Showing papers by "Yale University published in 2014"
TL;DR: Evaluated data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment, as well as across multiple cancer types.
Abstract: The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
4,227 citations
TL;DR: Black phosphorus (BP), the most stable allotrope of phosphorus with strong intrinsic in-plane anisotropy, is reintroduced to the layered-material family and shows great potential for thin-film electronics, infrared optoelectronics and novel devices in which anisotropic properties are desirable.
Abstract: The applications of graphene and transition metal dichalcogenides in electronics are limited by their zero-bandgap and low mobility, respectively. Here, the authors demonstrate the potential of an emerging layered material—black phosphorous—for thin film electronics and infrared optoelectronics.
2,983 citations
TL;DR: This paper presents a generic framework for permutation inference for complex general linear models (glms) when the errors are exchangeable and/or have a symmetric distribution, and shows that, even in the presence of nuisance effects, these permutation inferences are powerful while providing excellent control of false positives in a wide range of common and relevant imaging research scenarios.
2,756 citations
TL;DR: The status, threats, and ecological importance of the 31 largest mammalian carnivores globally are reviewed and a Global Large Carnivore Initiative is proposed to coordinate local, national, and international research, conservation, and policy.
Abstract: Large carnivores face serious threats and are experiencing massive declines in their populations and geographic ranges around the world. We highlight how these threats have affected the conservation status and ecological functioning of the 31 largest mammalian carnivores on Earth. Consistent with theory, empirical studies increasingly show that large carnivores have substantial effects on the structure and function of diverse ecosystems. Significant cascading trophic interactions, mediated by their prey or sympatric mesopredators, arise when some of these carnivores are extirpated from or repatriated to ecosystems. Unexpected effects of trophic cascades on various taxa and processes include changes to bird, mammal, invertebrate, and herpetofauna abundance or richness; subsidies to scavengers; altered disease dynamics; carbon sequestration; modified stream morphology; and crop damage. Promoting tolerance and coexistence with large carnivores is a crucial societal challenge that will ultimately determine the fate of Earth's largest carnivores and all that depends upon them, including humans.
2,441 citations
TL;DR: In this article, the optical properties and applications of various two-dimensional materials including transition metal dichalcogenides are reviewed with an emphasis on nanophotonic applications, and two different approaches for enhancing their interactions with light: through their integration with external photonic structures, and through intrinsic polaritonic resonances.
Abstract: The optical properties of graphene and emerging two-dimensional materials including transition metal dichalcogenides are reviewed with an emphasis on nanophotonic applications. Two-dimensional materials exhibit diverse electronic properties, ranging from insulating hexagonal boron nitride and semiconducting transition metal dichalcogenides such as molybdenum disulphide, to semimetallic graphene. In this Review, we first discuss the optical properties and applications of various two-dimensional materials, and then cover two different approaches for enhancing their interactions with light: through their integration with external photonic structures, and through intrinsic polaritonic resonances. Finally, we present a narrow-bandgap layered material — black phosphorus — that serendipitously bridges the energy gap between the zero-bandgap graphene and the relatively large-bandgap transition metal dichalcogenides. The plethora of two-dimensional materials and their heterostructures, together with the array of available approaches for enhancing the light–matter interaction, offers the promise of scientific discoveries and nanophotonics technologies across a wide range of the electromagnetic spectrum.
2,414 citations
TL;DR: It is estimated that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.
2,124 citations
TL;DR: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations, and responses were durable and persisted after drug discontinuation.
Abstract: Purpose Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients and Methods Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Results Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Sev...
2,036 citations
TL;DR: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 andPD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade.
Abstract: Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design: Patients ( N = 41) with melanoma, non–small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti–PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells ( P Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade. Clin Cancer Res; 20(19); 5064–74. ©2014 AACR .
1,985 citations
Case Western Reserve University1, Imperial College London2, South Dakota School of Mines and Technology3, University of Maryland, College Park4, Yale University5, Lawrence Livermore National Laboratory6, University of South Dakota7, University of California, Santa Barbara8, Brown University9, University of Coimbra10, University of Edinburgh11, University of Rochester12, Lawrence Berkeley National Laboratory13, University of California, Davis14, University College London15, University of California, Berkeley16, Texas A&M University17, Harvard University18
TL;DR: The first WIMP search data set is reported, taken during the period from April to August 2013, presenting the analysis of 85.3 live days of data, finding that the LUX data are in disagreement with low-mass W IMP signal interpretations of the results from several recent direct detection experiments.
