Showing papers by "Columbia University published in 2014"
University of Washington1, Sapienza University of Rome2, Mekelle University3, University of Texas at San Antonio4, King Saud bin Abdulaziz University for Health Sciences5, Debre markos University6, Emory University7, University of Oxford8, University of Cartagena9, United Nations Population Fund10, University of Birmingham11, Stanford University12, Aga Khan University13, University of Melbourne14, National Taiwan University15, University of Cambridge16, University of California, San Diego17, Public Health Foundation of India18, Public Health England19, University of Peradeniya20, Harvard University21, National Institutes of Health22, Tehran University of Medical Sciences23, Auckland University of Technology24, University of Sheffield25, University of Western Australia26, Karolinska Institutet27, Birzeit University28, Brandeis University29, American Cancer Society30, Ochsner Medical Center31, Yonsei University32, University of Bristol33, Heidelberg University34, Vanderbilt University35, South African Medical Research Council36, Jordan University of Science and Technology37, New Generation University College38, Northeastern University39, Simmons College40, Norwegian Institute of Public Health41, Boston University42, Chinese Center for Disease Control and Prevention43, University of Bari44, University of São Paulo45, University of Otago46, University of Crete47, International Centre for Diarrhoeal Disease Research, Bangladesh48, Fred Hutchinson Cancer Research Center49, Teikyo University50, Bhabha Atomic Research Centre51, University of Tokyo52, Finnish Institute of Occupational Health53, Heriot-Watt University54, University of Alabama at Birmingham55, Griffith University56, National Center for Disease Control and Public Health57, University of California, Irvine58, Johns Hopkins University59, New York University60, University of Queensland61, Universidade Federal de Minas Gerais62, National Research University – Higher School of Economics63, University of Bergen64, Columbia University65, Shandong University66, University of North Carolina at Chapel Hill67, Fujita Health University68, Korea University69, Chongqing Medical University70, Zhejiang University71
TL;DR: The global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013 is estimated using a spatiotemporal Gaussian process regression model to estimate prevalence with 95% uncertainty intervals (UIs).
9,180 citations
TL;DR: The review as discussed by the authors summarizes much of particle physics and cosmology using data from previous editions, plus 3,283 new measurements from 899 Japers, including the recently discovered Higgs boson, leptons, quarks, mesons and baryons.
Abstract: The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,283 new measurements from 899 Japers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as heavy neutrinos, supersymmetric and technicolor particles, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as Supersymmetry, Extra Dimensions, Particle Detectors, Probability, and Statistics. Among the 112 reviews are many that are new or heavily revised including those on: Dark Energy, Higgs Boson Physics, Electroweak Model, Neutrino Cross Section Measurements, Monte Carlo Neutrino Generators, Top Quark, Dark Matter, Dynamical Electroweak Symmetry Breaking, Accelerator Physics of Colliders, High-Energy Collider Parameters, Big Bang Nucleosynthesis, Astrophysical Constants and Cosmological Parameters.
7,337 citations
TL;DR: Associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses.
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
6,809 citations
TL;DR: This Review focuses on recent developments on flat, ultrathin optical components dubbed 'metasurfaces' that produce abrupt changes over the scale of the free-space wavelength in the phase, amplitude and/or polarization of a light beam.
Abstract: Metamaterials are artificially fabricated materials that allow for the control of light and acoustic waves in a manner that is not possible in nature. This Review covers the recent developments in the study of so-called metasurfaces, which offer the possibility of controlling light with ultrathin, planar optical components. Conventional optical components such as lenses, waveplates and holograms rely on light propagation over distances much larger than the wavelength to shape wavefronts. In this way substantial changes of the amplitude, phase or polarization of light waves are gradually accumulated along the optical path. This Review focuses on recent developments on flat, ultrathin optical components dubbed 'metasurfaces' that produce abrupt changes over the scale of the free-space wavelength in the phase, amplitude and/or polarization of a light beam. Metasurfaces are generally created by assembling arrays of miniature, anisotropic light scatterers (that is, resonators such as optical antennas). The spacing between antennas and their dimensions are much smaller than the wavelength. As a result the metasurfaces, on account of Huygens principle, are able to mould optical wavefronts into arbitrary shapes with subwavelength resolution by introducing spatial variations in the optical response of the light scatterers. Such gradient metasurfaces go beyond the well-established technology of frequency selective surfaces made of periodic structures and are extending to new spectral regions the functionalities of conventional microwave and millimetre-wave transmit-arrays and reflect-arrays. Metasurfaces can also be created by using ultrathin films of materials with large optical losses. By using the controllable abrupt phase shifts associated with reflection or transmission of light waves at the interface between lossy materials, such metasurfaces operate like optically thin cavities that strongly modify the light spectrum. Technology opportunities in various spectral regions and their potential advantages in replacing existing optical components are discussed.
