Create a translational medicine knowledge repository - Research downsizing, mergers and increased outsourcing have reduced the depth of in-house translational medicine expertise and institutional memory at many pharmaceutical and biotech companies: how will they avoid relearning old lessons?

Pharmaceutical industry consolidation and overall research downsizing threatens the ability of companies to benefit from their previous investments in translational research as key leaders with the most knowledge of the successful use of biomarkers and translational pharmacology models are laid off or accept their severance packages. Two recently published books may help to preserve this type of knowledge but much of this type of information is not in the public domain. Here we propose the creation of a translational medicine knowledge repository where companies can submit their translational research data and access similar data from other companies in a precompetitive environment. This searchable repository would become an invaluable resource for translational scientists and drug developers that could speed and reduce the cost of new drug development

Discovery and characterization of small molecule Rac1 inhibitors

Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1. Fluorescence polarization studies indicate that these compounds target the nucleotide-binding site of Rac1. In cells, both compounds blocked Rac1 binding to its effector PAK1 following EGF-induced Rac1 activation in a dose-dependent manner, while showing no inhibition of the closely related Cdc42 and RhoA activity. Furthermore, functional studies indicate that both compounds reduced cell proliferation and migration in a dose-dependent manner in multiple pancreatic cancer cell lines. Additionally, the two compounds suppressed the clonogenic survival of pancreatic cancer cells, while they had no effect on the survival of normal pancreatic ductal cells. These compounds do not share the core structure of the known Rac1 inhibitors and could serve as additional lead compounds to target pancreatic cancers with high Rac1 activity

Spatial patterns and cell surface clusters in perineuronal nets

© 2016 Elsevier B.V.Perineuronal nets (PNN) ensheath GABAergic and glutamatergic synapses on neuronal cell surface in the central nervous system (CNS), have neuroprotective effect in animal models of Alzheimer disease and regulate synaptic plasticity during development and regeneration. Crucial insights were obtained recently concerning molecular composition and physiological importance of PNN but the microstructure of the network remains largely unstudied. Here we used histochemistry, fluorescent microscopy and quantitative image analysis to study the PNN structure in adult mouse and rat neurons from layers IV and VI of the somatosensory cortex. Vast majority of meshes have quadrangle, pentagon or hexagon shape with mean mesh area of 1.29 µm2 in mouse and 1.44 µm2 in rat neurons. We demonstrate two distinct patterns of chondroitin sulfate distribution within a single mesh – with uniform (nonpolar) and node-enriched (polar) distribution of the Wisteria floribunda agglutinin-positive signal. Vertices of the node-enriched pattern match better with local maxima of chondroitin sulfate density as compared to the uniform pattern. PNN is organized into clusters of meshes with distinct morphologies on the neuronal cell surface. Our findings suggest the role for the PNN microstructure in the synaptic transduction and plasticity

sPlotOpen – An environmentally balanced, open-access, global dataset of vegetation plots

Assessing biodiversity status and trends in plant communities is critical for understanding, quantifying and predicting the effects of global change on ecosystems. Vegetation plots record the occurrence or abundance of all plant species co-occurring within delimited local areas. This allows species absences to be inferred, information seldom provided by existing global plant datasets. Although many vegetation plots have been recorded, most are not available to the global research community. A recent initiative, called ?sPlot?, compiled the first global vegetation plot database, and continues to grow and curate it. The sPlot database, however, is extremely unbalanced spatially and environmentally, and is not open-access. Here, we address both these issues by (a) resampling the vegetation plots using several environmental variables as sampling strata and (b) securing permission from data holders of 105 local-to-regional datasets to openly release data. We thus present sPlotOpen, the largest open-access dataset of vegetation plots ever released. sPlotOpen can be used to explore global diversity at the plant community level, as ground truth data in remote sensing applications, or as a baseline for biodiversity monitoring. Main types of variable contained: Vegetation plots (n = 95,104) recording cover or abundance of naturally co-occurring vascular plant species within delimited areas. sPlotOpen contains three partially overlapping resampled datasets (c. 50,000 plots each), to be used as replicates in global analyses. Besides geographical location, date, plot size, biome, elevation, slope, aspect, vegetation type, naturalness, coverage of various vegetation layers, and source dataset, plot-level data also include community-weighted means and variances of 18 plant functional traits from the TRY Plant Trait Database. Spatial location and grain: Global, 0.01?40,000 m². Time period and grain: 1888-2015, recording dates. Major taxa and level of measurement: 42,677 vascular plant taxa, plot-level records.Fil: Sabatini, Francesco Maria. Martin-universität Halle-wittenberg; Alemania. German Centre For Integrative Biodiversity Research (idiv) Halle-jena-leipzig; AlemaniaFil: Lenoir, Jonathan. Université de Picardie Jules Verne; FranciaFil: Hattab, Tarek. Université de Montpellier; FranciaFil: Arnst, Elise Aimee. Manaaki Whenua - Landcare Research; Nueva ZelandaFil: Chytrý, Milan. Masaryk University; República ChecaFil: Giorgis, Melisa Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Vanselow, Kim André. University of Erlangen-Nuremberg; AlemaniaFil: Vásquez Martínez, Rodolfo. Jardín Botánico de Missouri Oxapampa; PerúFil: Vassilev, Kiril. Bulgarian Academy of Sciences; BulgariaFil: Vélez-Martin, Eduardo. ILEX Consultoria Científica; BrasilFil: Venanzoni, Roberto. University of Perugia; ItaliaFil: Vibrans, Alexander Christian. Universidade Regional de Blumenau; BrasilFil: Violle, Cyrille. Paul Valéry Montpellier University; FranciaFil: Virtanen, Risto. German Centre for Integrative Biodiversity Research; AlemaniaFil: von Wehrden, Henrik. Leuphana University of Lüneburg; AlemaniaFil: Wagner, Viktoria. University of Alberta; CanadáFil: Walker, Donald A.. University of Alaska; Estados UnidosFil: Waller, Donald M.. University of Wisconsin-Madison; Estados UnidosFil: Wang, Hua-Feng. Hainan University; ChinaFil: Wesche, Karsten. Senckenberg Museum of Natural History Görlitz; Alemania. Technische Universität Dresden; AlemaniaFil: Whitfeld, Timothy J. S.. University of Minnesota; Estados UnidosFil: Willner, Wolfgang. University of Vienna; AustriaFil: Wiser, Susan K.. Manaaki Whenua. Landcare Research; Nueva ZelandaFil: Wohlgemuth, Thomas. Swiss Federal Institute for Forest, Snow and Landscape Research; SuizaFil: Yamalov, Sergey. Russian Academy of Sciences; RusiaFil: Zobel, Martin. University of Tartu; EstoniaFil: Bruelheide, Helge. German Centre for Integrative Biodiversity Research; Alemani