Abstract: The Large Underground Xenon (LUX) experiment is a dual-phase xenon time-projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota). The LUX cryostat was filled for the first time in the underground laboratory in February 2013. We report results of the first WIMP search data set, taken during the period from April to August 2013, presenting the analysis of 85.3 live days of data with a fiducial volume of 118 kg. A profile-likelihood analysis technique shows our data to be consistent with the background-only hypothesis, allowing 90% confidence limits to be set on spin-independent WIMP-nucleon elastic scattering with a minimum upper limit on the cross section of 7.6 × 10(-46) cm(2) at a WIMP mass of 33 GeV/c(2). We find that the LUX data are in disagreement with low-mass WIMP signal interpretations of the results from several recent direct detection experiments.
1,962 citations
New York University1, Nathan Kline Institute for Psychiatric Research2, MIND Institute3, Katholieke Universiteit Leuven4, University of Utah5, Yale University6, University of California, Los Angeles7, Massachusetts Institute of Technology8, Trinity College, Dublin9, Carnegie Mellon University10, Ben-Gurion University of the Negev11, Ludwig Maximilian University of Munich12, Oregon Health & Science University13, California Institute of Technology14, Indiana University15, San Diego State University16, University of Groningen17, Netherlands Institute for Neuroscience18, University of Wisconsin-Madison19, Cornell University20, University of Pittsburgh21, Stanford University22, University of Michigan23, Kennedy Krieger Institute24, Johns Hopkins University25
TL;DR: W Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity.
Abstract: Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
TL;DR: The pathway of ncRNA research is described, where every established "rule" seems destined to be overturned.
TL;DR: It is shown that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages and this effect is mediated by hypoxia-inducible factor 1α (HIF1α).
Abstract: Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.
TL;DR: By evaluating the local resolution of single-particle reconstructions and subtomogram averages for four example data sets, this work reports variable resolution across a 4- to 40-Å range.
Abstract: We propose a definition of local resolution for three-dimensional electron cryo-microscopy (cryo-EM) density maps that uses local sinusoidal features. Our algorithm has no free parameters and is applicable to other imaging modalities, including tomography. By evaluating the local resolution of single-particle reconstructions and subtomogram averages for four example data sets, we report variable resolution across a 4- to 40-A range.
TL;DR: Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.
Abstract: Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.
Nicholas J Kassebaum1, Amelia Bertozzi-Villa1, Megan Coggeshall1, Katya Anne Shackelford1 +349 more•Institutions (179)
TL;DR: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015, with evidence of continued acceleration in the MMR, and MMR was highest in the oldest age groups in both 1990 and 2013.
TL;DR: It is demonstrated that the short-chain fatty acid n-butyrate, which is secreted in high amounts by commensal bacteria, can modulate the function of intestinal macrophages, the most abundant immune cell type in the lamina propria, and elucidate a pathway in which the host may maintain tolerance to intestinal microbiota by rendering lamina Propria macrophage hyporesponsive to commensals through the down-regulation of proinflammatory effectors.
Abstract: Given the trillions of microbes that inhabit the mammalian intestines, the host immune system must constantly maintain a balance between tolerance to commensals and immunity against pathogens to avoid unnecessary immune responses against otherwise harmless bacteria. Misregulated responses can lead to inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. The mechanisms by which the immune system maintains this critical balance remain largely undefined. Here, we demonstrate that the short-chain fatty acid n-butyrate, which is secreted in high amounts by commensal bacteria, can modulate the function of intestinal macrophages, the most abundant immune cell type in the lamina propria. Treatment of macrophages with n-butyrate led to the down-regulation of lipopolysaccharide-induced proinflammatory mediators, including nitric oxide, IL-6, and IL-12, but did not affect levels of TNF-α or MCP-1. These effects were independent of toll-like receptor signaling and activation of G-protein-coupled receptors, two pathways that could be affected by short-chain fatty acids. In this study, we provide several lines of evidence that suggest that these effects are due to the inhibition of histone deacetylases by n-butyrate. These findings elucidate a pathway in which the host may maintain tolerance to intestinal microbiota by rendering lamina propria macrophages hyporesponsive to commensal bacteria through the down-regulation of proinflammatory effectors.
