Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia

Measurement invariance of the patient health questionnaire-9 (PHQ-9) depression screener in U.S. adults across sex, race/ethnicity, and education level: NHANES 2005–2016

Background: Despite its popularity, little is known about the measurement invariance of the Patient Health Questionnaire-9 (PHQ-9) across U.S. sociodemographic groups. Use of a screener shown not to possess measurement invariance could result in under-detection/treatment of depression, potentially exacerbating sociodemographic disparities in depression. Therefore, we assessed the factor structure and measurement invariance of the PHQ-9 across major U.S. sociodemographic groups. Methods: U.S. population representative data came from the 2005–2016 National Health and Nutrition Examination Survey (NHANES) cohorts We conducted a measurement invariance analysis of 31,366 respondents across sociodemographic factors of sex, race/ethnicity, and education level. Results: Considering results of single-group confirmatory factor analyses (CFAs), depression theory, and research utility, we justify a two-factor structure for the PHQ-9 consisting of a cognitive/affective factor and a somatic factor (RMSEA=0.034, TLI=0.985, CFI=0.989). Based on multiple-group CFAs testing configural, scalar, and strict factorial invariance, we determined that invariance held for sex, race/ethnicity, and education level groups, as all models demonstrated close model fit (RMSEA=0.025–0.025, TLI=0.985–0.992, CFI=0.986–0.991). Finally, for all steps ΔCFI was < −0.004, and ΔRMSEA was < 0.01. Conclusions: We demonstrate that the PHQ-9 is acceptable to use in major U.S. sociodemographic groups and allows for meaningful comparisons in total, cognitive/affective, and somatic depressive symptoms across these groups, extending its use to the community. This knowledge is timely as medicine moves towards alternative payment models emphasizing high-quality and cost-efficient care, which will likely incentivize behavioral and population health efforts. We also provide a consistent, evidence-based approach for calculating PHQ-9 subscale scores

ZnO and MgZnO Nanocrystalline Flexible Films: Optical and Material Properties

An emerging material for flexible UV applications is MgxZn1−xO which is capable of tunable bandgap and luminescence in the UV range of ~3.4 eV–7.4 eV depending on the composition x. Studies on the optical and material characteristics of ZnO and Mg0.3Zn0.7O nanocrystalline flexible films are presented. The analysis indicates that the ZnO and Mg0.3Zn0.7O have bandgaps of 3.34 eV and 4.02 eV, respectively. The photoluminescence (PL) of the ZnO film was found to exhibit a structural defect-related emission at ~3.316 eV inherent to the nanocrystalline morphology. The PL of the Mg0.3Zn0.7O film exhibits two broad peaks at 3.38 eV and at 3.95 eV that are discussed in terms of the solubility limit of the ZnO-MgO alloy system. Additionally, external deformation of the film did not have a significant impact on its properties as indicated by the Raman LO-mode behavior, making these films attractive for UV flexible applications

Cerebral edema in intracerebral hemorrhage : pathogenesis, natural history and potential treatments from translation to clinical trials

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.Peer reviewedPublisher PD

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure

We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytokine gene expression. Energy expenditure and brown adipose tissue metabolism in Asxl2ΔLysM mice were protected from the suppressive effects of HFD, a phenomenon associated with relatively increased catecholamines likely due to their suppressed degradation by macrophages. White adipose tissue of HFD-fed Asxl2ΔLysM mice also exhibited none of the pathological remodeling extant in their control counterparts. Suppression of macrophage Asxl2 expression, via nanoparticle-based siRNA delivery, prevented HFD-induced obesity. Thus, ASXL2 controlled the response of macrophages to dietary factors to regulate metabolic homeostasis, suggesting modulation of the cells\u27 inflammatory phenotype may impact obesity and its complications

Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser.

G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a ∼20° rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology

Signal Transmission in the Auditory System

Contains table of contents for Section 3 and reports on four research projects.National Institutes of Health Grant R01 DC00194National Institutes of Health Grant P01 DC00119National Science Foundation Grant IBN 96-04642W.M. Keck Foundation Career Development ProfessorshipNational Institutes of Health Grant R01 DC00238Thomas and Gerd Perkins Award ProfessorshipAlfred P Sloan Foundation Instrumentation GrantJohn F. and Virginia B. Taplin Award in Health Sciences and TechnologyNational Institutes of Health/National Institute of Deafness and Other Communication DisordersNational Institutes of Health/National Institute of Deafness and Other Communication Disorders Grant PO1 DC0011

Nanoscale Electronic Inhomogeneity in In2Se3 Nanoribbons Revealed by Microwave Impedance Microscopy

Driven by interactions due to the charge, spin, orbital, and lattice degrees of freedom, nanoscale inhomogeneity has emerged as a new theme for materials with novel properties near multiphase boundaries. As vividly demonstrated in complex metal oxides and chalcogenides, these microscopic phases are of great scientific and technological importance for research in high-temperature superconductors, colossal magnetoresistance effect, phase-change memories, and domain switching operations. Direct imaging on dielectric properties of these local phases, however, presents a big challenge for existing scanning probe techniques. Here, we report the observation of electronic inhomogeneity in indium selenide (In2Se3) nanoribbons by near-field scanning microwave impedance microscopy. Multiple phases with local resistivity spanning six orders of magnitude are identified as the coexistence of superlattice, simple hexagonal lattice and amorphous structures with 100nm inhomogeneous length scale, consistent with high-resolution transmission electron microscope studies. The atomic-force-microscope-compatible microwave probe is able to perform quantitative sub-surface electronic study in a noninvasive manner. Finally, the phase change memory function in In2Se3 nanoribbon devices can be locally recorded with big signal of opposite signs.Comment: 11 pages, 4 figure

Enhanced electric conductivity at ferroelectric vortex cores in BiFeO3

In many large ensembles, the property of the system as a whole cannot be understood from studying the individual entities alone ¿ these ensembles can be made up by neurons in the brain, transport users in traffic networks or data packages in the Internet. The past decade has seen important progress in our fundamental understanding of what such seemingly disparate 'complex systems' have in common; some of these advances are surveyed here

Developing a Series of AI Challenges for the United States Department of the Air Force

Through a series of federal initiatives and orders, the U.S. Government has been making a concerted effort to ensure American leadership in AI. These broad strategy documents have influenced organizations such as the United States Department of the Air Force (DAF). The DAF-MIT AI Accelerator is an initiative between the DAF and MIT to bridge the gap between AI researchers and DAF mission requirements. Several projects supported by the DAF-MIT AI Accelerator are developing public challenge problems that address numerous Federal AI research priorities. These challenges target priorities by making large, AI-ready datasets publicly available, incentivizing open-source solutions, and creating a demand signal for dual use technologies that can stimulate further research. In this article, we describe these public challenges being developed and how their application contributes to scientific advances