Showing papers by "University of Chicago published in 2014"

Review of Particle Physics

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.

Biological insights from 108 schizophrenia-associated genetic loci

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.

XSEDE: Accelerating Scientific Discovery

Abstract: Computing in science and engineering is now ubiquitous: digital technologies underpin, accelerate, and enable new, even transformational, research in all domains. Access to an array of integrated and well-supported high-end digital services is critical for the advancement of knowledge. Driven by community needs, the Extreme Science and Engineering Discovery Environment (XSEDE) project substantially enhances the productivity of a growing community of scholars, researchers, and engineers (collectively referred to as "scientists"' throughout this article) through access to advanced digital services that support open research. XSEDE's integrated, comprehensive suite of advanced digital services federates with other high-end facilities and with campus-based resources, serving as the foundation for a national e-science infrastructure ecosystem. XSEDE's e-science infrastructure has tremendous potential for enabling new advancements in research and education. XSEDE's vision is a world of digitally enabled scholars, researchers, and engineers participating in multidisciplinary collaborations to tackle society's grand challenges.

N6-methyladenosine-dependent regulation of messenger RNA stability

Abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

Transiting Exoplanet Survey Satellite

Abstract: The Transiting Exoplanet Survey Satellite (TESS) will search for planets transiting bright and nearby stars. TESS has been selected by NASA for launch in 2017 as an Astrophysics Explorer mission. The spacecraft will be placed into a highly elliptical 13.7-day orbit around the Earth. During its 2-year mission, TESS will employ four wide-field optical charge-coupled device cameras to monitor at least 200,000 main-sequence dwarf stars with I C ≈4−13 for temporary drops in brightness caused by planetary transits. Each star will be observed for an interval ranging from 1 month to 1 year, depending mainly on the star’s ecliptic latitude. The longest observing intervals will be for stars near the ecliptic poles, which are the optimal locations for follow-up observations with the James Webb Space Telescope. Brightness measurements of preselected target stars will be recorded every 2 min, and full frame images will be recorded every 30 min. TESS stars will be 10 to 100 times brighter than those surveyed by the pioneering Kepler mission. This will make TESS planets easier to characterize with follow-up observations. TESS is expected to find more than a thousand planets smaller than Neptune, including dozens that are comparable in size to the Earth. Public data releases will occur every 4 months, inviting immediate community-wide efforts to study the new planets. The TESS legacy will be a catalog of the nearest and brightest stars hosting transiting planets, which will endure as highly favorable targets for detailed investigations.

Comprehensive molecular characterization of urothelial bladder carcinoma

Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.

A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation

Abstract: Certain adenosine residues within mammalian RNAs undergo reversible N6 methylation. Two methyltransferase enzymes, METTL3 and METTL14, as well as the splicing factor WTAP are identified as core components of the multiprotein complex that deposits RNA N6-methyladenosine (m6A) in nuclear RNAs.

Detection of $B$-Mode Polarization at Degree Angular Scales by BICEP2

Abstract: We report results from the BICEP2 experiment, a cosmic microwave background (CMB) polarimeter specifically designed to search for the signal of inflationary gravitational waves in the B -mode power spectrum around l∼80 . The telescope comprised a 26 cm aperture all-cold refracting optical system equipped with a focal plane of 512 antenna coupled transition edge sensor 150 GHz bolometers each with temperature sensitivity of ≈300 μK CMB s √ . BICEP2 observed from the South Pole for three seasons from 2010 to 2012. A low-foreground region of sky with an effective area of 380 square deg was observed to a depth of 87 nK deg in Stokes Q and U . In this paper we describe the observations, data reduction, maps, simulations, and results. We find an excess of B -mode power over the base lensed-ΛCDM expectation in the range 30 5σ . Through jackknife tests and simulations based on detailed calibration measurements we show that systematic contamination is much smaller than the observed excess. Cross correlating against WMAP 23 GHz maps we find that Galactic synchrotron makes a negligible contribution to the observed signal. We also examine a number of available models of polarized dust emission and find that at their default parameter values they predict power ∼(5–10)× smaller than the observed excess signal (with no significant cross-correlation with our maps). However, these models are not sufficiently constrained by external public data to exclude the possibility of dust emission bright enough to explain the entire excess signal. Cross correlating BICEP2 against 100 GHz maps from the BICEP1 experiment, the excess signal is confirmed with 3σ significance and its spectral index is found to be consistent with that of the CMB, disfavoring dust at 1.7σ . The observed B -mode power spectrum is well fit by a lensed-ΛCDM+tensor theoretical model with tensor-to-scalar ratio r=0.20 +0.07 −0.05 , with r=0 disfavored at 7.0σ . Accounting for the contribution of foreground, dust will shift this value downward by an amount which will be better constrained with upcoming data sets

