bluuebunny/crossref_metadata_2025 huggingface dataset:
Model reduction for discrete and elastic structures with inertial quadratic non-linearities
Authors: Wang F , Bajaj A K
Published: August 2011

This work discusses model reduction for non-linear structural systems under harmonic excitations. Model reduction can be achieved by different techniques, one of the recent techniques being the non-linear normal modes (NNMs) of the system. The dimension reduction achievable depends on the possibilities of internal resonances. A master–slave separation of degrees of freedom is used, and a non-linear relation between the slave and master coordinates is constructed based on the method of multiple timescales. More specifically, three cases involving external resonance of a mode without any internal resonance, and subharmonic as well as superharmonic resonances for systems with 1:2 internal resonances are considered. Reduced-order models based on the ‘ Conservative NNMs’ as well as ‘ Damped NNMs’ are constructed. The steady-state periodic responses of the reduced models determined by the method of multiple timescales are compared to exact solutions of the system models computed by the bifurcation analysis and parameter continuation software AUTO. The analysis is specifically applied to a spring-mass-pendulum system with external excitation, and to an elastic three-beam-tip-mass structure, which is first reduced to a high-fidelity non-linear discretized model through a Galerkin approximation. Both systems exhibit essential quadratic non-linearities and couplings between the various generalized coordinates. The NNMs of the two systems are used to perform model reductions when excited by harmonic excitations. It is seen that for systems with essential inertial quadratic non-linearities, the technique for model-order reduction through multiple timescales approximation based on NNMs over-predicts the softening non-linear response in each of the cases studied.
Investigation of active vibration control system for trailed two-wheeled implements
Authors: Kim H-J
Published: August 2011

This paper presents an active vibration control (AVC) system for trailed two-wheeled implements (TTWI) equipped with high precision electronic devices. With the aim of isolating disturbance forces to the devices, a hydraulically actuated vibration control system is devised. In order to suppress vibratory motions to the body components, considering the TTWI system characteristics, a vibration control and a force tracking control strategy is adopted. As the vibration controller, the adaptive and skyhook control schemes are applied. From full order and reduced order model for the actuating module, as the tracking controller, the sliding mode control scheme is adopted regarding parameter variations. On the basis of the roll plane TTWI system model, simulation work is performed. Finally, after implementation of the experimental setup with the TTWI system and the road simulating module considering practical requirements, actual performance of the devised AVC system is evaluated in various disturbance conditions.
Equine athletes and interspecies sport
Authors: Gilbert Michelle , Gillett James
Published: August 2011

This article draws on a range of sociological literature including studies of sport, subculture, interspecies relationships and animal advocacy to understand the social processes that have contributed to the horse being defined as an athlete in equestrian sports. Using a combination of qualitative interviews and archival analysis, we identify trends in the equine industry that have provided the foundation for the emergence of a new type of equine athlete – the sport pony – in the context of late modern societies. We conclude by arguing that the popularity of the sport pony is a reflection of a general trend within the equine industry placing value on athleticism and esthetics.
Social identity as a determinant of college enrollment
Authors: Fletcher Jason M.
Published: August 2011

This paper combines ideas from several branches of the social sciences into an economic model of college enrollment, following recent theoretical work by Akerlof and Kranton (2002). Basic to the model are notions of ‘fitting in,’ social status, and investments in human capital during high school. After using the NELS data and maximum likelihood estimation to uncover the behavioral parameters of the model, I predict the effects of ‘economic’ and ‘social’ policy interventions. I find that policies implemented during high school are often too late to reduce disparities in college enrollments; the exceptions are policies that shape adolescents’ social environments.
Not ‘Just the two of us’: Third party externalities of social dilemmas
Authors: van der Iest Hanne , Dijkstra Jacob , Stokman Frans N.
Published: August 2011

Many real-life social dilemmas contain third parties who cannot make decisions in the dilemma, but are affected by its outcome (receive externalities) nonetheless. Dilemmas with identical payoffs for decision-making actors may greatly vary in their externalities for third parties. If actors value the welfare of thirds, externalities will affect actors’ decisions. We test behavioral predictions from three leading ideas on social preferences (altruism, inequality aversion, competition) in two studies that employ four one-shot, 2-person prisoner’s dilemmas (PDs) that differ only in their externalities. The PDs respectively include a third party that (i) is indifferent, (ii) prefers defection, (iii) prefers cooperation. Our results show that while aggregate behavior is not affected by externalities, individual behavior is. Compared to a PD without externalities, prosocial individuals cooperate more when a third benefits from cooperation, but do not defect more when a third benefits from defection. The opposite pattern is found for competitive individuals.
The two-model problem in rational decision making
Authors: Boumans Marcel
Published: August 2011

