Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.
. This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
We study the question of feature sets for robust visual object recognition; adopting linear SVM based human detection as a test case. After reviewing existing edge and gradient based descriptors, we show experimentally that grids of histograms of oriented gradient (HOG) descriptors significantly outperform existing feature sets for human detection. We study the influence of each stage of the computation on performance, concluding that fine-scale gradients, fine orientation binning, relatively coarse spatial binning, and high-quality local contrast normalization in overlapping descriptor blocks are all important for good results. The new approach gives near-perfect separation on the original MIT pedestrian database, so we introduce a more challenging dataset containing over 1800 annotated human images with a large range of pose variations and backgrounds.
Abstract Self-determination theory (SDT) maintains that an understanding of human motivation requires a consideration of innate psychological needs for competence, autonomy, and relatedness. We discuss the SDT concept of needs as it relates to previous need theories, emphasizing that needs specify the necessary conditions for psychological growth, integrity, and well-being. This concept of needs leads to the hypotheses that different regulatory processes underlying goal pursuits are differentially associated with effective functioning and well-being and also that different goal contents have different relations to the quality of behavior and mental health, specifically because different regulatory processes and different goal contents are associated with differing degrees of need satisfaction. Social contexts and individual differences that support satisfaction of the basic needs facilitate natural growth processes including intrinsically motivated behavior and integration of extrinsic motivations, whereas those that forestall autonomy, competence, or relatedness are associated with poorer motivation, performance, and well-being. We also discuss the relation of the psychological needs to cultural values, evolutionary processes, and other contemporary motivation theories.
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There are two broad intellectual streams in the description and explanation of social action. One, characteristic of the work of most sociologists, sees the actor as socialized and action as governed by social norms, rules, and obligations. The principal virtues of this intellectual stream lie in its ability to describe action in social context and to explain the way action is shaped, constrained, and redirected by the social context. The other intellectual stream, characteristic of the work of most economists, sees the actor as having goals independently arrived at, as acting independently, and as wholly self-interested. Its principal virtue lies in having a principle of action, that of maximizing utility. This principle of action, together with a single empirical generalization (declining marginal utility), has generated the extensive growth of neoclassical economic theory, as well as the growth of political philosophy of several varieties: utilitarianism, contractarianism, and natural rights. In earlier works (Coleman 1986a, 1986b), I have argued for and engaged in the development of a theoretical orientation in sociology that includes components from both these intellectual streams. It accepts the principle of rational or purposive action and attempts to show how that principle, in conjunction with particular social contexts, can account not only for the actions of individuals in particular contexts but also for the development of social organization. In the present paper, I introduce a conceptual tool for use in this theoretical enterprise: social capital. As background for introducing this concept, it is useful to see some of the criticisms of and attempts to modify the two intellectual streams. Both these intellectual streams have serious defects. The sociological stream has what may be a fatal flaw as a theoretical enterprise: the actor has no “engine of action.” The actor is shaped by the environment, but there are no internal springs of action that give the actor a purpose or direction. The very conception of action as wholly a product of the environment has led sociologists themselves to criticize this intellectual stream, as in Dennis Wrong’s (1961) “Oversocialized Conception of Man in Modern Sociology.”
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
To understand the way children develop, Bronfenbrenner believes that it is necessary to observe their behavior in natural settings, while they are interacting with familiar adults over prolonged periods of time. His book offers an important blueprint for constructing a new and ecologically valid psychology of development.
Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source (http://bowtie.cbcb.umd.edu).
A hypothesized need to form and maintain strong, stable interpersonal relationships is evaluated in light of the empirical literature. The need is for frequent, nonaversive interactions within an ongoing relational bond. Consistent with the belongingness hypothesis, people form social attachments readily under most conditions and resist the dissolution of existing bonds. Belongingness appears to have multiple and strong effects on emotional patterns and on cognitive processes. Lack of attachments is linked to a variety of ill effects on health, adjustment, and well-being. Other evidence, such as that concerning satiation, substitution, and behavioral consequences, is likewise consistent with the hypothesized motivation. Several seeming counterexamples turned out not to disconfirm the hypothesis. Existing evidence supports the hypothesis that the need to belong is a powerful, fundamental, and extremely pervasive motivation.
Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
In a previous paper (13) various propositions were presented which would have to be included in any theory of human motivation that could lay claim to being definitive. These conclusions may be briefly summarized as follows: 1. The integrated wholeness of the organism must be one of the foundation stones of
The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
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S ummary The technique of disc electrophoresis has been presented, including a discussion of the technical variables with special reference to the separation of protein fractions of normal human serum.
Rectified activation units (rectifiers) are essential for state-of-the-art neural networks. In this work, we study rectifier neural networks for image classification from two aspects. First, we propose a Parametric Rectified Linear Unit (PReLU) that generalizes the traditional rectified unit. PReLU improves model fitting with nearly zero extra computational cost and little overfitting risk. Second, we derive a robust initialization method that particularly considers the rectifier nonlinearities. This method enables us to train extremely deep rectified models directly from scratch and to investigate deeper or wider network architectures. Based on the learnable activation and advanced initialization, we achieve 4.94% top-5 test error on the ImageNet 2012 classification dataset. This is a 26% relative improvement over the ILSVRC 2014 winner (GoogLeNet, 6.66% [33]). To our knowledge, our result is the first to surpass the reported human-level performance (5.1%, [26]) on this dataset.
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Human blastocyst-derived, pluripotent cell lines are described that have normal karyotypes, express high levels of telomerase activity, and express cell surface markers that characterize primate embryonic stem cells but do not characterize other early lineages. After undifferentiated proliferation in vitro for 4 to 5 months, these cells still maintained the developmental potential to form trophoblast and derivatives of all three embryonic germ layers, including gut epithelium (endoderm); cartilage, bone, smooth muscle, and striated muscle (mesoderm); and neural epithelium, embryonic ganglia, and stratified squamous epithelium (ectoderm). These cell lines should be useful in human developmental biology, drug discovery, and transplantation medicine.