Showing papers by "Columbia University published in 2011"
Brigham and Women's Hospital1, University of California, San Diego2, University of California, Davis3, Rush University Medical Center4, University of Washington5, Washington University in St. Louis6, University of Tokyo7, Mayo Clinic8, Oregon Health & Science University9, University of Texas at Dallas10, University of Melbourne11, Eli Lilly and Company12, Columbia University13, University of California, San Francisco14, Alzheimer's Association15, National Institutes of Health16
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
5,671 citations
TL;DR: In high-risk patients with severe aortic stenosis, transcatheter and surgical procedures for aorti-valve replacement were associated with similar rates of survival at 1 year, although there were important differences in periprocedural risks.
Abstract: A b s t r ac t Background The use of transcatheter aortic-valve replacement has been shown to reduce mortality among high-risk patients with aortic stenosis who are not candidates for surgical replacement. However, the two procedures have not been compared in a randomized trial involving high-risk patients who are still candidates for surgical replacement. Methods At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either transcatheter aortic-valve replacement with a balloon-expandable bovine pericardial valve (either a transfemoral or a transapical approach) or surgical replacement. The primary end point was death from any cause at 1 year. The primary hypothesis was that transcatheter replacement is not inferior to surgical replacement. Results The rates of death from any cause were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P = 0.07) and 24.2% and 26.8%, respectively, at 1 year (P = 0.44), a reduction of 2.6 percentage points in the transcatheter group (upper limit of the 95% confidence interval, 3.0 percentage points; predefined margin, 7.5 percentage points; P = 0.001 for noninferiority). The rates of major stroke were 3.8% in the transcatheter group and 2.1% in the surgical group at 30 days (P = 0.20) and 5.1% and 2.4%, respectively, at 1 year (P = 0.07). At 30 days, major vascular compli- cations were significantly more frequent with transcatheter replacement (11.0% vs. 3.2%, P<0.001); adverse events that were more frequent after surgical replacement included major bleeding (9.3% vs. 19.5%, P<0.001) and new-onset atrial fibrillation (8.6% vs. 16.0%, P = 0.006). More patients undergoing transcatheter replacement had an improvement in symptoms at 30 days, but by 1 year, there was not a significant between-group difference. Conclusions In high-risk patients with severe aortic stenosis, transcatheter and surgical proce- dures for aortic-valve replacement were associated with similar rates of survival at 1 year, although there were important differences in periprocedural risks. (Funded by Edwards Lifesciences; Clinical Trials.gov number, NCT00530894.)
5,272 citations
TL;DR: This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.
3,850 citations
TL;DR: This is the first study to use a consistent transformation framework to provide a reproducible evaluation of the isolated effect of the similarity metric on optimal template construction and brain labeling, and to quantify the similarity of templates derived from different subgroups.
3,491 citations
TL;DR: It was found that in the cropping regions and growing seasons of most countries, with the important exception of the United States, temperature trends from 1980 to 2008 exceeded one standard deviation of historic year-to-year variability.
Abstract: Efforts to anticipate how climate change will affect future food availability can benefit from understanding the impacts of changes to date. We found that in the cropping regions and growing seasons of most countries, with the important exception of the United States, temperature trends from 1980 to 2008 exceeded one standard deviation of historic year-to-year variability. Models that link yields of the four largest commodity crops to weather indicate that global maize and wheat production declined by 3.8 and 5.5%, respectively, relative to a counterfactual without climate trends. For soybeans and rice, winners and losers largely balanced out. Climate trends were large enough in some countries to offset a significant portion of the increases in average yields that arose from technology, carbon dioxide fertilization, and other factors.
3,231 citations
TL;DR: Findings suggest that the Columbia-Suicide Severity Rating Scale is suitable for assessment of suicidal ideation and behavior in clinical and research settings.
