits of Adding Hardware Support for Broadcast and Reduce Operations in MPSoC Applications
Authors: Peng Yuanxi , Saldaña Manuel , Madill Christopher A. , Zou Xiaofeng , Chow Paul
Published: August 2014

MPI has been used as a parallel programming model for supercomputers and clusters and recently in MultiProcessor Systems-on-Chip (MPSoC). One component of MPI is collective communication and its performance is key for certain parallel applications to achieve good speedups. Previous work showed that, with synthetic communication-only benchmarks, communication improvements of up to 11.4-fold and 22-fold for broadcast and reduce operations, respectively, can be achieved by providing hardware support at the network level in a Network-on-Chip (NoC). However, these numbers do not provide a good estimation of the advantage for actual applications, as there are other factors that affect performance besides communications, such as computation. To this end, we extend our previous work by evaluating the impact of hardware support over a set of five parallel application kernels of varying computation-to-communication ratios. By introducing some useful computation to the performance evaluation, we obtain more representative results of the benefits of adding hardware support for broadcast and reduce operations. The experiments show that applications with lower computation-to-communication ratios benefit the most from hardware support as they highly depend on efficient collective communications to achieve better scalability. We also extend our work by doing more analysis on clock frequency, resource usage, power, and energy. The results show reasonable scalability for resource utilization and power in the network interfaces as the number of channels increases and that, even though more power is dissipated in the network interfaces due to the added hardware, the total energy used can still be less if the actual speedup is sufficient. The application kernels are executed in a 24-embedded-processor system distributed across four FPGAs.
ULP-SRP
Authors: Kim Changmoo , Chung Mookyoung , Cho Yeongon , Konijnenburg Mario , Ryu Soojung , Kim Jeongwook
Published: August 2014

The latest biomedical applications require low energy consumption, high performance, and wide energy-performance scalability to adapt to various working environments. In this study, we present ULP-SRP, an energy-efficient reconfigurable processor for biomedical applications. ULP-SRP uses a Coarse-Grained Reconfigurable Array (CGRA) for high-performance data processing with low energy consumption. We adopted a compact-size CGRA and modified it to support dynamically switchable three performance modes with fine-grained power gating in order to further optimize the energy consumption. The energy-performance scalability is also accomplished with multiple performance modes and a Unified Memory Architecture (UMA). Experimental results show that ULP-SRP achieved 59% energy reduction compared to previous works. A technique of dynamic CGRA mode changing gives 18.9% energy reduction. ULP-SRP is a good candidate for future mobile healthcare devices.
A Low-Stretch-Guaranteed and Lightweight Geographic Routing Protocol for Large-Scale Wireless Sensor Networks
Authors: Won Myounggyu , Stoleru Radu
Published: August 2014

Geographic routing is well suited for large-scale wireless sensor networks (WSNs) because it is nearly stateless. One important challenge is that network holes may arbitrarily increase the routing path length. Fortunately, recent studies have shown that constant path stretch is achievable using nonlocal information. The constant stretch, however, is possible at the cost of high communication and storage overhead: a source node must complete a “path-setup” process prior to data transmission by exchanging a message with a destination node using a default geographic routing (e.g., GPSR).
In this article, we propose the first geographic routing protocol (LVGR) that provably achieves worst-case stretch of Θ (D/γ) (where D is the diameter of the network and γ is the communication range of nodes) with low communication and storage overhead
. LVGR represents a hole as a convex hull, the internal structure of which is represented as a
local visibility graph
. Based on the convex hulls and local visibility graphs, LVGR generates paths with guaranteed stretch. Through theoretical analysis and extensive simulations, we prove the worst-case stretch of LVGR and demonstrate that LVGR reduces communication overhead by up to 97% and storage overhead by up to 60%, compared with the state of the art.
Model-Checking Linear-Time Properties of Quantum Systems
Authors: Ying Mingsheng , Li Yangjia , Yu Nengkun , Feng Yuan
Published: August 2014