A model of a decision problem frames that problem in three dimensions: sample space, target probability and information structure. Each specific model imposes a specific rational decision. As a result, different models may impose different, even contradictory, rational decisions, creating choice ‘anomalies’ and ‘paradoxes’. So, decision making in real-life situations is different from decision making in an experiment. An experiment is a designed setting according to an experimenter’s model of the decision problem, while for a real-life situation it is not always obvious what the design is. A subject in an experiment may initially have a different model of the task than the experimenter and thus possibly make apparently irrational decisions from the experimenter’s model perspective. As a consequence a choice anomaly can be eliminated by learning what the experiment’s model is.
Modeling of Wire-on-Drum Shape Memory Actuators for Linear and Rotary Motion
Authors: Scirè Mammano Giovanni , Dragoni Eugenio
Published: August 2011

The article presents the analytical model of a linear/rotary solid-state actuator formed by a shape memory wire wound over a cylindrical drum. The model assumes a bilinear stress-strain behavior of the wire in the martensitic state (low temperature) and a linear elastic response in the austenitic state (high temperature). Based on simple equilibrium conditions, the model calculates the stress and strain distributions in the wire when subjected to a constant external backup force and undergoing frictional sliding forces at the contact with the drum. Closed-form expressions are supplied for the stroke produced by whatever actuator geometry and are validated numerically against finite element results. For a particular actuator configuration, the analytical forecasts are also checked experimentally on a proof-of-concept prototype. The analytical model shows that large strokes (up to one-half of the drum’s diameter) are achieved if the frictional coefficient is kept below 0.01. Rolling-contact architectures or sonic-pulse excitations of the drum are discussed as technical solutions to obtain such low friction values.
Genetic Architecture of Declarative Memory
Authors: Bearden Carrie E. , Karlsgodt Katherine H. , Bachman Peter , van Erp Theo G. M. , Winkler Anderson M. , Glahn David C.
Published: August 2011

Why do memory abilities vary so greatly across individuals and cognitive domains? Although memory functions are highly heritable, what exactly is being genetically transmitted? Here we review evidence for the contribution of both common and partially independent inheritance of distinct aspects of memory function. We begin by discussing the assessment of long-term memory and its underlying neural and molecular basis. We then consider evidence for both specialist and generalist genes underlying individual variability in memory, indicating that carving memory into distinct subcomponents may yield important information regarding its genetic architecture. And finally we review evidence from both complex and single-gene disorders, which provide insight into the molecular mechanisms underlying the genetic basis of human memory function.
COPE for the Treatment of Depressed Adolescents
Authors: Lusk Pamela , Melnyk Bernadette Mazurek
Published: August 2011

Background: Despite a U.S. prevalence of 9%, less than 25% of depressed adolescents receive evidence-based treatment. Objective: To describe lessons learned from implementing the COPE (Creating Opportunities for Personal Empowerment) program in a community mental health practice as part of an evidence-based practice change to improve an advanced practice psychiatric nurse’s clinical practice and provide treatment for depressed teens. Design: A preexperimental one-group pre- and posttest design was used to assess the feasibility and effects of a brief manualized seven-session cognitive-behavioral skills–building intervention titled COPE delivered to 15 depressed adolescents in routine 30-minute mental health medication management outpatient visits. Results: Applying the evidence-based practice model led to improved adolescent outcomes. Adolescents reported significant decreases in depression, anxiety, anger, and destructive behavior as well as increases in self-concept and personal beliefs about managing negative emotions. Challenges (limited organizational resources) needed to be addressed to implement the advanced practice psychiatric nurse’s evidence-based practice change. Conclusions: COPE is a promising brief cognitive-behavioral therapy–based intervention that can be delivered within 30-minute individual outpatient visits. With this intervention, advanced practice nurses can work with current practice limitations and still provide evidence-based treatment for depressed teens. Collaboration between research-focused and clinically based nursing colleagues is a model of clinical scholarship that holds great promise in bridging the gap between research and practice.
Transforming the negotiator: The impact of critical learning on teaching and practicing negotiation
Authors: Mazen Abdelmagid
Published: August 2011

A long-standing debate in the negotiation field is whether negotiators can actually change their styles. In this article I offer two contributions to the literature and its pedagogy by suggesting that we shift the focus of the debate. Instead of considering negotiator styles as fixed predispositions, I propose that we view them as actions resulting from learning. From this perspective, the conflict-negotiation dynamic can be conceived as a critical learning process and negotiators as critical learners. We can then trace and incorporate the impact of negative emotions on learning and on the action it informs. I offer a system dynamic model to account for the cyclical links between actual conflicts, defensiveness, learning, and negotiators’ habitual responses to conflicts. Pedagogically, the model can be used descriptively to help negotiators understand such responses to actual conflicts, and prescriptively to garner their potential to change and transform. I share the experience of using the model in my classes and provide examples from helping negotiators unsettle their frames of reference and the assumptions they hold.
A Dynamic Simulation of Indoor Polydispersion of Particles in All-Air Air-Conditioned Environment with Dynamical Particle Sources
Authors: Li Min , Wu Chun-Liang , Sun Liang-Liang , Lai Alvin C. K.
Published: August 2011