Abstract: The Columbia–Suicide Severity Rating Scale was initially designed to assess suicidal ideation and behavior in clinical trials. Psychometric analysis of data on adolescents indicated that a lifetime history of worst-point suicidal ideation including either suicidal intent or intent with a plan predicts a future risk of an actual attempt that is four times as great as the risk associated with a history of current suicidal ideation—including a desire to be dead—or increased general ratings of depression.
2,942 citations
TL;DR: The development and psychometric evaluation of a second version of the Acceptance and Action Questionnaire (AAQ-II), which assesses the construct referred to as, variously, acceptance, experiential avoidance, and psychological inflexibility, indicates the satisfactory structure, reliability, and validity of this measure.
2,818 citations
23 Oct 2011
TL;DR: The degree distribution, twopoint correlations, and clustering are the studied topological properties and an evolution of networks is studied to shed light on the influence the dynamics has on the network topology.
Abstract: Networks have become a general concept to model the structure of arbitrary relationships among entities. The framework of a network introduces a fundamentally new approach apart from ‘classical’ structures found in physics to model the topology of a system. In the context of networks fundamentally new topological effects can emerge and lead to a class of topologies which are termed ‘complex networks’. The concept of a network successfully models the static topology of an empirical system, an arbitrary model, and a physical system. Generally networks serve as a host for some dynamics running on it in order to fulfill a function. The question of the reciprocal relationship among a dynamical process on a network and its topology is the context of this Thesis. This context is studied in both directions. The network topology constrains or enhances the dynamics running on it, while the reciprocal interaction is of the same importance. Networks are commonly the result of an evolutionary process, e.g. protein interaction networks from biology. Within such an evolution the dynamics shapes the underlying network topology with respect to an optimal achievement of the function to perform. Answering the question what the influence on a dynamics of a particular topological property has requires the accurate control over the topological properties in question. In this Thesis the degree distribution, twopoint correlations, and clustering are the studied topological properties. These are motivated by the ubiquitous presence and importance within almost all empirical networks. An analytical framework to measure and to control such quantities of networks along with numerical algorithms to generate them is developed in a first step. Networks with the examined topological properties are then used to reveal their impact on two rather general dynamics on networks. Finally, an evolution of networks is studied to shed light on the influence the dynamics has on the network topology.
2,720 citations
TL;DR: In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions.
Abstract: A b s t r ac t Background Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. Methods In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. Results The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm 2 or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P = 0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). Conclusions In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.)
2,649 citations
TL;DR: A simulation model used to project the probable health and economic consequences in the next two decades from a continued rise in obesity in two ageing populations--the USA and the UK used to find that effective policies to promote healthier weight also have economic benefits.
2,473 citations
10 May 2011
TL;DR: A Markov chain Monte Carlo based analysis of a multilevel model for functional MRI data and its applications in environmental epidemiology, educational research, and fisheries science are studied.
Abstract: Foreword Stephen P. Brooks, Andrew Gelman, Galin L. Jones, and Xiao-Li Meng Introduction to MCMC, Charles J. Geyer A short history of Markov chain Monte Carlo: Subjective recollections from in-complete data, Christian Robert and George Casella Reversible jump Markov chain Monte Carlo, Yanan Fan and Scott A. Sisson Optimal proposal distributions and adaptive MCMC, Jeffrey S. Rosenthal MCMC using Hamiltonian dynamics, Radford M. Neal Inference and Monitoring Convergence, Andrew Gelman and Kenneth Shirley Implementing MCMC: Estimating with confidence, James M. Flegal and Galin L. Jones Perfection within reach: Exact MCMC sampling, Radu V. Craiu and Xiao-Li Meng Spatial point processes, Mark Huber The data augmentation algorithm: Theory and methodology, James P. Hobert Importance sampling, simulated tempering and umbrella sampling, Charles J.Geyer Likelihood-free Markov chain Monte Carlo, Scott A. Sisson and Yanan Fan MCMC in the analysis of genetic data on related individuals, Elizabeth Thompson A Markov chain Monte Carlo based analysis of a multilevel model for functional MRI data, Brian Caffo, DuBois Bowman, Lynn Eberly, and Susan Spear Bassett Partially collapsed Gibbs sampling & path-adaptive Metropolis-Hastings in high-energy astrophysics, David van Dyk and Taeyoung Park Posterior exploration for computationally intensive forward models, Dave Higdon, C. Shane Reese, J. David Moulton, Jasper A. Vrugt and Colin Fox Statistical ecology, Ruth King Gaussian random field models for spatial data, Murali Haran Modeling preference changes via a hidden Markov item response theory model, Jong Hee Park Parallel Bayesian MCMC imputation for multiple distributed lag models: A case study in environmental epidemiology, Brian Caffo, Roger Peng, Francesca Dominici, Thomas A. Louis, and Scott Zeger MCMC for state space models, Paul Fearnhead MCMC in educational research, Roy Levy, Robert J. Mislevy, and John T. Behrens Applications of MCMC in fisheries science, Russell B. Millar Model comparison and simulation for hierarchical models: analyzing rural-urban migration in Thailand, Filiz Garip and Bruce Western
TL;DR: The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.