We define a formal framework for reasoning about linear-time properties of quantum systems in which quantum automata are employed in the modeling of systems and certain (closed) subspaces of state Hilbert spaces are used as the atomic propositions about the behavior of systems. We provide an algorithm for verifying invariants of quantum automata. Then, an automata-based model-checking technique is generalized for the verification of safety properties recognizable by reversible automata and ω--properties recognizable by reversible Büchi automata.
Circle & Search
Authors: Huang Junshi , Liu Si , Xing Junliang , Mei Tao , Yan Shuicheng
Published: August 2014

Taking the shoe as a concrete example, we present an innovative product retrieval system that leverages object detection and retrieval techniques to support a brand-new online shopping experience in this article. The system, called Circle & Search, enables users to naturally indicate any preferred product by simply circling the product in images as the visual query, and then returns visually and semantically similar products to the users. The system is characterized by introducing
attributes
in both the detection and retrieval of the shoe. Specifically, we first develop an attribute-aware part-based shoe detection model. By maintaining the consistency between shoe parts and attributes, this shoe detector has the ability to model high-order relations between parts and thus the detection performance can be enhanced. Meanwhile, the attributes of this detected shoe can also be predicted as the semantic relations between parts. Based on the result of shoe detection, the system ranks all the shoes in the repository using an attribute refinement retrieval model that takes advantage of query-specific information and attribute correlation to provide an accurate and robust shoe retrieval. To evaluate this retrieval system, we build a large dataset with 17,151 shoe images, in which each shoe is annotated with 10 shoe attributes e.g., heel height, heel shape, sole shape, etc.). According to the experimental result and the user study, our Circle & Search system achieves promising shoe retrieval performance and thus significantly improves the users' online shopping experience.
Evolvability of Real Functions
Authors: Valiant Paul
Published: August 2014

We formulate a notion of evolvability for functions with domain and range that are real-valued vectors, a compelling way of expressing many natural biological processes. We show that linear and fixed-degree polynomial functions are evolvable in the following dually-robust sense: There is a single evolution algorithm that, for all convex loss functions, converges for all distributions.

It is possible that such dually-robust results can be achieved by simpler and more-natural evolution algorithms. Towards this end, we introduce a simple and natural algorithm that we call
wide-scale random noise
and prove a corresponding result for the
L
2
metric. We conjecture that the algorithm works for a more general class of metrics.
Union-Find with Constant Time Deletions
Authors: Alstrup Stephen , Thorup Mikkel , Gørtz Inge Li , Rauhe Theis , Zwick Uri
Published: August 2014

A union-find data structure maintains a collection of disjoint sets under the operations makeset, union, and find. Kaplan, Shafrir, and Tarjan [SODA 2002] designed data structures for an extension of the union-find problem in which items of the sets maintained may be deleted. The cost of a delete operation in their implementations is essentially the same as the cost of a find operation; namely,
O
(log
n
) worst-case and
O
(α

⌈
M
/
N
⌉

(
n
)) amortized, where
n
is the number of items in the set returned by the find operation,
N
is the total number of makeset operations performed,
M
is the total number of find operations performed, and α

⌈
M
/
N
⌉

(
n
) is a functional inverse of Ackermann’s function. They left open the question whether delete operations can be implemented more efficiently than find operations, for example, in
o
(log
n
) worst-case time. We resolve this open problem by presenting a relatively simple modification of the classical union-find data structure that supports delete, as well as makeset and union operations, in
constant
worst-case time, while still supporting find operations in
O
(log
n
) worst-case time and
O
(α
⌈ M/N⌉
(
n
)) amortized time.

