A meta-analysis of genome-wide association studies of growth differentiation Factor-15 concentration in blood

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the“COPI-mediated anterograde transport” gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels

Sensitivity analysis of reactive ecological dynamics

Author Posting. © Springer, 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Bulletin of Mathematical Biology 70 (2008): 1634-1659, doi:10.1007/s11538-008-9312-7.Ecological systems with asymptotically stable equilibria may exhibit significant transient dynamics following perturbations. In some cases, these transient dynamics include the possibility of excursions away from the equilibrium before the eventual return; systems that exhibit such amplification of perturbations are called reactive. Reactivity is a common property of ecological systems, and the amplification can be large and long-lasting. The transient response of a reactive ecosystem depends on the parameters of the underlying model. To investigate this dependence, we develop sensitivity analyses for indices of transient dynamics (reactivity, the amplification envelope, and the optimal perturbation) in both continuous- and discrete-time models written in matrix form. The sensitivity calculations require expressions, some of them new, for the derivatives of equilibria, eigenvalues, singular values, and singular vectors, obtained using matrix calculus. Sensitivity analysis provides a quantitative framework for investigating the mechanisms leading to transient growth. We apply the methodology to a predator-prey model and a size-structured food web model. The results suggest predator-driven and prey-driven mechanisms for transient amplification resulting from multispecies interactions.Financial support provided by NSF grant DEB-0343820, NOAA grant NA03-NMF4720491, the Ocean Life Institute of the Woods Hole Oceanographic Institution, and the Academic Programs Office of the MIT-WHOI Joint Program in Oceanography

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Refining and regaining skills in fixation/diversification stage performers: The Five-A Model

Technical change is one of many factors underpinning success in elite, fixation/diversification stage performers. Surprisingly, however, there is a dearth of research pertaining to this process or the most efficacious methods used to bring about such a change. In this paper we highlight the emergent processes, yet also the lack in mechanistic comprehension surrounding technical change, addressing issues within the motor control, sport psychology, coaching and choking literature. More importantly, we seek an understanding of how these changes can be made more secure to competitive pressure, and how this can be embedded within the process of technical change. Following this review, we propose The Five-A Model based on successful coaching techniques, psychosocial concomitants, the avoidance of choking and principles of effective behaviour change. Specific mechanisms for each stage are discussed, with a focus on the use of holistic rhythm-based cues as a possible way of internalising changes. Finally, we suggest the need for further research to examine these five stages, to aid a more comprehensive construction of the content and delivery of such a programme within the applied setting

Fat and carbohydrate metabolism during and following hemorrhagic shock in puppies: A comparison of different resuscitation protocols