Abstract: The ability to respond to perturbations in endoplasmic reticulum (ER) function is a fundamentally important property of all cells, but ER stress can also lead to apoptosis. In settings of chronic ER stress, the associated apoptosis may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases, diabetes, atherosclerosis and renal disease. The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.
TL;DR: Single-cell “mass cytometry” analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.
Abstract: Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.
Max Planck Society1, National University of Cordoba2, Centre national de la recherche scientifique3, Macquarie University4, University of Paris-Sud5, University of Minnesota6, University of Western Sydney7, VU University Amsterdam8, University of Arizona9, University of California, Berkeley10, University of Guelph11, Australian National University12, University of Innsbruck13, University of Leeds14, University of Groningen15, Universidade Federal do Rio Grande do Sul16, University of Cape Town17, University of Wollongong18, New Jersey Institute of Technology19, Centro Agronómico Tropical de Investigación y Enseñanza20, Lawrence Berkeley National Laboratory21, University of Alaska Fairbanks22, University of Cambridge23, Kansas State University24, Helmholtz Centre for Environmental Research - UFZ25, Arizona State University26, University of Giessen27, Autonomous University of Barcelona28, University of Maryland, College Park29, Universidad del Tolima30, University of São Paulo31, University of La Réunion32, University of York33, University of Sydney34, Harvard University35, Goethe University Frankfurt36, University of Sheffield37, University of Ulm38, State University of Campinas39, Kenyon College40, Royal Botanic Gardens41, University of Florida42, University of Oldenburg43, University of Nebraska–Lincoln44, Tohoku University45, Northern Arizona University46, University of Wisconsin–Eau Claire47, Naturalis48, James Cook University49, Institut national de la recherche agronomique50, Newcastle University51, University of New South Wales52, Leipzig University53, Columbia University54, Estonian University of Life Sciences55, Polish Academy of Sciences56, Moscow State University57, Kyushu University58, Wageningen University and Research Centre59, Spanish National Research Council60, University of Regensburg61, University of Rennes62, Université du Québec à Trois-Rivières63, Potsdam Institute for Climate Impact Research64, Technical University of Denmark65, University of California, Los Angeles66, Hokkaido University67, Université de Sherbrooke68, Syracuse University69, Empresa Brasileira de Pesquisa Agropecuária70, University of Aberdeen71, Michigan State University72, Oak Ridge National Laboratory73, University of Leicester74, Utah State University75, Smithsonian Institution76, University of Missouri77
TL;DR: TRY as discussed by the authors is a global database of plant traits, including morphological, anatomical, physiological, biochemical and phenological characteristics of plants and their organs, which can be used for a wide range of research from evolutionary biology, community and functional ecology to biogeography.