4,613 citations
TL;DR: The authors' data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycoleytic enzyme pyruvate kinase.
Abstract: The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase This dataset will provide a powerful new resource for understanding the development and function of the brain To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://webstanfordedu/group/barres_lab/brain_rnaseqhtml) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain
3,891 citations
Stanford University1, HCL Technologies2, Universidad Mayor3, UCL Institute of Child Health4, University of Bonn5, University of California, Los Angeles6, Umeå University7, New York University8, Columbia University9, Yonsei University10, Albert Einstein College of Medicine11, University of Pavia12, University of Melbourne13, Karolinska Institutet14, University of Calgary15
TL;DR: A revised definition of epilepsy brings the term in concordance with common use for individuals who either had an age‐dependent epilepsy syndrome but are now past the applicable age or who have remained seizure‐free for the last 10 years and off antiseizure medicines for at least the last 5 years.
Abstract: Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
3,491 citations
TL;DR: Targeted metabolomic profiling and chemoproteomics revealed that GPX4 is an essential regulator of ferroptotic cancer cell death and sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPx4-regulated ferroPTosis.
3,457 citations
TL;DR: In this paper, the authors provide clarification and correction to their article "Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma" (Dec. 4, 2014, issue).
Abstract: To the Editor: We are writing to provide clarification and correction to our article “Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma” (Dec. 4, 2014, issue).1 Along with the publication, additional information on the data and methods that we used were posted in an online Supplementary Appendix, available with the full text of the article at NEJM.org. Some readers were confused by our incomplete description of part of the data analysis and our use of the term “validation set.” We acknowledge that our use of “validation set” was not appropriate in the context of the search for a . . .
3,451 citations
TL;DR: The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteiporosis Foundation in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF.
Abstract: The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.
2,926 citations
TL;DR: In this article, the authors provide a brief review of both theoretical and experimental advances in this field and uncover the interplay between real spin and pseudospins in layered transition metal dichalcogenides.
Abstract: The recent emergence of two-dimensional layered materials — in particular the transition metal dichalcogenides — provides a new laboratory for exploring the internal quantum degrees of freedom of electrons and their potential for new electronics. These degrees of freedom are the real electron spin, the layer pseudospin, and the valley pseudospin. New methods for the quantum control of the spin and these pseudospins arise from the existence of Berry phase-related physical properties and strong spin–orbit coupling. The former leads to the versatile control of the valley pseudospin, whereas the latter gives rise to an interplay between the spin and the pseudospins. Here, we provide a brief review of both theoretical and experimental advances in this field. Understanding the physics of two-dimensional materials beyond graphene is of both fundamental and practical interest. Recent theoretical and experimental advances uncover the interplay between real spin and pseudospins in layered transition metal dichalcogenides.
2,363 citations
TL;DR: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis.
Abstract: Background In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients. Methods In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis. Results In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P = 0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P = 0.16) or in rates of death from any cause (P = 0.10) or from idiopathic pulmonary fibrosis (P = 0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P = 0.01) and from idiopathic pulmonary fibrosis (P = 0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation. Conclusions Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable sideeffect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.)