Our analysis supplies, in particular, a very concise potential-based amortized analysis of the standard union-find data structure that yields an
O
(α

⌈
M
/
N
⌉

(
n
)) amortized bound on the cost of find operations. All previous potential-based analyses yielded the weaker amortized bound of
O
(α

⌈
M
/
N
⌉

(
N
)). Furthermore, our tighter analysis extends to one-path variants of the path compression technique such as
path splitting
.
Topology-Aware and Dependence-Aware Scheduling and Memory Allocation for Task-Parallel Languages
Authors: Drebes Andi , Heydemann Karine , Drach Nathalie , Pop Antoniu , Cohen Albert
Published: August 2014

We present a joint scheduling and memory allocation algorithm for efficient execution of task-parallel programs on non-uniform memory architecture (NUMA) systems. Task and data placement decisions are based on a static description of the memory hierarchy and on runtime information about intertask communication. Existing locality-aware scheduling strategies for fine-grained tasks have strong limitations: they are specific to some class of machines or applications, they do not handle task dependences, they require manual program annotations, or they rely on fragile profiling schemes. By contrast, our solution makes no assumption on the structure of programs or on the layout of data in memory. Experimental results, based on the OpenStream language, show that locality of accesses to main memory of scientific applications can be increased significantly on a 64-core machine, resulting in a speedup of up to 1.63× compared to a state-of-the-art work-stealing scheduler.
A Sketch-Based Approach for Interactive Organization of Video Clips
Authors: Liu Yong-Jin , Ma Cui-Xia , Fu Qiufang , Fu Xiaolan , Qin Sheng-Feng , Xie Lexing
Published: August 2014

With the rapid growth of video resources, techniques for efficient organization of video clips are becoming appealing in the multimedia domain. In this article, a sketch-based approach is proposed to intuitively organize video clips by: (1) enhancing their narrations using sketch annotations and (2) structurizing the organization process by gesture-based free-form sketching on touch devices. There are two main contributions of this work. The first is a sketch graph, a novel representation for the narrative structure of video clips to facilitate content organization. The second is a method to perform context-aware sketch recommendation scalable to large video collections, enabling common users to easily organize sketch annotations. A prototype system integrating the proposed approach was evaluated on the basis of five different aspects concerning its performance and usability. Two sketch searching experiments showed that the proposed context-aware sketch recommendation outperforms, in terms of accuracy and scalability, two state-of-the-art sketch searching methods. Moreover, a user study showed that the sketch graph is consistently preferred over traditional representations such as keywords and keyframes. The second user study showed that the proposed approach is applicable in those scenarios where the video annotator and organizer were the same person. The third user study showed that, for video content organization, using sketch graph users took on average 1/3 less time than using a mass-market tool Movie Maker and took on average 1/4 less time than using a state-of-the-art sketch alternative. These results demonstrated that the proposed sketch graph approach is a promising video organization tool.
Exploiting FPGA-Aware Merging of Custom Instructions for Runtime Reconfiguration
Authors: Lam Siew-Kei , Clarke Christopher T. , Srikanthan Thambipillai
Published: August 2014

Runtime reconfiguration is a promising solution for reducing hardware cost in embedded systems, without compromising on performance. We present a framework that aims to increase the performance benefits of reconfigurable processors that support full or partial runtime reconfiguration. The proposed framework achieves this by: (1) providing a means for choosing suitable custom instruction selection heuristics, (2) leveraging FPGA-aware merging of custom instructions to maximize the reconfigurable logic block utilization in each configuration, and (3) incorporating a hierarchical loop partitioning strategy to reduce runtime reconfiguration overhead. We show that the performance gain can be improved by employing suitable custom instruction selection heuristics that, in turn, depend on the reconfigurable resource constraints and the merging factor (extent to which the selected custom instructions can be merged). The hierarchical loop partitioning strategy leads to an average performance gain of over 31% and 46% for full and partial runtime reconfiguration, respectively. Performance gain can be further increased to over 52% and 70% for full and partial runtime reconfiguration, respectively, by exploiting FPGA-aware merging of custom instructions.
Graph Minor Approach for Application Mapping on CGRAs
Authors: Chen Liang , Mitra Tulika
Published: August 2014