This paper reports an investigation of the impact of indoor dynamic particle source on the operating strategies of all-air air-conditioning systems using a state-space model. In the case of constant air volume system, the simulation results indicated that if the designed air supply rate was properly determined, the indoor particle concentrations would satisfy the specified requirements of indoor air quality standards. For a variable air volume system, if the strength of indoor particle source is, in a relative sense, large compared to the cooling load, the particle concentrations could markedly increase and would probably bring about indoor air quality problem. The partial load ratio, a dimensionless ratio of the partial source ratio to the partial cooling/heating load ratio, has been suggested as an indicator to guide the design and operation of the air supply rate of variable air volume system. This operating strategy builds on the basis of the identification of indoor sources and takes the relative importance of cooling load and particle sources into the evaluation. The computational results showed that the ventilation performance of variable air volume system was improved by applying the partial load ratio to the operation of variable air volume system.
Interrogating planning’s power in an African city: Time for reorientation?
Authors: Kamete Amin Y.
Published: August 2011

As part of modern government, planning is concerned with ‘acting on others’ actions’ in spatial practices. This necessarily entails the exercise of power. This paper (re)frames planning’s power in the context of particular systems of governance and how this power is exercised in the relationship between planning systems and (ab)users of urban spaces. Using material from field research in Zimbabwe, the paper examines three forms of power exercised through planning in specific socio-economic contexts. The discussion interrogates planning’s handling of violations of spatial controls by two socio-economic groups: the privileged affluent and the marginalized poor. The paper demonstrates that planning exercises direct sovereign power and cruder and more overtly violent forms of disciplinary power in less privileged context while exercising pastoral power and subtler forms of disciplinary power in affluent contexts. The paper argues that planning’s continued affinity to and unbending deployment of sovereign and crude and overtly violent disciplinary techniques in its dealings with marginalized townspeople is counterproductive and ineffective. The paper proposes the cautious appropriation of pastoral power – especially as it relates to the co-opting of individual and group agency – into planning’s operations in less privileged contexts.
Income Inequality and Policy Representation in the American States
Authors: Flavin Patrick
Published: August 2011

Government representation of public opinion is a central component of democracy. Previous studies have documented a robust congruence between aggregated public opinion and public policies in the American states. However, an equally important question for evaluating the quality of democracy is “Who does government respond to when formulating public policies?” I investigate differential policy representation based on citizens’ household incomes and find that citizens with low incomes receive little substantive political representation (compared with more affluent citizens) in the policy decisions made by their state governments. This unequal policy representation occurs for both the general liberalism of state policies and on specific social issues like the death penalty and abortion. These findings suggest that examining the variation in political inequality across the 50 states can help scholars to better understand and explain “unequal democracy” in the United States.
Posterior Cortical Atrophy
Authors: Tsai Po-Heng , Teng Edmond , Liu Collin , Mendez Mario F.
Published: August 2011

Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s disease (AD) rather than amnestic AD with visual deficits. Methods: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. Results: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. Conclusion: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These results suggest that, in most cases, PCA syndromes are discrete clinical variants of AD.
Heterosexual Risk for HIV Among Black Men in the United States
Authors: Raj Anita , Bowleg Lisa
Published: August 2011

Recent data from the Centers for Disease Control and Prevention demonstrate that 1 in 16 Black men in the United States will be infected with HIV in their lifetime. Furthermore, the long-standing HIV disparity in Black communities is actually increasing for Black men. National efforts to curb the epidemic among U.S. Black men focus primarily on men who have sex with men and injection drug users. Black men at heterosexual risk for HIV have largely been neglected by research, program, and policy. This article presents epidemiologic data documenting that heterosexual risk for HIV among Black men is a major concern for Black communities and is likely additional evidence among growing indications of a generalized epidemic in low-income and urban Black communities. The authors offer a call to action to increase support for research, program, and policies that can improve HIV prevention and testing among heterosexual Black men in the United States, as part of the national agenda to reduce rates of HIV in Black communities.
A tale of three labels: translating the JUPITER trial data into regulatory claims
Authors: Ridker Paul M
Published: August 2011

Background Whether a pivotal randomized trial will be interpreted in a similar and consistent manner by different regulatory agencies is uncertain as policy perspectives may play a role in data interpretation and the translation of trial results into clinical practice.

Purpose Using a contemporary example, to compare and contrast regulatory claims in the United States, Europe, and Canada that derive from a pivotal clinical trial.

Methods The recently completed JUPITER trial of rosuvastatin as compared to placebo conducted among 17,802 men and women with LDL-C <130 mg/dL and hsCRP ≥2 mg/L, provides the only available data on rosuvastatin for primary prevention of cardiovascular disease. Thus, the JUPITER trial provides an opportunity to compare and contrast how regulatory agencies in the United States, Canada, and Europe chose to interpret an identical database. Labeling indications based on earlier statin trials of primary and secondary prevention were also reviewed.

Results JUPITER demonstrated a 44% reduction ( p < 0.000001) in the trial pre-specified primary endpoint (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, coronary revascularization, or cardiovascular death) with no evidence of heterogeneity across geographic regions. In response to these data, the US Food and Drug Administration label for rosuvastatin in primary prevention came closest to the actual JUPITER trial population by stipulating that those eligible for treatment should be older men and women with hsCRP >2 mg/L, plus one additional risk factor for heart disease. The Canadian label is silent on age and hsCRP (the major trial inclusion criterion), stipulating instead that treatment can be considered for those with ‘at least two conventional risk factors for cardiovascular disease,’ a group more inclusive than that studied. In contrast, the European Medicines Agency label limits treatment only to ‘high risk individuals' ignoring hsCRP and using instead a post hoc definition of ‘high risk’ that comprised a subgroup of less than 10% of the study population who contributed but 67 events to the study total and did not show statistical significance when compared to placebo. None of the regulatory labels included the trial primary endpoint; instead, each focused on separate and different components of the primary endpoint. Similar discrepancies were found between European and North American regulatory agencies with regard to earlier pivotal trials of statins for primary prevention, but not for secondary prevention.

Limitations The JUPITER experience represents a case study and is not a systematic review of the regulatory decision process.

Conclusions Labeling indications can vary widely in different regulatory environments even when based on the same trial data.
Incorporating lower grade toxicity information into dose finding designs
Authors: Iasonos Alexia , Zohar Sarah , O'Quigley John
Published: August 2011

Background Toxicity grades underlie the definition of a dose-limiting toxicity but in the majority of phase I designs, the information contained in the individual grades is not used. Some authors have argued that it may be more appropriate to consider a polytomous rather than dichotomous response.

Purpose We investigate whether the added information on individual grades can improve the operating characteristics of the continual reassessment method.

Methods We compare the original continual reassessment method design for a binary response with two stage continual reassessment method designs which make different use of lower grade toxicity information via simulations. Specifically, we study a two-stage design that utilizes lower grade toxicities in the first stage only, during the initial non-model-based escalation, and two-stage designs where lower grades are used throughout the trial via explicit models. We postulate a model relating the rates of lower grade toxicities to the rate of dose-limiting toxicity, or assume the relative rates of low-to-high grade toxicities is unknown. The designs were compared in terms of accuracy, patient allocation, and precision.

Results Significant gains can be achieved when using grades in the first stage of a two-stage design. Otherwise, only modest improvements are seen when the information on grades is exploited via the use of explicit models, where the parameters are known precisely. Continual reassessment method with some use of grade information, increases the number of patients treated at the maximum tolerated dose by approximately 5%. The additional information from lower grades can lead to a small increase in the precision of our estimate of the maximum tolerated dose.

Limitations Our comparisons are not exhaustive and it would be worth studying other models and situations.

Conclusions Although the gains in performance were not as great as we had hoped, we observed no cases where the performance of continual reassessment method was poorer. Our recommendation is that investigators might consider using graded toxicities at the design stage.
Some essential considerations in the design and conduct of non-inferiority trials
Authors: Fleming Thomas R , Odem-Davis Katherine , Rothmann Mark D , Li Shen Yuan
Published: August 2011

Background Suppose a standard therapy (Standard) has been established to provide a clinically important reduction in risk of irreversible morbidity or mortality. In that setting, the safety and efficacy of an experimental intervention likely would be assessed in a clinical trial providing a comparison with Standard rather than a placebo arm. Such a trial often is designed to assess whether the efficacy of the experimental intervention is not unacceptably worse than that of Standard, and is called a non-inferiority trial. Formally, the non-inferiority trial usually is designed to rule out a non-inferiority margin, defined as the minimum threshold for what would constitute an unacceptable loss of efficacy.

Purpose Even though the literature has many important articles identifying various approaches to the design and conduct of non-inferiority trials, confusion remains especially regarding key considerations for selecting the non-inferiority margin. The purpose of this article is to provide improved clarity regarding these considerations.

Methods We present scientific insights into many factors that should be addressed in the design and conduct of non-inferiority trials to enhance their integrity and reliability, and provide motivation for key considerations that guide the selection of non-inferiority margins. We also provide illustrations and insights from recent experiences.