Abstract: Plant traits – the morphological, anatomical, physiological, biochemical and phenological characteristics of plants and their organs – determine how primary producers respond to environmental factors, affect other trophic levels, influence ecosystem processes and services and provide a link from species richness to ecosystem functional diversity. Trait data thus represent the raw material for a wide range of research from evolutionary biology, community and functional ecology to biogeography. Here we present the global database initiative named TRY, which has united a wide range of the plant trait research community worldwide and gained an unprecedented buy-in of trait data: so far 93 trait databases have been contributed. The data repository currently contains almost three million trait entries for 69 000 out of the world's 300 000 plant species, with a focus on 52 groups of traits characterizing the vegetative and regeneration stages of the plant life cycle, including growth, dispersal, establishment and persistence. A first data analysis shows that most plant traits are approximately log-normally distributed, with widely differing ranges of variation across traits. Most trait variation is between species (interspecific), but significant intraspecific variation is also documented, up to 40% of the overall variation. Plant functional types (PFTs), as commonly used in vegetation models, capture a substantial fraction of the observed variation – but for several traits most variation occurs within PFTs, up to 75% of the overall variation. In the context of vegetation models these traits would better be represented by state variables rather than fixed parameter values. The improved availability of plant trait data in the unified global database is expected to support a paradigm shift from species to trait-based ecology, offer new opportunities for synthetic plant trait research and enable a more realistic and empirically grounded representation of terrestrial vegetation in Earth system models.
TL;DR: The central roles of macrophages in each of the stages of disease pathogenesis are discussed, including atherosclerosis, stroke, and sudden cardiac death.
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
TL;DR: The Alzheimer Disease Genetics Consortium performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1), two replication stages (stages 2 and 3), and both joint analysis and meta-analysis approaches were used.
Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.
TL;DR: Results of atomic-level molecular dynamics simulations of 12 proteins reveal a set of common principles underlying the folding of 12 structurally diverse proteins that spontaneously and repeatedly fold to their experimentally determined native structures.
Abstract: An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally diverse proteins. In simulations conducted with a single physics-based energy function, the proteins, representing all three major structural classes, spontaneously and repeatedly fold to their experimentally determined native structures. Early in the folding process, the protein backbone adopts a nativelike topology while certain secondary structure elements and a small number of nonlocal contacts form. In most cases, folding follows a single dominant route in which elements of the native structure appear in an order highly correlated with their propensity to form in the unfolded state.
Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
23 Jun 2011
TL;DR: This article introduced POS-specific prior polarity features and explored the use of a tree kernel to obviate the need for tedious feature engineering for sentiment analysis on Twitter data, which outperformed the state-of-the-art baseline.
Abstract: We examine sentiment analysis on Twitter data. The contributions of this paper are: (1) We introduce POS-specific prior polarity features. (2) We explore the use of a tree kernel to obviate the need for tedious feature engineering. The new features (in conjunction with previously proposed features) and the tree kernel perform approximately at the same level, both outperforming the state-of-the-art baseline.
TL;DR: It is now widely appreciated that chronic low-grade inflammation plays a key role in the initiation, propagation, and development of metabolic diseases, and numerous recent studies have implicated the transcription factor NF-κB in the development of such diseases, thereby further establishing inflammation as a critical factor in their etiology.
TL;DR: In this paper, a variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs, and the intricate crosstalk is crucial to shaping the diverse biological functions of NF-KB into cell type-and context-specific responses.
Abstract: NF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. A variety of stimuli coalesce on NF-κB activation, which can in turn mediate varied transcriptional programs. Consequently, NF-κB-dependent transcription is not only tightly controlled by positive and negative regulatory mechanisms but also closely coordinated with other signaling pathways. This intricate crosstalk is crucial to shaping the diverse biological functions of NF-κB into cell type– and context-specific responses.
TL;DR: In this article, the authors discuss how extrinsic incentives may come into conflict with other motivations and examine the research literature on three important examples in which monetary incentives have been used in a non-employment context to foster the desired behavior: education, increasing contributions to public goods, and helping people change their lifestyles, particularly with regard to smoking and exercise.
