Temperature does matter-an additional dimension in kinase inhibitor development

Kinase inhibitors are a major focus in drug development. Recent work shows that subtle temperature changes in the physiologically relevant temperature range can dramatically alter kinase activity and specificity. We argue that temperature is an essential factor that should be considered in inhibitor screening campaigns. In many cases, high-throughput screening is performed at room temperature or 30 degrees C, which may lead to many false positives and false negatives when evaluating potential inhibitors in the physiological temperature range. As one example, we discuss a new antimalaria compound that inhibits the highly temperature-sensitive kinase CLK3 (CDC2-like kinase 3) fromPlasmodium falciparum

The international transfer of wind power technology to Brazil and China

Enhancing developing countries' access to climate technologies is an important contribution to effectively addressing climate change at the global level. In this study, we analyses the drivers and barriers for the transfer of wind power technology from the perspective of multinational technology suppliers. The findings and comparison of two case studies on the transfer of wind power technology to China and Brazil are presented, focusing on which transfer channels were chosen and why, as well as what kind of impact this choice had on the local diffusion of the transferred technology. While the case study on China arrives at the conclusion that a variety of transfer channels are used and hybrid governance modes, such as licensing and joint ventures, are favored in particular, the Brazilian case revealed that transfers within multinational companies to their subsidiaries are by far the dominant transfer channel. Both case studies revealed that government restrictions have a considerable impact on the choice of transfer channel, which is due both to the strong involvement of the receiving countries' governments in market creation activities for renewable energies and to their control over energy markets and infrastructures. [...

Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Mammalian body temperature oscillates with the time of the day and is altered in diverse pathological conditions. We recently identified a body temperature‐sensitive thermometer‐like kinase, which alters SR protein phosphorylation and thereby globally controls alternative splicing (AS). AS can generate unproductive variants which are recognized and degraded by diverse mRNA decay pathways—including nonsense‐mediated decay (NMD). Here we show extensive coupling of body temperature‐controlled AS to mRNA decay, leading to global control of temperature‐dependent gene expression (GE). Temperature‐controlled, decay‐inducing splicing events are evolutionarily conserved and pervasively found within RNA‐binding proteins, including most SR proteins. AS‐coupled poison exon inclusion is essential for rhythmic GE of SR proteins and has a global role in establishing temperature‐dependent rhythmic GE profiles, both in mammals under circadian body temperature cycles and in plants in response to ambient temperature changes. Together, these data identify body temperature‐driven AS‐coupled mRNA decay as an evolutionary ancient, core clock‐independent mechanism to generate rhythmic GE

Rezensionen

Rezension zu: 1) Dinkelaker, Jörg; Herrle, Matthias: Erziehungswissenschaftliche Videographie: eine Einführung. Wiesbaden: VS Verl. f. Sozialwissenschaften 2009. ISBN 978-3-531-16863-0. 2) Hugger, Kai-Uwe; Walber, Markus (Hg.): Digitale Lernwelten: Konzepte, Beispiele und Perspektiven. Wiesbaden: VS Verl. f. Sozialwissenschaften 2010. ISBN 978-3-531-16365-9. 3) Lenk, Christel: Freiberufler in der Weiterbildung: empirische Studie am Beispiel Hessen. Bielefeld: W. Bertelsmann Verl. 2010. ISBN 978-7639-3348-8 (Print), ISBN 978-7639-3348-5 (E-Book). 4) Merriam, Sharan B. u.a.: Non-Western Perspectives on Learning and Knowing. Malabar: Krieger Publ. Company 2007. ISBN 1-57524-280-X. 5) Meueler, Erhard: Die Türen des Käfigs: subjektorientierte Erwachsenenbildung. Baltmannsweiler: Schneider Verl. Hohengehren 2009. ISBN 978-3-8340-0527-4. 6) Neuber, Nils (Hg.): Informelles Lernen im Sport – Beiträge zur allgemeinen Bildungsdebatte. Wiesbaden: VS Verl. f. Sozialwissenschaften 2010. ISBN 978-3-531-17009-1. 7) Widany, Sarah: Lernen Erwachsener im Bildungsmonitoring: Operationalisierung der Weiterbildungsbeteiligung in empirischen Studien. Wiesbaden: VS Verl. f. Sozialwissenschaften 2009. ISBN 978-3-531-16896-8. 8) Zimmermann, Hildegard: Weiterbildung im späteren Erwerbsleben: empirische Befunde und Gestaltungsvorschläge. Bielefeld: W. Bertelsmann Verl. 2009. ISBN 978-3-7639-1132-4

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms