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PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB versus diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103Q(Exon1)–EGFP expression. Quantitative image analysis indicated that 80–90% of this mHtt protein initially appears as “diffuse” signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse versus IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron–derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.

Remote sensing observations suggest Greenland ice sheet (GrIS) albedo has declined since 2001, even in the dry snow zone. We seek to explain the apparent dry snow albedo decline. We analyze samples representing 2012–2014 snowfall across NW Greenland for black carbon and dust light-absorbing impurities (LAI) and model their impacts on snow albedo. Albedo reductions due to LAI are small, averaging 0.003, with episodic enhancements resulting in reductions of 0.01–0.02. No significant increase in black carbon or dust concentrations relative to recent decades is found. Enhanced deposition of LAI is not, therefore, causing significant dry snow albedo reduction or driving melt events. Analysis of Collection 5 Moderate Resolution Imaging Spectroradiometer (MODIS) surface reflectance data indicates that the decline and spectral shift in dry snow albedo contains important contributions from uncorrected Terra sensor degradation. Though discrepancies are mostly below the stated accuracy of MODIS products, they will require revisiting some prior conclusions with C6 data.

The MuSiC system has been widely used over the last 5 years by the scientific community for analyzing genomic data across the cancer spectrum. However, the desired scope of analysis has now increased dramatically, due to advances in instrumentation and experimental methods, vastly expanding sample availability, and the general appreciation of many newfound subtleties of the cancer initiation and progression processes themselves. We have extended MuSiC in several ways to address both new requirements and several long-standing issues that have not been manageable with any current analysis system. Here, we focus on three aspects. First, to answer the growing need for noncoding analysis, MuSiC2 extends the common idea of a “significantly mutated gene” model to one of “significantly mutated regions,” including the attendant tasks of interfacing to ENCODE, calculating region-appropriate background mutation rates (BMRs) for hypothesis testing, etc. Second, to address the statistical artifacts realized with most analysis software, we have designed two new filters: one for longer-than-average genes and another for cancer types having elevated BMRs, both scenarios of which typically show appreciably inflated false-positive rates because of upwardly biased passenger mutation counts. Finally, we describe a number of new visualization capabilities designed to give the investigator new interpretive capabilities, including for complex genomic rearrangements that may stem from viral integration. Taken together with improved programmatic efficiencies, the new MuSiC2 system should be useful for discovering and visualizing coding and noncoding cancer drivers in pediatric and adult cancers. Citation Format: Matthew A. Wyczalkowski, Matthew H. Bailey, Carolyn Lou, Felix Hu, Justin Y. Chen, Prag Batra, Michael D. McLellan, Li Ding, Michael C. Wendl. The MuSiC2 system for discovery and visualization of coding and noncoding cancer drivers [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B11.