Results Two considerations are essential, and should be addressed in separate steps, in the formulation of the non-inferiority margin. First, the margin should be formulated using adjustments to account for bias or lack of reliability in the estimate of the effect of Standard in the non-inferiority trial setting. Second, the non-inferiority margin should be formulated to achieve preservation of an appropriate percentage of the effect of Standard.

Limitations The considerations, in particular regarding the importance of preservation of effect, might not apply to settings where it would be ethical as well as clinically relevant to include both Standard and placebo arms in the trial for direct comparisons with the experimental intervention arm.

Conclusions Non-inferiority trials with non-rigorous margins allow substantial risk for accepting inadequately effective experimental regimens, leading to the risk of erosion in quality of health care. The design and conduct of non-inferiority trials, including selection of non-inferiority margins, should account for many factors that can induce bias in the estimated effect of Standard in the non-inferiority trial and thus lead to bias in the estimated effect of the experimental treatment, for the need to ensure the experimental treatment preserves a clinically acceptable fraction of Standard's effect, and for the particular vulnerability of the integrity of a non-inferiority trial to the irregularities in trial conduct. Due to the inherent uncertainties in non-inferiority trials, alternative designs should be pursued whenever possible.
Chattering reduction on the dynamic tracking control of a nonholonomic mobile robot using exponential sliding mode
Authors: Mehrjerdi H , Saad M
Published: August 2011

This paper considers the problem of improving chattering reduction and trajectory tracking along a desired trajectory for a mobile robot. It is proposed that exponential sliding mode control is an effective solution to reduce chattering for the trajectory tracking of a nonholonomic mobile robot. Compared to conventional and second-order sliding modes, the developed sliding mode control reduces chattering and delivers a high dynamic tracking performance in a steady state mode. The developed algorithm instructs the robot to keep moving continuously on the desired trajectory while reducing tracking errors. Experimental results on a wheeled mobile robot are presented to demonstrate the performance of the exponential sliding mode controller algorithm compared to both conventional and second-order sliding mode algorithms.
Tetraspanin CD151 maintains vascular stability by balancing the forces of cell adhesion and cytoskeletal tension
Authors: Zhang Feng , Michaelson Jarett E. , Moshiach Simon , Sachs Norman , Zhao Wenyuan , Sun Yao , Sonnenberg Arnoud , Lahti Jill M. , Huang Hayden , Zhang Xin A.
Published: August 2011

Tetraspanin CD151 is highly expressed in endothelial cells and regulates pathologic angiogenesis. However, the mechanism by which CD151 promotes vascular morphogenesis and whether CD151 engages other vascular functions are unclear. Here we report that CD151 is required for maintaining endothelial capillary-like structures formed in vitro and the integrity of endothelial cell-cell and cell-matrix contacts in vivo. In addition, vascular permeability is markedly enhanced in the absence of CD151. As a global regulator of endothelial cell-cell and cell-matrix adhesions, CD151 is needed for the optimal functions of various cell adhesion proteins. The loss of CD151 elevates actin cytoskeletal traction by up-regulating RhoA signaling and diminishes actin cortical meshwork by down-regulating Rac1 activity. The inhibition of RhoA or activation of cAMP signaling stabilizes CD151-silenced or -null endothelial structure in vascular morphogenesis. Together, our data demonstrate that CD151 maintains vascular stability by promoting endothelial cell adhesions, especially cell-cell adhesion, and confining cytoskeletal tension.
Romiplostim safety and efficacy for immune thrombocytopenia in clinical practice: 2-year results of 72 adults in a romiplostim compassionate-use program
Authors: Khellaf Mehdi , Michel Marc , Quittet Philippe , Viallard Jean-François , Alexis Magda , Roudot-Thoraval Françoise , Cheze Stéphane , Durand Jean-Marc , Lefrère François , Galicier Lionel , Lambotte Olivier , Panelatti Gérard , Slama Borhane , Damaj Gandhi , Sebahoun Gérard , Gyan Emmanuel , Delbrel Xavier , Dhedin Nathalie , Royer Bruno , Schleinitz Nicolas , Rossi Jean-François , Mahévas Matthieu , Languille Laetitia , Bierling Philippe , Godeau Bertrand
Published: August 2011

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 109/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 109/L (interquartile range, 75-167 × 109/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 109/L (interquartile range, 35-44 × 109/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at www.clinicaltrials.gov as #NCT01013181.
Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling
Authors: Kigel Boaz , Rabinowicz Noa , Varshavsky Asya , Kessler Ofra , Neufeld Gera
Published: August 2011