Coarse-Grained Reconfigurable Arrays (CGRAs) exhibit high performance, improved flexibility, low cost, and power efficiency for various application domains. Compute-intensive loop kernels, which are perfect candidates to be executed on CGRAs, are usually mapped through modified modulo scheduling algorithms. These algorithms should be capable of performing both placement and routing. We formalize the CGRA mapping problem as a graph minor containment problem. We essentially test whether the dataflow graph representing the loop kernel is a minor of the modulo routing resource graph representing the CGRA resources and their interconnects. We design an exact graph minor testing approach that exploits the unique properties of both the dataflow graph and the routing resource graph to significantly prune the search space. We introduce additional heuristic strategies that drastically improve the compilation time while still generating optimal or near-optimal mapping solutions. Experimental evaluation confirms the efficiency of our approach.
Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts
Authors: Karamanlidis Georgios , Garcia-Menendez Lorena , Kolwicz Stephen C. , Lee Chi Fung , Tian Rong
Published: August 2014

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.
Fundamental relationships between blood pressure and cerebral blood flow in humans
Authors: Tzeng Y. C. , MacRae B. A. , Ainslie P. N. , Chan G. S. H.
Published: August 2014

Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R2 values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04–0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.
Active muscle stiffness in the human medial gastrocnemius muscle in vivo
Authors: Kubo Keitaro
Published: August 2014

The aims of this study were to 1) directly assess active muscle stiffness according to actual length changes in muscle fibers (fascicles) during short range stretching; and 2) compare actual measured active muscle and tendon stiffness using ultrasonography with the stiffness of active (i.e., muscle) and passive (i.e., tendon) parts in series elastic component of plantar flexors using the alpha method. Twenty-four healthy men volunteered for this study. Active muscle stiffness in the medial gastrocnemius muscle was calculated according to changes in estimated muscle force and fascicle length during fast stretching after submaximal isometric contractions [10, 30, 50, 70, and 90% maximal voluntary contractions (MVC)]. Using the variables measured during this fast stretch experiment, the stiffness of active (i.e., muscle) and passive (i.e., tendon) parts in plantar flexors was assessed using alpha method. Tendon stiffness was determined during isometric plantar flexion by ultrasonography. Active muscle stiffness increased with the exerted torque levels. At 30, 50, 70, and 90% MVC, there were no significant correlations between muscle stiffness using ultrasonography and stiffness of active part (i.e., muscle) by alpha method, although this relationship at 10% MVC was significant ( r = 0.552, P = 0.005). In addition, no correlation was noted in tendon stiffness between the two different methods ( r = 0.226, P = 0.209). The present study demonstrated that ultrasonography could quantified active muscle stiffness in vivo. Furthermore, active muscle stiffness and tendon stiffness using ultrasonography were not related to active (i.e., muscle) or passive (i.e., tendon) stiffness in series elastic component of plantar flexors by alpha method.
Muscle-specific calpastatin overexpression prevents diaphragm weakness in cecal ligation puncture-induced sepsis
Authors: Supinski Gerald S. , Wang Lin , Song Xiao-Hong , Moylan Jennifer S. , Callahan Leigh Ann
Published: August 2014