Declining mortality following acute myocardial infarction in the Department of Veterans Affairs Health Care System

<p>Abstract</p> <p>Background</p> <p>Mortality from acute myocardial infarction (AMI) is declining worldwide. We sought to determine if mortality in the Veterans Health Administration (VHA) has also been declining.</p> <p>Methods</p> <p>We calculated 30-day mortality rates between 2004 and 2006 using data from the VHA External Peer Review Program (EPRP), which entails detailed abstraction of records of all patients with AMI. To compare trends within VHA with other systems of care, we estimated relative mortality rates between 2000 and 2005 for all males 65 years and older with a primary diagnosis of AMI using administrative data from the VHA Patient Treatment File and the Medicare Provider Analysis and Review (MedPAR) files.</p> <p>Results</p> <p>Using EPRP data on 11,609 patients, we observed a statistically significant decline in adjusted 30-day mortality following AMI in VHA from 16.3% in 2004 to 13.9% in 2006, a relative decrease of 15% and a decrease in the odds of dying of 10% per year (p = .011). Similar declines were found for in-hospital and 90-day mortality.</p> <p>Based on administrative data on 27,494 VHA patients age 65 years and older and 789,400 Medicare patients, 30-day mortality following AMI declined from 16.0% during 2000-2001 to 15.7% during 2004-June 2005 in VHA and from 16.7% to 15.5% in private sector hospitals. After adjusting for patient characteristics and hospital effects, the overall relative odds of death were similar for VHA and Medicare (odds ratio 1.02, 95% C.I. 0.96-1.08).</p> <p>Conclusion</p> <p>Mortality following AMI within VHA has declined significantly since 2003 at a rate that parallels that in Medicare-funded hospitals.</p

Gene-enhanced tissue engineering for dental hard tissue regeneration: (2) dentin-pulp and periodontal regeneration

Potential applications for gene-based tissue engineering therapies in the oral and maxillofacial complex include the delivery of growth factors for periodontal regeneration, pulp capping/dentin regeneration, and bone grafting of large osseous defects in dental and craniofacial reconstruction. Part 1 reviewed the principals of gene-enhanced tissue engineering and the techniques of introducing DNA into cells. This manuscript will review recent advances in gene-based therapies for dental hard tissue regeneration, specifically as it pertains to dentin regeneration/pulp capping and periodontal regeneration

Identification of Bayesian posteriors for coefficients of chaos expansions

International audienceThis article is concerned with the identification of probabilistic characterizations of random variables and fields from experimental data. The data used for the identification consist of measurements of several realizations of the uncertain quantities that must be characterized. The random variables and fields are approximated by a polynomial chaos expansion, and the coefficients of this expansion are viewed as unknown parameters to be identified. It is shown how the Bayesian paradigm can be applied to formulate and solve the inverse problem. The estimated polynomial chaos coefficients are hereby themselves characterized as random variables whose probability density function is the Bayesian posterior. This allows to quantify the impact of missing experimental information on the accuracy of the identified coefficients, as well as on subsequent predictions. An illustration in stochastic aeroelastic stability analysis is provided to demonstrate the proposed methodology

Identification de modèles probabilistes non paramétriques

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