Plexin-A4 is a receptor for sema6A and sema6B and associates with neuropilins to transduce signals of class-3 semaphorins. We observed that plexin-A1 and plexin-A4 are required simultaneously for transduction of inhibitory sema3A signals and that they form complexes. Unexpectedly, inhibition of plexin-A1 or plexin-A4 expression in endothelial cells using specific shRNAs resulted in prominent plexin type specific rearrangements of the actin cytoskeleton that were accompanied by inhibition of bFGF and VEGF-induced cell proliferation. The two responses were not interdependent since silencing plexin-A4 in U87MG glioblastoma cells inhibited cell proliferation and strongly inhibited the formation of tumors from these cells without affecting cytoskeletal organization. Plexin-A4 formed stable complexes with the FGFR1 and VEGFR-2 tyrosine-kinase receptors and enhanced VEGF-induced VEGFR-2 phosphorylation in endothelial cells as well as bFGF-induced cell proliferation. We also obtained evidence suggesting that some of the pro-proliferative effects of plexin-A4 are due to transduction of autocrine sema6B-induced pro-proliferative signals, since silencing sema6B expression in endothelial cells and in U87MG cells mimicked the effects of plexin-A4 silencing and also inhibited tumor formation from the U87MG cells. Our results suggest that plexin-A4 may represent a target for the development of novel anti-angiogenic and anti-tumorigenic drugs.
A novel approach for in vivo measurement of mouse red cell redox status
Authors: Xu Xiuling , von Löhneysen Katharina , Soldau Katrin , Noack Deborah , Vu Andrew , Friedman Jeffrey S.
Published: August 2011

Maintenance of a reducing redox balance is a critical physiologic function of red cells (RBC) that can be perturbed in variety of RBC pathologies. Here we describe a new approach to evaluate in vivo RBC redox status using a redox sensitive GFP (roGFP2) sensor under control of a β-globin mini-promoter, directing expression specifically to erythroid cells. RoGFP2 expressing RBCs demonstrate ratiometric and reversible shifts in fluorescence on exposure to oxidants and reductants. We demonstrate that roGFP2 expressing RBC can be used to monitor thiol redox status during in vitro phenylhydrazine treatment and over the course of in vivo RBC aging, where a shift to a more oxidized state is observed in older cells. Thus, roGFP2 transgenic mice are a new and versatile tool that can be used to probe how RBC redox status responds in the context of drug therapy, physiologic stressors and pathologic states.
Blood platelets contain tumor-derived RNA biomarkers
Authors: Nilsson R. Jonas A. , Balaj Leonora , Hulleman Esther , van Rijn Sjoerd , Pegtel D. Michiel , Walraven Maudy , Widmark Anders , Gerritsen Winald R. , Verheul Henk M. , Vandertop W. Peter , Noske David P. , Skog Johan , Würdinger Thomas
Published: August 2011

Diagnostic platforms providing biomarkers that are highly predictive for diagnosing, monitoring, and stratifying cancer patients are key instruments in the development of personalized medicine. We demonstrate that tumor cells transfer (mutant) RNA into blood platelets in vitro and in vivo, and show that blood platelets isolated from glioma and prostate cancer patients contain the cancer-associated RNA biomarkers EGFRvIII and PCA3, respectively. In addition, gene-expression profiling revealed a distinct RNA signature in platelets from glioma patients compared with normal control subjects. Because platelets are easily accessible and isolated, they may form an attractive platform for the companion diagnostics of cancer.
Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice
Authors: Machlus Kellie R. , Lin Feng-Chang , Wolberg Alisa S.
Published: August 2011

Studies have correlated elevated plasma factor VIII (FVIII) with thrombosis; however, it is unclear whether elevated FVIII is a proinflammatory biomarker, causative agent, or both. We raised FVIII levels in mice and measured the time to vessel occlusion (TTO) after ferric chloride–induced injury. Compared with control (saline-infused) mice, elevated FVIII had no effect after longer (3-minute) carotid artery injury, but it shortened the TTO after shorter (2-minute) injury (P < .008). After injury, circulating thrombin-antithrombin (TAT) complexes were lower after short versus long injury (P < .04), suggesting short treatment produced less coagulation activation. TAT levels in FVIII-infused mice were higher than in controls after short, but not longer, injury. Accordingly, elevated FVIII had no effect on in vitro thrombin generation or platelet aggregation triggered by high tissue factor, but it increased thrombin generation rate and peak (2.4- and 1.5-fold, respectively), and it accelerated platelet aggregation (up to 1.6-fold) when initiated by low tissue factor. Compared with control mice, elevated FVIII stabilized thrombi (fewer emboli) after short injury, but it had no effect after longer injury. TTO and emboli correlated with TATs. These results demonstrate dependence of FVIII activity on extent of vascular injury. We propose elevated plasma FVIII is an etiologic, prothrombotic agent after moderate but not extensive vascular damage.
Constructing gene regulatory networks for long term photosynthetic light acclimation in Arabidopsis thaliana
Authors: Yao Cheng-Wei , Hsu Ban-Dar , Chen Bor-Sen
Published: August 2011

Background

Photosynthetic light acclimation is an important process that allows plants to optimize the efficiency of photosynthesis, which is the core technology for green energy. However, currently little is known about the molecular mechanisms behind the regulation of the photosynthetic light acclimation response. In this study, a systematic method is proposed to investigate this mechanism by constructing gene regulatory networks from microarray data of Arabidopsis thaliana.