Recent work indicates that infections are a major contributor to diaphragm weakness in patients who are critically ill and mechanically ventilated, and that diaphragm weakness is a risk factor for death and prolonged mechanical ventilation. Infections activate muscle calpain, but many believe this is an epiphenomenon and that other proteolytic processes are responsible for infection-induced muscle weakness. We tested the hypothesis that muscle-specific overexpression of calpastatin (CalpOX; an endogenous calpain inhibitor) would attenuate diaphragm dysfunction in cecal ligation puncture (CLP)-induced sepsis. We studied 1) wild-type (WT) sham-operated mice, 2) WT CLP-operated mice, 3) CalpOX sham-operated mice, and 4) CalpOX CLP-operated mice ( n = 9–10/group). Twenty-four hours after surgery, we assessed the diaphragm force-frequency relationship, diaphragm mass, and total protein content and diaphragm levels of talin and myosin heavy chain (MHC). CLP markedly reduced diaphragm-specific force generation (force/cross-sectional area), which was prevented by calpastatin overexpression (force averaged 21.4 ± 0.5, 6.9 ± 0.8, 22.4 ± 1.0, and 18.3 ± 1.3 N/cm2, respectively, for WT sham, WT CLP, CalpOX sham, and CalpOX CLP groups, P < 0.001). Diaphragm mass and total protein content were similar in all groups. CLP induced talin cleavage and reduced MHC levels; CalpOX prevented these alterations. CLP-induced sepsis rapidly reduces diaphragm-specific force generation and is associated with cleavage and/or depletion of key muscle proteins (talin, MHC), effects prevented by muscle-specific calpastatin overexpression. These data indicate that calpain activation is a major cause of diaphragm weakness in response to CLP-induced sepsis.
TrkB kinase activity maintains synaptic function and structural integrity at adult neuromuscular junctions
Authors: Mantilla Carlos B. , Stowe Jessica M. , Sieck Dylan C. , Ermilov Leonid G. , Greising Sarah M. , Zhang Chao , Shokat Kevan M. , Sieck Gary C.
Published: August 2014

Activation of the tropomyosin-related kinase receptor B (TrkB) by brain-derived neurotrophic factor acutely regulates synaptic transmission at adult neuromuscular junctions (NMJs). The role of TrkB kinase activity in the maintenance of NMJ function and structure at diaphragm muscle NMJs was explored using a chemical-genetic approach that permits reversible inactivation of TrkB kinase activity in TrkBF616Amice by 1NMPP1. Inhibiting TrkB kinase activity for 7 days resulted in significant, yet reversible, impairments in neuromuscular transmission at diaphragm NMJs. Neuromuscular transmission failure following 2 min of repetitive phrenic nerve stimulation increased from 42% in control to 59% in 1NMPP1-treated TrkBF616Amice ( P = 0.010). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment improved neuromuscular transmission ( P = 0.006). Electrophysiological measurements at individual diaphragm NMJs documented lack of differences in quantal content in control and 1NMPP1-treated mice ( P = 0.845). Morphological changes at diaphragm NMJs were modest following inhibition and recovery of TrkB kinase activity. Three-dimensional reconstructions of diaphragm NMJs revealed no differences in volume at motor end plates (labeled by α-bungarotoxin; P = 0.982) or presynaptic terminals (labeled by synaptophysin; P = 0.515). Inhibition of TrkB kinase activity by 1NMPP1 resulted in more compact NMJs, with increased apposition of presynaptic terminals and motor end plates ( P = 0.017) and reduced fragmentation of motor end plates ( P = 0.005). Recovery of TrkB kinase activity following withdrawal of 1NMPP1 treatment resulted in postsynaptic remodeling likely reflecting increased gutter depth ( P = 0.007), without significant presynaptic changes. These results support an essential role for TrkB kinase activity in maintaining synaptic function and structural integrity at NMJs in the adult mouse diaphragm muscle.
Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling
Authors: Gao Shan , Bajrami Ilirjana , Verrill Clare , Kigozi Asha , Ouaret Djamila , Aleksic Tamara , Asher Ruth , Han Cheng , Allen Paul , Bailey Deborah , Feller Stephan , Kashima Takeshi , Athanasou Nicholas , Blay Jean-Yves , Schmitz Sandra , Machiels Jean-Pascal , Upile Nav , Jones Terry M. , Thalmann George , Ashraf Shazad Q. , Wilding Jennifer L. , Bodmer Walter F. , Middleton Mark R. , Ashworth Alan , Lord Christopher J. , Macaulay Valentine M.
Published: August 2014

Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK–ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor–bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc–Grb2–SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 5866–77. ©2014 AACR.
HE4 Tissue Expression and Serum HE4 Levels in Healthy Individuals and Patients with Benign or Malignant Tumors: A Systematic Review
Authors: Karlsen Nikoline S. , Karlsen Mona A. , Høgdall Claus K. , Høgdall Estrid V.S.
Published: August 2014

Human epididymis protein 4 (HE4) has received major attention as a potential tumor marker in epithelial ovarian cancer; however, evidence of significant overexpression of HE4 in several other human cancers is expanding. To assess the possible limitations or benefits of HE4 in a clinical setting, this review aims to systematically outline published results of HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors. Our findings suggest scientific basis for a potential diagnostic ability of HE4 in gynecologic cancer and lung cancer, and further research is needed regarding other cancers. Yet, it is important to recognize that other malignancies can cause increased HE4 levels. Furthermore, attention should be paid to the influence of age and renal function on HE4 serum levels in future studies as well as in the clinic for proper interpretation of serum HE4 test results. Cancer Epidemiol Biomarkers Prev; 23(11); 2285–95. ©2014 AACR.
The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor
Authors: Nakanishi Yoshito , Akiyama Nukinori , Tsukaguchi Toshiyuki , Fujii Toshihiko , Sakata Kiyoaki , Sase Hitoshi , Isobe Takehito , Morikami Kenji , Shindoh Hidetoshi , Mio Toshiyuki , Ebiike Hirosato , Taka Naoki , Aoki Yuko , Ishii Nobuya
Published: August 2014

The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEGFR) or platelet-derived growth factor receptor (PDGFR) family displayed clinical benefits in cohorts of patients with FGFR genetic alterations. However, to achieve more potent and prolonged activity in such populations, a selective FGFR inhibitor is still needed. Here, we report the identification of CH5183284/Debio 1347, a selective and orally available FGFR1, FGFR2, and FGFR3 inhibitor that has a unique chemical scaffold. By interacting with unique residues in the ATP-binding site of FGFR1, FGFR2, or FGFR3, CH5183284/Debio 1347 selectively inhibits FGFR1, FGFR2, and FGFR3 but does not inhibit kinase insert domain receptor (KDR) or other kinases. Consistent with its high selectivity for FGFR enzymes, CH5183284/Debio 1347 displayed preferential antitumor activity against cancer cells with various FGFR genetic alterations in a panel of 327 cancer cell lines and in xenograft models. Because of its unique binding mode, CH5183284/Debio 1347 can inhibit FGFR2 harboring one type of the gatekeeper mutation that causes resistance to other FGFR inhibitors and block FGFR2 V564F–driven tumor growth. CH5183284/Debio 1347 is under clinical investigation for the treatment of patients harboring FGFR genetic alterations. Mol Cancer Ther; 13(11); 2547–58. ©2014 AACR.
Left Ventricular Hypertrophy With Strain and Aortic Stenosis
Authors: Shah Anoop S.V. , Chin Calvin W.L. , Vassiliou Vassilis , Cowell S. Joanna , Doris Mhairi , Kwok T’ng Choong , Semple Scott , Zamvar Vipin , White Audrey C. , McKillop Graham , Boon Nicholas A. , Prasad Sanjay K. , Mills Nicholas L. , Newby David E. , Dweck Marc R.
Published: August 2014

Background—

ECG left ventricular hypertrophy with strain is associated with an adverse prognosis in aortic stenosis. We investigated the mechanisms and outcomes associated with ECG strain.

Methods and Results—

One hundred and two patients (age, 70 years [range, 63–75 years]; male, 66%; aortic valve area, 0.9 cm
2
[range, 0.7–1.2 cm
2
]) underwent ECG, echocardiography, and cardiovascular magnetic resonance. They made up the mechanism cohort. Myocardial fibrosis was determined with late gadolinium enhancement (replacement fibrosis) and T1 mapping (diffuse fibrosis). The relationship between ECG strain and cardiovascular magnetic resonance was then assessed in an external validation cohort (n=64). The outcome cohort was made up of 140 patients from the Scottish Aortic Stenosis and Lipid Lowering Trial Impact on Regression (SALTIRE) study and was followed up for 10.6 years (1254 patient-years). Compared with those without left ventricular hypertrophy (n=51) and left ventricular hypertrophy without ECG strain (n=30), patients with ECG strain (n=21) had more severe aortic stenosis, increased left ventricular mass index, more myocardial injury (high-sensitivity plasma cardiac troponin I concentration, 4.3 ng/L [interquartile range, 2.5–7.3 ng/L] versus 7.3 ng/L [interquartile range, 3.2–20.8 ng/L] versus 18.6 ng/L [interquartile range, 9.0–45.2 ng/L], respectively;
P
<0.001) and increased diffuse fibrosis (extracellular volume fraction, 27.4±2.2% versus 27.2±2.9% versus 30.9±1.9%, respectively;
P
<0.001). All patients with ECG strain had midwall late gadolinium enhancement (positive and negative predictive values of 100% and 86%, respectively). Indeed, late gadolinium enhancement was independently associated with ECG strain (odds ratio, 1.73; 95% confidence interval, 1.08–2.77;
P
=0.02), a finding confirmed in the validation cohort. In the outcome cohort, ECG strain was an independent predictor of aortic valve replacement or cardiovascular death (hazard ratio, 2.67; 95% confidence interval, 1.35–5.27;
P
<0.01).

Conclusion—

ECG strain is a specific marker of midwall myocardial fibrosis and predicts adverse clinical outcomes in aortic stenosis.
External Validation of the Boston Acute Stroke Imaging Scale and M1-BASIS in Thrombolyzed Patients
Authors: Yeo Leonard L.L. , Paliwal Prakash R. , Wakerley Benjamin , Khoo Chin M. , Teoh Hock L. , Ahmad Aftab , Ting Eric Y. , Seet Raymond C. , Ong Venetia , Chan Bernard P. , Yohanna Kusama , Gopinathan Anil , Rathakrishnan Rahul , Sharma Vijay K.
Published: August 2014

Background and Purpose—

Radiological findings play an essential role in therapeutic decision making and prognostication in acute ischemic stroke (AIS). The Boston Acute Stroke Imaging Scale (BASIS) and Middle Cerebral Artery-BASIS (M1-BASIS) methodologies are rapid purely radiological instruments and easily applicable for patients with AIS. We validated these methods in patients with AIS treated with intravenous tissue-type plasminogen activator.

Methods—

For BASIS, patients were labeled as having major stroke if there was occlusion of distal internal carotid artery, proximal (both M1 and M2 segments) of middle cerebral artery or the basilar artery, or an Alberta Stroke Program Early CT Score ≤7. M1-BASIS differs from BASIS by classifying AIS patients with M2 occlusion as a minor stroke. We evaluated these classification systems for predicting functional outcomes (modified Rankin Scale score 0–1) at 3 months.

Results—

Two hundred sixty-five consecutive AIS patients treated with intravenous tissue-type plasminogen activator were included. On multivariate analysis, younger age (odds ratio, 1.039, 95% confidence interval, 1.009–1.070;
P
=0.011), lower National Institutes of Health Stroke Scale score (odds ratio, 1.140; 95% confidence interval, 1.073–1.210;
P
<0.001), and minor stroke by M1-BASIS (odds ratio, 2.376; 95% confidence interval, 1.047–5.393;
P
=0.039) were independent predictors of good functional outcome. When compared with National Institutes of Health Stroke Scale, the receiver operating characteristic curves for both BASIS (area under the curve, 0.721) and M1-BASIS (area under the curve, 0.795) correlated well with clinical severity scores. M1-BASIS has an additive effect with the National Institutes of Health Stroke Scale score to predict good outcomes.

Conclusions—

The purely radiological M1-BASIS correlates well with the clinical severity of stroke and can be a reliable prognostication tool in thrombolyzed AIS patients. This system might find an important place in the current era of telestroke.