Prevention of Apoptosis by Mitochondrial Phosphatase PGAM5 in the Mushroom Body Is Crucial for Heat Shock Resistance in Drosophila melanogaster

The heat shock (HS) response is essential for survival of all organisms. Although the machinery of the HS response has been extensively investigated at the cellular level, it is poorly understood at the level of the organism. Here, we show the crucial role of the mushroom body (MB) in the HS response in Drosophila. Null mutants of the mitochondrial phosphatase Drosophila PGAM5 (dPGAM5) exhibited increased vulnerability to HS, which was reversed by MB-specific expression of the caspase inhibitor p35, and similar vulnerability was induced in wild-type flies by knockdown of MB dPGAM5. Elimination of the MB did not affect the HS response of wild-type flies, but did increase the resistance of dPGAM5-deficient flies to HS. Thus, the MB may possess an apoptosis-dependent toxic function, the suppression of which by dPGAM5 appears to be crucial for HS resistance

GW8510 Increases Insulin Expression in Pancreatic Alpha Cells through Activation of p53 Transcriptional Activity

Background: Expression of insulin in terminally differentiated non-beta cell types in the pancreas could be important to treating type-1 diabetes. Previous findings led us to hypothesize involvement of kinase inhibition in induction of insulin expression in pancreatic alpha cells. Methodology/Principal Findings: Alpha (αTC1.6) cells and human islets were treated with GW8510 and other small-molecule inhibitors for up to 5 days. Alpha cells were assessed for gene- and protein-expression levels, cell-cycle status, promoter occupancy status by chromatin immunoprecipitation (ChIP), and p53-dependent transcriptional activity. GW8510, a putative CDK2 inhibitor, up-regulated insulin expression in mouse alpha cells and enhanced insulin secretion in dissociated human islets. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested up-regulation of the p53 pathway. Accordingly, the compound increased p53 transcriptional activity and expression levels of p53 transcriptional targets. A predicted p53 response element in the promoter region of the mouse Ins2 gene was verified by chromatin immunoprecipitation (ChIP). Further, inhibition of Jun N-terminal kinase (JNK) and p38 kinase activities suppressed insulin induction by GW8510. Conclusions/Significance: The induction of Ins2 by GW8510 occurred through p53 in a JNK- and p38-dependent manner. These results implicate p53 activity in modulation of Ins2 expression levels in pancreatic alpha cells, and point to a potential approach toward using small molecules to generate insulin in an alternative cell type.Chemistry and Chemical BiologyMolecular and Cellular Biolog

Fundamental Physics with Brown Dwarfs: The Mass-Radius Relation

To be published in the Decadal Survey on Astronomy and Astrophysics (Astro2020)The lowest-mass stars, brown dwarfs and giant exoplanets span a minimum in the mass-radius relationship that probes the fundamental physics of extreme states of matter, magnetism, and fusion. This White Paper outlines scientific opportunities and the necessary resources for modeling and measuring the mass-radius relationship in this regime

Towards the improved treatment of generalization of knowledge claims in IS research : drawing general conclusions from samples

This paper presents a framework for justifying generalization in information systems (IS) research. First, using evidence from an analysis of two leading IS journals, we show that the treatment of generalization in many empirical papers in leading IS research journals is unsatisfactory. Many quantitative studies need clearer definition of populations and more discussion of the extent to which &lsquo;significant&rsquo; statistics and use of non-probability sampling affect support for their knowledge claims. Many qualitative studies need more discussion of boundary conditions for their sample-based general knowledge claims. Second, the proposed new framework is presented. It defines eight alternative logical pathways for justifying generalizations in IS research. Three key concepts underpinning the framework are the need for researcher judgment when making any claim about the likely truth of sample-based knowledge claims in other settings; the importance of sample representativeness and its assessment in terms of the knowledge claim of interest; and the desirability of integrating a study&rsquo;s general knowledge claims with those from prior research. Finally, we show how the framework may be applied by researchers and reviewers. Observing the pathways in the framework has potential to improve both research rigour and practical relevance for IS research.<br /