Methods

The potential TF-gene regulatory pairs of photosynthetic light acclimation have been obtained by data mining of literature and databases. Following the identification of these potential TF-gene pairs, they have been refined using Pearson's correlation, allowing the construction of a rough gene regulatory network. This rough gene regulatory network is then pruned using time series microarray data of Arabidopsis thaliana via the maximum likelihood system identification method and Akaike's system order detection method to approach the real gene regulatory network of photosynthetic light acclimation.

Results

By comparing the gene regulatory networks under the PSI-to-PSII light shift and the PSII-to-PSI light shift, it is possible to identify important transcription factors for the different light shift conditions. Furthermore, the robustness of the gene network, in particular the hubs and weak linkage points, are also discussed under the different light conditions to gain further insight into the mechanisms of photosynthesis.

Conclusions

This study investigates the molecular mechanisms of photosynthetic light acclimation for Arabidopsis thaliana from the physiological level. This has been achieved through the construction of gene regulatory networks from the limited data sources and literature via an efficient computation method. If more experimental data for whole-genome ChIP-chip data and microarray data with multiple sampling points becomes available in the future, the proposed method will be improved on by constructing the whole-genome gene regulatory network. These advances will greatly improve our understanding of the mechanisms of the photosynthetic system.
Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing
Authors: O'Driscoll Kate E , Pipe Rachel A , Britton Fiona C
Published: August 2011

Background

TMEM16A (Anoctamin 1; ANO1) is an eight transmembrane protein that functions as a calcium-activated chloride channel. TMEM16A in human exhibits alternatively spliced exons (6b, 13 and 15), which confer important roles in the regulation of channel function. Mouse Tmem16a is reported to consist of 25 exons that code for a 956 amino acid protein. In this study our aim was to provide details of mouse Tmem16a genomic structure and to investigate if Tmem16a transcript undergoes alternative splicing to generate channel diversity.

Results

We identified Tmem16a transcript variants consisting of alternative exons 6b, 10, 13, 14, 15 and 18. Our findings indicate that many of these exons are expressed in various combinations and that these splicing events are mostly conserved between mouse and human. In addition, we confirmed the expression of these exon variants in other mouse tissues. Additional splicing events were identified including a novel conserved exon 13b, tandem splice sites of exon 1 and 21 and two intron retention events.

Conclusion

Our results suggest that Tmem16a gene is significantly more complex than previously described. The complexity is especially evident in the region spanning exons 6 through 16 where a number of the alternative splicing events are thought to affect calcium sensitivity, voltage dependence and the kinetics of activation and deactivation of this calcium-activated chloride channel. The identification of multiple Tmem16a splice variants suggests that alternative splicing is an exquisite mechanism that operates to diversify TMEM16A channel function in both physiological and pathophysiological conditions.
Serum-free microcarrier based production of replication deficient Influenza vaccine candidate virus lacking NS1 using Vero cells
Authors: Chen Allen , Poh Swan Li , Dietzsch Christian , Roethl Elisabeth , Yan Mylene L , Ng Say Kong
Published: August 2011

Background

Influenza virus is a major health concern that has huge impacts on the human society, and vaccination remains as one of the most effective ways to mitigate this disease. Comparing the two types of commercially available Influenza vaccine, the live attenuated virus vaccine is more cross-reactive and easier to administer than the traditional inactivated vaccines. One promising live attenuated Influenza vaccine that has completed Phase I clinical trial is deltaFLU, a deletion mutant lacking the viral Nonstructural Protein 1 (NS1) gene. As a consequence of this gene deletion, this mutant virus can only propagate effectively in cells with a deficient interferon-mediated antiviral response. To demonstrate the manufacturability of this vaccine candidate, a batch bioreactor production process using adherent Vero cells on microcarriers in commercially available animal-component free, serum-free media is described.

Results

Five commercially available animal-component free, serum-free media (SFM) were evaluated for growth of Vero cells in agitated Cytodex 1 spinner flask microcarrier cultures. EX-CELL Vero SFM achieved the highest cell concentration of 2.6 × 10^6 cells/ml, whereas other SFM achieved about 1.2 × 10^6 cells/ml. Time points for infection between the late exponential and stationary phases of cell growth had no significant effect in the final virus titres. A virus yield of 7.6 Log10 TCID50/ml was achieved using trypsin concentration of 10 μg/ml and MOI of 0.001. The Influenza vaccine production process was scaled up to a 3 liter controlled stirred tank bioreactor to achieve a cell density of 2.7 × 10^6 cells/ml and virus titre of 8.3 Log10 TCID50/ml. Finally, the bioreactor system was tested for the production of the corresponding wild type H1N1 Influenza virus, which is conventionally used in the production of inactivated vaccine. High virus titres of up to 10 Log10 TCID50/ml were achieved.