Shock states continue to carry a high mortality rate in the pediatric age group. Using a puppy model, we measured the initial metabolic response to hemorrhagic shock and to 3 resuscitation regimens: whole blood 1∶1 (replacement∶shed), lactated Ringer's 3∶1, and 5% albumin in lactated Ringer's 1∶1. Despite the immature nature of the puppy's enzyme, cardiovascular, and nervous systems, responses very similar to those in adult animals were seen. Serum glucose and free fatty acids rose during shock and declined with resuscitation as cardiac output returned toward normal. Serum lactate levels rose similarly but continued to rise for a short period after resuscitation and were associated with a further fall in pH consistent with “hidden acidosis.” Only small changes were noted in triglyceride and cholesterol levels. The metabolic responses noted following each of the 3 resuscitation protocols were similar. This study suggests that the immature animal responds to hemorrhagic shock in ways similar to the adult. The better initial hemodynamic response to resuscitation with high-volume lactated Ringer's or lactated Ringer's with 5% albumin was offset by the better buffering capacity of blood resuscitation. All 3 regimens were equally efficacious in providing initial metabolic recovery in this experimental hemorrhagic shock model. Les états de choc s'accompagnent d'une mortalité élevée chez les enfants. En ayant recours à l'expérimentation chez le chiot, les auteurs ont mesuré les modifications métaboliques initiales en réponse au choc hémoragique et à sa correction par 3 agents différents: sang complet (1∶1), solution de Ringer (3∶1) et solution de Ringer enrichie de 5% d'albumine. Malgré la nature immature des enzymes du chiot, du système cardio-vasculaire et du système nerveux, les réponses furent identiques à celles observées chez le chien adulte. Le glucose et les acides gras libres s'élevèrent au cours du choc et s'abaissèrent lors de la réanimation dès que le débit cardiaque revint à la normale. Les niveaux du lactate sanguin s'élevèrent de la même manière mais l'élévation continua pendant une courte période après la réanimation, cependant que le pH s'abaissait, démasquant une “acidose cachée”. Les taux des triglycérides et du cholestérol furent seulement discrètement altérés. Les réponses métaboliques étudiées en fonction des 3 méthodes de réanimation furent identiques. Cette étude suggère que le chiot répond de la même façon que le chien adulte au choc hémorragique et que les 3 méthodes de réanimation employant chacune des agents différents ont une efficacité identique. Los estados shock mantienen una elevada mortalidad en los grupos de edad pediátrica. Utilizando un modelo de shock en cachorros, se determinó la respuesta metabólica inicial al shock hemorrágico y a tres diferentes regimenes de resucitación: sangre total 1∶1 (reemplazo: pérdida), lactato de Ringer 3∶1, y albúmina al 5% en lactato de Ringer 1∶1. A pesar de la naturaleza inmadura de los sistemas enzimático, cardiovascular y nervioso del cachorro, las respuestas fueron muy similares a las observadas en animales adultos. La glucosa sérica y los ácidos grasos libres ascendieron durante el shock y declinarion en la medida que el débito cardiaco retornaba a lo normal. Los niveles de lactato sérico ascendieron en forma similar, pero continuaron su ascenso por un corto periodo de tiempo después de la resucitación, encontrándose asociados con una caida adicional del pH consistente con “acidosis oculta”. Sólo se presentaron cambios leves en los niveles de triglicéridos y colesterol. Las respuestas metabólicas observadas en cada uno de los tres protocolos de resucitación fueron similares. Este estudio sugiere que el animal inmaduro responde al shock hemorrágico de manera similar al adulto. La mejor respuesta hemodinámica inicial a la resucitación con altos volúmenes de lactato de Ringer o con lactato de Ringer con albúmina al 5%, fue compensada con una mejor capacidad de amortiguación observada en la resucitación con sangre. Los tres regimenes fueron igualmente eficaces en lograr la recuperación metabólica inicial en este modelo experimental de shock hemorrágico.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41311/1/268_2005_Article_BF01655348.pd

Multiscale Computing in the Exascale Era

We expect that multiscale simulations will be one of the main high performance computing workloads in the exascale era. We propose multiscale computing patterns as a generic vehicle to realise load balanced, fault tolerant and energy aware high performance multiscale computing. Multiscale computing patterns should lead to a separation of concerns, whereby application developers can compose multiscale models and execute multiscale simulations, while pattern software realises optimized, fault tolerant and energy aware multiscale computing. We introduce three multiscale computing patterns, present an example of the extreme scaling pattern, and discuss our vision of how this may shape multiscale computing in the exascale era

Phase Behavior of Aqueous Na-K-Mg-Ca-CI-NO3 Mixtures: Isopiestic Measurements and Thermodynamic Modeling

A comprehensive model has been established for calculating thermodynamic properties of multicomponent aqueous systems containing the Na{sup +}, K{sup +}, Mg{sup 2+}, Ca{sup 2+}, Cl{sup -}, and NO{sub 3}{sup -} ions. The thermodynamic framework is based on a previously developed model for mixed-solvent electrolyte solutions. The framework has been designed to reproduce the properties of salt solutions at temperatures ranging from the freezing point to 300 C and concentrations ranging from infinite dilution to the fused salt limit. The model has been parameterized using a combination of an extensive literature database and new isopiestic measurements for thirteen salt mixtures at 140 C. The measurements have been performed using Oak Ridge National Laboratory's (ORNL) previously designed gravimetric isopiestic apparatus, which makes it possible to detect solid phase precipitation. Water activities are reported for mixtures with a fixed ratio of salts as a function of the total apparent salt mole fraction. The isopiestic measurements reported here simultaneously reflect two fundamental properties of the system, i.e., the activity of water as a function of solution concentration and the occurrence of solid-liquid transitions. The thermodynamic model accurately reproduces the new isopiestic data as well as literature data for binary, ternary and higher-order subsystems. Because of its high accuracy in calculating vapor-liquid and solid-liquid equilibria, the model is suitable for studying deliquescence behavior of multicomponent salt systems