Abstract: First we discuss how extrinsic incentives may come into conflict with other motivations. For example, monetary incentives from principals may change how tasks are perceived by agents, with negative effects on behavior. In other cases, incentives might have the desired effects in the short term, but they still weaken intrinsic motivations. To put it in concrete terms, an incentive for a child to learn to read might achieve that goal in the short term, but then be counterproductive as an incentive for students to enjoy reading and seek it out over their lifetimes. Next we examine the research literature on three important examples in which monetary incentives have been used in a nonemployment context to foster the desired behavior: education; increasing contributions to public goods; and helping people change their lifestyles, particularly with regard to smoking and exercise. The conclusion sums up some lessons on when extrinsic incentives are more or less likely to alter such behaviors in the desired directions.
TL;DR: It is shown that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished, which is indicative of enhanced pattern separation.
Abstract: Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.
TL;DR: Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors.
Abstract: Background Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. Methods We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry–based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. Results We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with...
TL;DR: It is demonstrated that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and -2) and AMPK-dependent phosphorylation of SREBP may offer therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.
TL;DR: It is proposed that this literature can be informed by an interactionist approach in which the effects of oxytocin are constrained by features of situations and/or individuals.
Boston University1, University of Manchester2, Medical University of Vienna3, University of Ottawa4, VU University Amsterdam5, Leiden University6, Columbia University7, Johns Hopkins University8, University of Pisa9, University of Melbourne10, University of York11, University of Florence12, University of Paris13, University of Leeds14, University of California, Los Angeles15, University of Santiago de Compostela16, University of Toronto17, University of Bristol18, Maastricht University19, University of Nebraska Medical Center20, Autonomous University of Madrid21, New York University22, Genentech23, Food and Drug Administration24, Stanford University25, University of Basel26, MedImmune27, University of Kansas28
TL;DR: It is proposed that a patient's RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint counts, CRP level, and patient global assessment are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.
Abstract: Objective Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used defi nition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a defi nition. Methods A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecifi ed analyses from RA clinical trials. The committee requested a stringent defi nition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to defi ne remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate defi nitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as defi nitions using disease activity indexes. To select a defi nition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes. Results Survey results for the defi nition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0–10 scale). Analyses suggested the need to include a patientreported measure. Examination of 2-year follow-up data suggested that many candidate defi nitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score–based measures of remission did not
01 Jan 2011
TL;DR: The Million Song Dataset, a freely-available collection of audio features and metadata for a million contemporary popular music tracks, is introduced and positive results on year prediction are shown, and the future development of the dataset is discussed.
Abstract: We introduce the Million Song Dataset, a freely-available collection of audio features and metadata for a million contemporary popular music tracks. We describe its creation process, its content, and its possible uses. Attractive features of the Million Song Database include the range of existing resources to which it is linked, and the fact that it is the largest current research dataset in our field. As an illustration, we present year prediction as an example application, a task that has, until now, been difficult to study owing to the absence of a large set of suitable data. We show positive results on year prediction, and discuss more generally the future development of the dataset.
TL;DR: It is demonstrated that engagement of a subset of Toll-like receptors results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production, revealing a novel pathway linking innate immune signalling to mitochondria, implicate mR OS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signaling.
Abstract: Reactive oxygen species (ROS) are essential components of the innate immune response against intracellular bacteria and it is thought that professional phagocytes generate ROS primarily via the phagosomal NADPH oxidase machinery. However, recent studies have suggested that mitochondrial ROS (mROS) also contribute to mouse macrophage bactericidal activity, although the mechanisms linking innate immune signalling to mitochondria for mROS generation remain unclear. Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. These results reveal a novel pathway linking innate immune signalling to mitochondria, implicate mROS as an important component of antibacterial responses and further establish mitochondria as hubs for innate immune signalling.