TL;DR: In this paper, inspired by the plenary panel at the 2013 meeting of the International Society for Traumatic Stress Studies, Steven Southwick and multidisciplinary panelists tackle some of the most pressing current questions in the field of resilience research including how do the authors define resilience, what are the most important determinants of resilience, and how are new technologies informing the science of resilience?
Abstract: In this paper, inspired by the plenary panel at the 2013 meeting of the International Society for Traumatic Stress Studies, Dr. Steven Southwick (chair) and multidisciplinary panelists Drs. George Bonanno, Ann Masten, Catherine Panter-Brick, and Rachel Yehuda tackle some of the most pressing current questions in the field of resilience research including: (1) how do we define resilience, (2) what are the most important determinants of resilience, (3) how are new technologies informing the science of resilience, and (4) what are the most effective ways to enhance resilience? These multidisciplinary experts provide insight into these difficult questions, and although each of the panelists had a slightly different definition of resilience, most of the proposed definitions included a concept of healthy, adaptive, or integrated positive functioning over the passage of time in the aftermath of adversity. The panelists agreed that resilience is a complex construct and it may be defined differently in the context of individuals, families, organizations, societies, and cultures. With regard to the determinants of resilience, there was a consensus that the empirical study of this construct needs to be approached from a multiple level of analysis perspective that includes genetic, epigenetic, developmental, demographic, cultural, economic, and social variables. The empirical study of determinates of resilience will inform efforts made at fostering resilience, with the recognition that resilience may be enhanced on numerous levels (e.g., individual, family, community, culture). Keywords: Resilience; stress; trauma; post-traumatic stress disorder Responsible Editors: Ananda Amstadter, Virginia Institute for Psychiatric and Behavioral Genetics, VA, USA; Nicole Nugent, Warren Alpert Medical School of Brown University, RI, USA. This paper is part of the Special Issue: Resilience and Trauma . More papers from this issue can be found at http://www.eurojnlofpsychotraumatol.net (Published: 1 October 2014) Citation: European Journal of Psychotraumatology 2014, 5 : 25338 - http://dx.doi.org/10.3402/ejpt.v5.25338
TL;DR: A meta-analysis of 48 neuroimaging studies of reappraisal suggests that reappRAisal involves the use of cognitive control to modulate semantic representations of an emotional stimulus, and these altered representations in turn attenuate activity in the amygdala.
Abstract: In recent years, an explosion of neuroimaging studies has examined cognitive reappraisal, an emotion regulation strategy that involves changing the way one thinks about a stimulus in order to change its affective impact Existing models broadly agree that reappraisal recruits frontal and parietal control regions to modulate emotional responding in the amygdala, but they offer competing visions of how this is accomplished One view holds that control regions engage ventromedial prefrontal cortex (vmPFC), an area associated with fear extinction, that in turn modulates amygdala responses An alternative view is that control regions modulate semantic representations in lateral temporal cortex that indirectly influence emotion-related responses in the amygdala Furthermore, while previous work has emphasized the amygdala, whether reappraisal influences other regions implicated in emotional responding remains unknown To resolve these questions, we performed a meta-analysis of 48 neuroimaging studies of reappraisal, most involving downregulation of negative affect Reappraisal consistently 1) activated cognitive control regions and lateral temporal cortex, but not vmPFC, and 2) modulated the bilateral amygdala, but no other brain regions This suggests that reappraisal involves the use of cognitive control to modulate semantic representations of an emotional stimulus, and these altered representations in turn attenuate activity in the amygdala
Pennsylvania State University1, University of California, San Diego2, Stanford University3, University of Washington4, University of Michigan5, New College of Florida6, Florida State University7, Cold Spring Harbor Laboratory8, California Institute of Technology9, University of Vienna10, Emory University11, Fred Hutchinson Cancer Research Center12, Massachusetts Institute of Technology13, Broad Institute14, University of California, Irvine15, University of California, Santa Cruz16, University of California, San Francisco17, Yale University18, University of Florida19, Johns Hopkins University20, University College London21, University of Oxford22, Cornell University23, Memorial Sloan Kettering Cancer Center24, Harvard University25, University of Iowa26, Yeshiva University27, University of Pennsylvania28, Washington University in St. Louis29, National Institutes of Health30, University of North Carolina at Chapel Hill31
TL;DR: The mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types as mentioned in this paper.
Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases
North Shore-LIJ Health System1, University of Colorado Denver2, Karolinska Institutet3, Great Ormond Street Hospital4, Johns Hopkins University School of Medicine5, University of South Florida6, Harvard University7, University of Washington8, University of Toronto9, Emory University10, Yale University11
TL;DR: An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children intended for use by primary care and subspecialty providers who care for immuno-compromised patients.
Abstract: An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.
Christopher P. Ahn1, Rachael M. Alexandroff2, Carlos Allende Prieto3, Carlos Allende Prieto4 +272 more•Institutions (69)
TL;DR: The 10th public data release (DR10) from the Sloan Digital Sky Survey (SDSS-III) was released in 2013 as mentioned in this paper, which includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopy data from Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July.
Abstract: The Sloan Digital Sky Survey (SDSS) has been in operation since 2000 April. This paper presents the Tenth Public Data Release (DR10) from its current incarnation, SDSS-III. This data release includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July. The APOGEE instrument is a near-infrared R ~ 22,500 300 fiber spectrograph covering 1.514-1.696 μm. The APOGEE survey is studying the chemical abundances and radial velocities of roughly 100,000 red giant star candidates in the bulge, bar, disk, and halo of the Milky Way. DR10 includes 178,397 spectra of 57,454 stars, each typically observed three or more times, from APOGEE. Derived quantities from these spectra (radial velocities, effective temperatures, surface gravities, and metallicities) are also included. DR10 also roughly doubles the number of BOSS spectra over those included in the Ninth Data Release. DR10 includes a total of 1,507,954 BOSS spectra comprising 927,844 galaxy spectra, 182,009 quasar spectra, and 159,327 stellar spectra selected over 6373.2 deg2.
Harvard University1, National Institutes of Health2, Medical College of Wisconsin3, University of Washington4, University of Michigan5, Stanford University6, University of Geneva7, Wellcome Trust Sanger Institute8, Washington University in St. Louis9, University of Chicago10, Yale University11, Duke University12, Boston Children's Hospital13, Baylor College of Medicine14, Lawrence Berkeley National Laboratory15, Johns Hopkins University16, University of Pennsylvania17, Broad Institute18
TL;DR: The key challenges of assessing sequence variants in human disease are discussed, integrating both gene-level and variant-level support for causality and guidelines for summarizing confidence in variant pathogenicity are proposed.
Abstract: The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
TL;DR: A global species-level compilation of key attributes for all 9993 and 5400 extant bird and mammal species derived from key literature sources enables a much finer distinction of species' foraging ecology than typical categorical guild assignments allow.
Abstract: Species are characterized by physiological, behavioral, and ecological attributes that are all subject to varying evolutionary and ecological constraints and jointly determine species' role and function in ecosystems. Attributes such as diet, foraging strata, foraging time, and body size, in particular, characterize a large portion of the “Eltonian” niches of species. Here we present a global species-level compilation of these key attributes for all 9993 and 5400 extant bird and mammal species derived from key literature sources. Global handbooks and monographs allowed the consistent sourcing of attributes for most species. For diet and foraging stratum we followed a defined protocol to translate the verbal descriptions into standardized, semiquantitative information about relative importance of different categories. Together with body size (continuous) and activity time (categorical) this enables a much finer distinction of species' foraging ecology than typical categorical guild assignments allow. Attri...
TL;DR: An anatomically comprehensive atlas of the mid-gestational human brain is described, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions.
Abstract: The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
University of Tokyo1, University of Wisconsin-Madison2, University of Toronto3, University of Kentucky4, University of Texas at Austin5, University of Washington6, University of St Andrews7, University of Portsmouth8, European Southern Observatory9, University of Nottingham10, National Autonomous University of Mexico11, University of Pittsburgh12, University of Cambridge13, New Mexico State University14, Carnegie Institution for Science15, University of Sydney16, New York University17, University of Utah18, University of Oxford19, University of California, Santa Cruz20, Max Planck Society21, Claude Bernard University Lyon 122, École normale supérieure de Lyon23, Texas Christian University24, University of Iowa25, Princeton University26, Case Western Reserve University27, University of La Laguna28, Chinese Academy of Sciences29, Academia Sinica30, University of Manchester31, Australian Astronomical Observatory32, Macquarie University33, Yale University34, Lawrence Berkeley National Laboratory35, University of Potsdam36, University of Victoria37, University of Groningen38
TL;DR: MaNGA (Mapping Nearby Galaxies at Apache Point Observatory) as mentioned in this paper employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers).