Icahn School of Medicine at Mount Sinai1, Carnegie Mellon University2, Harvard University3, University of Toronto4, Wellcome Trust Sanger Institute5, University of Pittsburgh6, Nagoya University7, University of Freiburg8, King's College London9, Vanderbilt University10, King Abdulaziz University11, University of Santiago de Compostela12, University of Utah13, Duke University14, Memorial University of Newfoundland15, Trinity College, Dublin16, University of Pennsylvania17, University of Illinois at Chicago18, Boston Children's Hospital19, Columbia University20, German Cancer Research Center21, University College London22, Kaiser Permanente23, Broad Institute24, Cardiff University25, Complutense University of Madrid26, Newcastle University27, Baylor College of Medicine28, University of California, San Francisco29, RWTH Aachen University30, National Health Service31, McMaster University32, Saarland University33, Karolinska Institutet34, National Institutes of Health35, University of Helsinki36, Emory University37
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Journal Article•
TL;DR: The No-U-Turn Sampler (NUTS), an extension to HMC that eliminates the need to set a number of steps L, and derives a method for adapting the step size parameter {\epsilon} on the fly based on primal-dual averaging.
Abstract: Hamiltonian Monte Carlo (HMC) is a Markov chain Monte Carlo (MCMC) algorithm that avoids the random walk behavior and sensitivity to correlated parameters that plague many MCMC methods by taking a series of steps informed by first-order gradient information. These features allow it to converge to high-dimensional target distributions much more quickly than simpler methods such as random walk Metropolis or Gibbs sampling. However, HMC's performance is highly sensitive to two user-specified parameters: a step size e and a desired number of steps L. In particular, if L is too small then the algorithm exhibits undesirable random walk behavior, while if L is too large the algorithm wastes computation. We introduce the No-U-Turn Sampler (NUTS), an extension to HMC that eliminates the need to set a number of steps L. NUTS uses a recursive algorithm to build a set of likely candidate points that spans a wide swath of the target distribution, stopping automatically when it starts to double back and retrace its steps. Empirically, NUTS performs at least as efficiently as (and sometimes more effciently than) a well tuned standard HMC method, without requiring user intervention or costly tuning runs. We also derive a method for adapting the step size parameter e on the fly based on primal-dual averaging. NUTS can thus be used with no hand-tuning at all, making it suitable for applications such as BUGS-style automatic inference engines that require efficient "turnkey" samplers.
TL;DR: The tunnelling-assisted interlayer recombination of the majority carriers is responsible for the tunability of the electronic and optoelectronic processes in atomically thin p-n heterojunctions fabricated using van der Waals assembly of transition-metal dichalcogenides.
Abstract: In heterostructures of the transition metal dichalcogenides MoS2 and WSe2, atomically thin p–n junctions are created that show gate-tunable rectifying and photovoltaic behaviour mediated by tunnelling-assisted interlayer recombination. Semiconductor p–n junctions are essential building blocks for electronic and optoelectronic devices1,2. In conventional p–n junctions, regions depleted of free charge carriers form on either side of the junction, generating built-in potentials associated with uncompensated dopant atoms. Carrier transport across the junction occurs by diffusion and drift processes influenced by the spatial extent of this depletion region. With the advent of atomically thin van der Waals materials and their heterostructures, it is now possible to realize a p–n junction at the ultimate thickness limit3,4,5,6,7,8,9,10. Van der Waals junctions composed of p- and n-type semiconductors—each just one unit cell thick—are predicted to exhibit completely different charge transport characteristics than bulk heterojunctions10,11,12. Here, we report the characterization of the electronic and optoelectronic properties of atomically thin p–n heterojunctions fabricated using van der Waals assembly of transition-metal dichalcogenides. We observe gate-tunable diode-like current rectification and a photovoltaic response across the p–n interface. We find that the tunnelling-assisted interlayer recombination of the majority carriers is responsible for the tunability of the electronic and optoelectronic processes. Sandwiching an atomic p–n junction between graphene layers enhances the collection of the photoexcited carriers. The atomically scaled van der Waals p–n heterostructures presented here constitute the ultimate functional unit for nanoscale electronic and optoelectronic devices.
TL;DR: Strong but unconventional electron-hole interactions are expected to be ubiquitous in atomically thin materials using a microscopic theory in which the nonlocal nature of the effective dielectric screening modifies the functional form of the Coulomb interaction.