Improved cosmological constraints from a joint analysis of the SDSS-II and SNLS supernova samples

Abstract: Aims. We present cosmological constraints from a joint analysis of type Ia supernova (SN Ia) observations obtained by the SDSS-II and SNLS collaborations. The dataset includes several low-redshift samples (z< 0.1), all three seasons from the SDSS-II (0.05

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

The Concept of Flow

Abstract: What constitutes a good life? Few questions are of more fundamental importance to a positive psychology. Flow research has yielded one answer, providing an understanding of experiences during which individuals are fully involved in the present moment. Viewed through the experiential lens of flow, a good life is one that is characterized by complete absorption in what one does. In this chapter, we describe the flow model of optimal experience and optimal development, explain how flow and related constructs have been measured, discuss recent work in this area, and identify some promising directions for future research.

A Controlled Trial of Renal Denervation for Resistant Hypertension

Abstract: A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was −14.13±23.93 mm Hg in the denervation group as compared with −11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of −2.39 mm Hg (95% confidence interval [CI], −6.89 to 2.12; P = 0.26 for superiority with a margin of 5 mm Hg). The change in 24-hour ambulatory systolic blood pressure was −6.75±15.11 mm Hg in the denervation group and −4.79±17.25 mm Hg in the sham-procedure group, for a difference of −1.96 mm Hg (95% CI, −4.97 to 1.06; P = 0.98 for superiority with a margin of 2 mm Hg). There were no significant differences in safety between the two groups. Conclusions This blinded trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control. (Funded by Medtronic; SYMPLICITY HTN-3 ClinicalTrials.gov number, NCT01418261.)

Planck 2013 results. I. Overview of products and scientific results

Abstract: The European Space Agency’s Planck satellite, dedicated to studying the early Universe and its subsequent evolution, was launched 14 May 2009 and has been scanning the microwave and submillimetre sky continuously since 12 August 2009. In March 2013, ESA and the Planck Collaboration released the initial cosmology products based on the first 15.5 months of Planck data, along with a set of scientific and technical papers and a web-based explanatory supplement. This paper gives an overview of the mission and its performance, the processing, analysis, and characteristics of the data, the scientific results, and the science data products and papers in the release. The science products include maps of the cosmic microwave background (CMB) and diffuse extragalactic foregrounds, a catalogue of compact Galactic and extragalactic sources, and a list of sources detected through the Sunyaev-Zeldovich effect. The likelihood code used to assess cosmological models against the Planck data and a lensing likelihood are described. Scientific results include robust support for the standard six-parameter ΛCDM model of cosmology and improved measurements of its parameters, including a highly significant deviation from scale invariance of the primordial power spectrum. The Planck values for these parameters and others derived from them are significantly different from those previously determined. Several large-scale anomalies in the temperature distribution of the CMB, first detected by WMAP, are confirmed with higher confidence. Planck sets new limits on the number and mass of neutrinos, and has measured gravitational lensing of CMB anisotropies at greater than 25σ. Planck finds no evidence for non-Gaussianity in the CMB. Planck’s results agree well with results from the measurements of baryon acoustic oscillations. Planck finds a lower Hubble constant than found in some more local measures. Some tension is also present between the amplitude of matter fluctuations (σ8) derived from CMB data and that derived from Sunyaev-Zeldovich data. The Planck and WMAP power spectra are offset from each other by an average level of about 2% around the first acoustic peak. Analysis of Planck polarization data is not yet mature, therefore polarization results are not released, although the robust detection of E-mode polarization around CMB hot and cold spots is shown graphically.