Conclusions

We describe for the first time the production of Influenza viruses using Vero cells in commercially available animal-component free, serum-free medium. This work can be used as a basis for efficient production of attenuated as well as wild type Influenza virus for research and vaccine production.
Determinants of compliance with anti-vectorial protective measures among non-immune travellers during missions to tropical Africa
Authors: Sagui Emmanuel , Resseguier Noémie , Machault Vanessa , Ollivier Lénaïck , Orlandi-Pradines Eve , Texier Gaetan , Pages Frédéric , Michel Remy , Pradines Bruno , Briolant Sébastien , Buguet Alain , Tourette-Turgis Catherine , Rogier Christophe
Published: August 2011

Background

The effectiveness of anti-vectorial malaria protective measures in travellers and expatriates is hampered by incorrect compliance. The objective of the present study was to identify the determinants of compliance with anti-vectorial protective measures (AVPMs) in this population that is particularly at risk because of their lack of immunity.

Methods

Compliance with wearing long clothing, sleeping under insecticide-impregnated bed nets (IIBNs) and using insect repellent was estimated and analysed by questionnaires administered to 2,205 French military travellers from 20 groups before and after short-term missions (approximately four months) in six tropical African countries (Senegal, Ivory Coast, Chad, Central African Republic, Gabon and Djibouti). For each AVPM, the association of "correct compliance" with individual and collective variables was investigated using random-effect mixed logistic regression models to take into account the clustered design of the study.

Results

The correct compliance rates were 48.6%, 50.6% and 18.5% for wearing long clothing, sleeping under bed nets and using repellents, respectively. Depending on the AVPM, correct compliance was significantly associated with the following factors: country, older than 24 years of age, management responsibilities, the perception of a personal malaria risk greater than that of other travellers, the occurrence of life events, early bedtime (i.e., before midnight), the type of stay (field operation compared to training), the absence of medical history of malaria, the absence of previous travel in malaria-endemic areas and the absence of tobacco consumption.

There was no competition between compliance with the different AVPMs or between compliance with any AVPM and malaria chemoprophylaxis.

Conclusion

Interventions aimed at improving compliance with AVPMs should target young people without management responsibilities who are scheduled for non-operational activities in countries with high risk of clinical malaria. Weak associations between compliance and history of clinical malaria or variables that pertain to threat perception suggest that cognition-based interventions referencing a "bad experience" with clinical malaria could have only a slight impact on the improvement of compliance. Further studies should focus on the cognitive and behavioural predictors of compliance with AVPMs.
Exercise training improves sleep pattern and metabolic profile in elderly people in a time-dependent manner
Authors: Lira Fábio S , Pimentel Gustavo D , Santos Ronaldo VT , Oyama Lila M , Damaso Ana R , Oller do Nascimento Cláudia M , Viana Valter AR , Boscolo Rita A , Grassmann Viviane , Santana Marcos G , Esteves Andrea M , Tufik Sergio , de Mello Marco T
Published: August 2011

Aging and physical inactivity are two factors that favors the development of cardiovascular disease, metabolic syndrome, obesity, diabetes, and sleep dysfunction. In contrast, the adoption a habitual of moderate exercise may present a non-pharmacological treatment alternative for sleep and metabolic disorders. We aimed to assess the effects of moderate exercise training on sleep quality and on the metabolic profile of elderly people with a sedentary lifestyle. Fourteen male sedentary, healthy, elderly volunteers performed moderate training for 60 minutes/day, 3 days/week for 24 wk at a work rate equivalent to the ventilatory aerobic threshold. The environment was kept at a temperature of 23 ± 2°C, with an air humidity 60 ± 5%. Blood and polysomnographs analysis were collected 3 times: at baseline (1 week before training began), 3 and 6 months (after 3 and 6 months of training). Training promoted increasing aerobic capacity (relative VO2, time and velocity to VO2max; p < 0.05), and reduced serum NEFA, and insulin concentrations as well as improved HOMA index (p < 0.05), and increased adiponectin levels (p < 0.05), after 3 months of training when compared with baseline data. The sleep parameters, awake time and REM sleep latency were decreased after 6 months exercise training (p < 0.05) in relation baseline values. Our results demonstrate that the moderate exercise training protocol improves the sleep profile in older people, but the metabolism adaptation does not persist. Suggesting that this population requires training strategy modifications as to ensure consistent alterations regarding metabolism.