Abstract: We have experimentally determined the energies of the ground and first four excited excitonic states of the fundamental optical transition in monolayer ${\mathrm{WS}}_{2}$, a model system for the growing class of atomically thin two-dimensional semiconductor crystals. From the spectra, we establish a large exciton binding energy of 0.32 eV and a pronounced deviation from the usual hydrogenic Rydberg series of energy levels of the excitonic states. We explain both of these results using a microscopic theory in which the nonlocal nature of the effective dielectric screening modifies the functional form of the Coulomb interaction. These strong but unconventional electron-hole interactions are expected to be ubiquitous in atomically thin materials.
Alistair R. R. Forrest, Hideya Kawaji, Michael Rehli1, J Kenneth Baillie2 +277 more•Institutions (63)
TL;DR: For example, the authors mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body.
Abstract: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research
Goddard Institute for Space Studies1, University of Chicago2, Columbia University3, University of East Anglia4, Potsdam Institute for Climate Impact Research5, Karlsruhe Institute of Technology6, University of Florida7, Swiss Federal Institute of Aquatic Science and Technology8, International Institute for Applied Systems Analysis9, Netherlands Environmental Assessment Agency10, University of Natural Resources and Life Sciences, Vienna11
TL;DR: Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies.
Abstract: Here we present the results from an intercomparison of multiple global gridded crop models (GGCMs) within the framework of the Agricultural Model Intercomparison and Improvement Project and the Inter-Sectoral Impacts Model Intercomparison Project. Results indicate strong negative effects of climate change, especially at higher levels of warming and at low latitudes; models that include explicit nitrogen stress project more severe impacts. Across seven GGCMs, five global climate models, and four representative concentration pathways, model agreement on direction of yield changes is found in many major agricultural regions at both low and high latitudes; however, reducing uncertainty in sign of response in mid-latitude regions remains a challenge. Uncertainties related to the representation of carbon dioxide, nitrogen, and high temperature effects demonstrated here show that further research is urgently needed to better understand effects of climate change on agricultural production and to devise targeted adaptation strategies.
TL;DR: It is shown that cyclic stretching and releasing of thin MoS2 flakes with an odd number of atomic layers produces oscillating piezoelectric voltage and current outputs, whereas no output is observed for flakes with even number of layers, which may enable the development of applications in powering nanodevices, adaptive bioprobes and tunable/stretchable electronics/optoelectronics.
Abstract: The two-dimensional semiconducting material molybdenum disulphide shows strong piezoelectricity in its single-layered form, suggesting possible applications in nanoscale electromechanical devices for sensing and energy harvesting. Two-dimensional semiconducting materials are the focus of much research effort thanks to their unusual and potentially useful physical properties. Wenzhou Wu and colleagues now confirm theoretical expectations that one such material — molybdenum disulphide — exhibits strong piezoelectricity in its single-layered form. Such a coupling of mechanical and electrical properties suggests possible applications in nanoscale electromechanical devices for sensing and energy harvesting. The piezoelectric characteristics of nanowires, thin films and bulk crystals have been closely studied for potential applications in sensors, transducers, energy conversion and electronics1,2,3. With their high crystallinity and ability to withstand enormous strain4,5,6, two-dimensional materials are of great interest as high-performance piezoelectric materials. Monolayer MoS2 is predicted to be strongly piezoelectric, an effect that disappears in the bulk owing to the opposite orientations of adjacent atomic layers7,8. Here we report the first experimental study of the piezoelectric properties of two-dimensional MoS2 and show that cyclic stretching and releasing of thin MoS2 flakes with an odd number of atomic layers produces oscillating piezoelectric voltage and current outputs, whereas no output is observed for flakes with an even number of layers. A single monolayer flake strained by 0.53% generates a peak output of 15 mV and 20 pA, corresponding to a power density of 2 mW m−2 and a 5.08% mechanical-to-electrical energy conversion efficiency. In agreement with theoretical predictions, the output increases with decreasing thickness and reverses sign when the strain direction is rotated by 90°. Transport measurements show a strong piezotronic effect in single-layer MoS2, but not in bilayer and bulk MoS2. The coupling between piezoelectricity and semiconducting properties in two-dimensional nanomaterials may enable the development of applications in powering nanodevices, adaptive bioprobes and tunable/stretchable electronics/optoelectronics.