Metal–organic frameworks for artificial photosynthesis and photocatalysis

Abstract: Solar energy is an alternative, sustainable energy source for mankind. Finding a convenient way to convert sunlight energy into chemical energy is a key step towards realizing large-scale solar energy utilization. Owing to their structural regularity and synthetic tunability, metal–organic frameworks (MOFs) provide an interesting platform to hierarchically organize light-harvesting antennae and catalytic centers to achieve solar energy conversion. Such photo-driven catalytic processes not only play a critical role in the solar to chemical energy conversion scheme, but also provide a novel methodology for the synthesis of fine chemicals. In this review, we summarize the fundamental principles of energy transfer and photocatalysis and provide an overview of the latest progress in energy transfer, light-harvesting, photocatalytic proton and CO2 reduction, and water oxidation using MOFs. The applications of MOFs in organic photocatalysis and degradation of model organic pollutants are also discussed.

Assessing agricultural risks of climate change in the 21st century in a global gridded crop model intercomparison

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.

The Global Decline of the Labor Share

Abstract: The stability of the labor share of income is a key foundation in macroeconomic models. We document, however, that the global labor share has signicantly declined since the early 1980s, with the decline occurring within the large majority of countries and industries. We show that the decrease in the relative price of investment goods, often attributed to advances in information technology and the computer age, induced rms

Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

Abstract: High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death–ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti–PD-L1 enhanced the efficacy of IR through a cytotoxic T cell–dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti–PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.

Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer

Abstract: BackgroundChromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non–small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. MethodsWe enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase–polymerase-chain-reaction assays. ResultsThe objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of respon...

Planck 2013 results. XXII. Constraints on inflation

Abstract: We present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey, which includes more than twice the integration time of the nominal survey used for the 2013 release papers. The Planck full mission temperature data and a first release of polarization data on large angular scales measure the spectral index of curvature perturbations to be ns = 0.968 ± 0.006 and tightly constrain its scale dependence to dns/ dlnk = −0.003 ± 0.007 when combined with the Planck lensing likelihood. When the Planck high-l polarization data are included, the results are consistent and uncertainties are further reduced. The upper bound on the tensor-to-scalar ratio is r0.002< 0.11 (95% CL). This upper limit is consistent with the B-mode polarization constraint r< 0.12 (95% CL) obtained from a joint analysis of the BICEP2/Keck Array and Planck data. These results imply that V(φ) ∝ φ2 and natural inflation are now disfavoured compared to models predicting a smaller tensor-to-scalar ratio, such as R2 inflation. We search for several physically motivated deviations from a simple power-law spectrum of curvature perturbations, including those motivated by a reconstruction of the inflaton potential not relying on the slow-roll approximation. We find that such models are not preferred, either according to a Bayesian model comparison or according to a frequentist simulation-based analysis. Three independent methods reconstructing the primordial power spectrum consistently recover a featureless and smooth over the range of scales 0.008 Mpc-1 ≲ k ≲ 0.1 Mpc-1. At large scales, each method finds deviations from a power law, connected to a deficit at multipoles l ≈ 20−40 in the temperature power spectrum, but at an uncompelling statistical significance owing to the large cosmic variance present at these multipoles. By combining power spectrum and non-Gaussianity bounds, we constrain models with generalized Lagrangians, including Galileon models and axion monodromy models. The Planck data are consistent with adiabatic primordial perturbations, and the estimated values for the parameters of the base Λ cold dark matter (ΛCDM) model are not significantly altered when more general initial conditions are admitted. In correlated mixed adiabatic and isocurvature models, the 95% CL upper bound for the non-adiabatic contribution to the observed CMB temperature variance is | αnon - adi | < 1.9%, 4.0%, and 2.9% for CDM, neutrino density, and neutrino velocity isocurvature modes, respectively. We have tested inflationary models producing an anisotropic modulation of the primordial curvature power spectrum findingthat the dipolar modulation in the CMB temperature field induced by a CDM isocurvature perturbation is not preferred at a statistically significant level. We also establish tight constraints on a possible quadrupolar modulation of the curvature perturbation. These results are consistent with the Planck 2013 analysis based on the nominal mission data and further constrain slow-roll single-field inflationary models, as expected from the increased precision of Planck data using the full set of observations.

Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

Abstract: Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncologic therapeutic armamentarium. Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction. Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ven- tricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and spe- cific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat ma- lignancies, the invasive nature of the procedure, and the remarkable progress made in noninvasive cardiac imaging. The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially car- diotoxic cancer treatment.

Gene expression regulation mediated through reversible m 6 A RNA methylation

Abstract: Cellular RNAs carry diverse chemical modifications that used to be regarded as static and having minor roles in 'fine-tuning' structural and functional properties of RNAs. In this Review, we focus on reversible methylation through the most prevalent mammalian mRNA internal modification, N(6)-methyladenosine (m(6)A). Recent studies have discovered protein 'writers', 'erasers' and 'readers' of this RNA chemical mark, as well as its dynamic deposition on mRNA and other types of nuclear RNA. These findings strongly indicate dynamic regulatory roles that are analogous to the well-known reversible epigenetic modifications of DNA and histone proteins. This reversible RNA methylation adds a new dimension to the developing picture of post-transcriptional regulation of gene expression.

fastSTRUCTURE: Variational Inference of Population Structure in Large SNP Data Sets

Abstract: Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a data set and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias toward detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html.

International Society of Geriatric Oncology Consensus on Geriatric Assessment in Older Patients With Cancer

Abstract: Purpose To update the International Society of Geriatric Oncology (SIOG) 2005 recommendations on geriatric assessment (GA) in older patients with cancer. Methods SIOG composed a panel with expertise in geriatric oncology to develop consensus statements after literature review of key evidence on the following topics: rationale for performing GA; findings from a GA performed in geriatric oncology patients; ability of GA to predict oncology treatment–related complications; association between GA findings and overall survival (OS); impact of GA findings on oncology treatment decisions; composition of a GA, including domains and tools; and methods for implementing GA in clinical care. Results GA can be valuable in oncology practice for following reasons: detection of impairment not identified in routine history or physical examination, ability to predict severe treatment-related toxicity, ability to predict OS in a variety of tumors and treatment settings, and ability to influence treatment choice and intensit...

The tenth data release of the Sloan digital sky survey: First spectroscopic data from the SDSS-iii apache point observatory galactic evolution experiment

Abstract: The Sloan Digital Sky Survey (SDSS) has been in operation since 2000 April. This paper presents the Tenth Public Data Release (DR10) from its current incarnation, SDSS-III. This data release includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July. The APOGEE instrument is a near-infrared R ~ 22,500 300 fiber spectrograph covering 1.514-1.696 μm. The APOGEE survey is studying the chemical abundances and radial velocities of roughly 100,000 red giant star candidates in the bulge, bar, disk, and halo of the Milky Way. DR10 includes 178,397 spectra of 57,454 stars, each typically observed three or more times, from APOGEE. Derived quantities from these spectra (radial velocities, effective temperatures, surface gravities, and metallicities) are also included. DR10 also roughly doubles the number of BOSS spectra over those included in the Ninth Data Release. DR10 includes a total of 1,507,954 BOSS spectra comprising 927,844 galaxy spectra, 182,009 quasar spectra, and 159,327 stellar spectra selected over 6373.2 deg2.

Proteogenomic characterization of human colon and rectal cancer

Abstract: Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA 'microsatellite instability/CpG island methylation phenotype' transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis- and trans-effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology.

Guidelines for investigating causality of sequence variants in human disease

Abstract: The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Obesity-associated variants within FTO form long-range functional connections with IRX3

Abstract: Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.