Abstract: We present an overview of a new integral field spectroscopic survey called MaNGA (Mapping Nearby Galaxies at Apache Point Observatory), one of three core programs in the fourth-generation Sloan Digital Sky Survey (SDSS-IV) that began on 2014 July 1. MaNGA will investigate the internal kinematic structure and composition of gas and stars in an unprecedented sample of 10,000 nearby galaxies. We summarize essential characteristics of the instrument and survey design in the context of MaNGA's key science goals and present prototype observations to demonstrate MaNGA's scientific potential. MaNGA employs dithered observations with 17 fiber-bundle integral field units that vary in diameter from 12'' (19 fibers) to 32'' (127 fibers). Two dual-channel spectrographs provide simultaneous wavelength coverage over 3600-10300 A at R ~ 2000. With a typical integration time of 3 hr, MaNGA reaches a target r-band signal-to-noise ratio of 4-8 (A–1 per 2'' fiber) at 23 AB mag arcsec–2, which is typical for the outskirts of MaNGA galaxies. Targets are selected with M * 109 M ☉ using SDSS-I redshifts and i-band luminosity to achieve uniform radial coverage in terms of the effective radius, an approximately flat distribution in stellar mass, and a sample spanning a wide range of environments. Analysis of our prototype observations demonstrates MaNGA's ability to probe gas ionization, shed light on recent star formation and quenching, enable dynamical modeling, decompose constituent components, and map the composition of stellar populations. MaNGA's spatially resolved spectra will enable an unprecedented study of the astrophysics of nearby galaxies in the coming 6 yr.
University of Florida1, University of Maryland, Baltimore2, Wake Forest University3, University of South Carolina4, Pennington Biomedical Research Center5, United States Department of Agriculture6, Yale University7, University of California, San Diego8, Veterans Health Administration9, Stanford University10, Northwestern University11, University of Pittsburgh12
TL;DR: The findings suggest mobility benefit from a structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability.
Abstract: Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). Conclusions and Relevance A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Trial Registration clinicaltrials.gov Identifier:NCT01072500
TL;DR: This report discusses how avoidable waste can be considered when research priorities are set and recommends ways to improve the yield from basic research, and the transparency of processes by which funders prioritise important uncertainties should be increased.
TL;DR: The structural topic model makes analyzing open-ended responses easier, more revealing, and capable of being used to estimate treatment effects, and is illustrated with analysis of text from surveys and experiments.
Abstract: Collection and especially analysis of open-ended survey responses are relatively rare in the discipline and when conducted are almost exclusively done through human coding. We present an alternative, semiautomated approach, the structural topic model (STM) (Roberts, Stewart, and Airoldi 2013; Roberts et al. 2013), that draws on recent developments in machine learning based analysis of textual data. A crucial contribution of the method is that it incorporates information about the document, such as the author's gender, political affiliation, and treatment assignment (if an experimental study). This article focuses on how the STM is helpful for survey researchers and experimentalists. The STM makes analyzing open-ended responses easier, more revealing, and capable of being used to estimate treatment effects. We illustrate these innovations with analysis of text from surveys and experiments.
TL;DR: Spin precession measurements in the polar molecule thorium monoxide indicate a nearly spherical charge distribution of an electron, which constrains T-violating physics at the TeV energy scale.
Abstract: The Standard Model of particle physics is known to be incomplete. Extensions to the Standard Model, such as weak-scale supersymmetry, posit the existence of new particles and interactions that are asymmetric under time reversal (T) and nearly always predict a small yet potentially measurable electron electric dipole moment (EDM), d(e), in the range of 10(-27) to 10(-30) e·cm. The EDM is an asymmetric charge distribution along the electron spin (S(→)) that is also asymmetric under T. Using the polar molecule thorium monoxide, we measured d(e) = (-2.1 ± 3.7stat ± 2.5syst) × 10(-29) e·cm. This corresponds to an upper limit of |d(e)| < 8.7 × 10(-29) e·cm with 90% confidence, an order of magnitude improvement in sensitivity relative to the previous best limit. Our result constrains T-violating physics at the TeV energy scale.