TL;DR: The Akaike, deviance, and Watanabe-Akaike information criteria are reviewed from a Bayesian perspective and it is better understood, through small examples, how these methods can apply in practice.
Abstract: We review the Akaike, deviance, and Watanabe-Akaike information criteria from a Bayesian perspective, where the goal is to estimate expected out-of-sample-prediction error using a bias-corrected adjustment of within-sample error. We focus on the choices involved in setting up these measures, and we compare them in three simple examples, one theoretical and two applied. The contribution of this paper is to put all these information criteria into a Bayesian predictive context and to better understand, through small examples, how these methods can apply in practice.
TL;DR: It is shown that both binding and cleavage of DNA by Cas9–RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM) and that PAM interactions trigger Cas9 catalytic activity.
Abstract: The clustered regularly interspaced short palindromic repeats (CRISPR)-associated enzyme Cas9 is an RNA-guided endonuclease that uses RNA-DNA base-pairing to target foreign DNA in bacteria. Cas9-guide RNA complexes are also effective genome engineering agents in animals and plants. Here we use single-molecule and bulk biochemical experiments to determine how Cas9-RNA interrogates DNA to find specific cleavage sites. We show that both binding and cleavage of DNA by Cas9-RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM). Non-target DNA binding affinity scales with PAM density, and sequences fully complementary to the guide RNA but lacking a nearby PAM are ignored by Cas9-RNA. Competition assays provide evidence that DNA strand separation and RNA-DNA heteroduplex formation initiate at the PAM and proceed directionally towards the distal end of the target sequence. Furthermore, PAM interactions trigger Cas9 catalytic activity. These results reveal how Cas9 uses PAM recognition to quickly identify potential target sites while scanning large DNA molecules, and to regulate scission of double-stranded DNA.
TL;DR: De deleting Shh in a well-defined mouse model of PDAC demonstrated that some components of the tumor stroma can act to restrain tumor growth, and administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors.
TL;DR: Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers.
Abstract: Background Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) e4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. Results There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE e4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE e4 allele carriers but not in noncarriers. Conclusions Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE e4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).
TL;DR: With the discovery of hexagonal boron nitride as an ideal dielectric, the materials are now in place to advance integrated flexible nanoelectronics, which uniquely take advantage of the unmatched portfolio of properties of two-dimensional crystals, beyond the capability of conventional thin films for ubiquitous flexible systems.
Abstract: The unique electrical, mechanical and physical properties of two-dimensional materials make them attractive candidates in flexible nanoelectronic systems. Here Akinwande et al. review the literature on two-dimensional materials in flexible nanoelectronics, and highlight barriers to their full implementation.
University of Pittsburgh1, California Pacific Medical Center2, University of Maryland, Baltimore3, Beth Israel Deaconess Medical Center4, National Institutes of Health5, University of Central Florida6, University of Connecticut Health Center7, Wake Forest University8, Columbia University9, Foundation for the National Institutes of Health10
TL;DR: Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 forMen and women.
Abstract: Background.
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
Cornell University1, Stanford University2, Georgetown University3, University of Washington4, St James's University Hospital5, Hofstra University6, Memorial Sloan Kettering Cancer Center7, University of California, San Diego8, Sarah Cannon Research Institute9, Vita-Salute San Raffaele University10, University of California, Los Angeles11, Columbia University12, Claude Bernard University Lyon 113, Royal Liverpool and Broadgreen University Hospital NHS Trust14, Northwestern University15, University of Ulm16, University of Cologne17, University of Texas MD Anderson Cancer Center18
TL;DR: The combination of idelalisib and rituximab, as compared with placebo and r ituximabs, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy.
Abstract: BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).
Valentina Escott-Price1, Céline Bellenguez2, Li-San Wang3, Seung Hoan Choi4 +191 more•Institutions (67)
TL;DR: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimers disease.
Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...
TL;DR: Iron-deficiency anemia was the top cause globally, although 10 different conditions were among the top 3 in regional rankings, and Malaria, schistosomiasis, and chronic kidney disease-related anemia were the only conditions to increase in prevalence.
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: 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