Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis

Our objective was to identify whether rare genetic variation in amyotrophic lateral sclerosis (ALS) candidate survival genes modifies ALS survival. Candidate genes were selected based on evidence for modifying ALS survival. Each tail of the extreme 1.5% of survival was selected from the UK MND DNA Bank and all samples available underwent whole genome sequencing. A replication set from the Netherlands was used for validation. Sequences of candidate survival genes were extracted and variants passing quality control with a minor allele frequency ≤0.05 were selected for association testing. Analysis was by burden testing using SKAT. Candidate survival genes UNC13A, KIFAP3, and EPHA4 were tested for association in a UK sample comprising 25 short survivors and 25 long survivors. Results showed that only SNVs in UNC13A were associated with survival (p = 6.57 × 10−3). SNV rs10419420:G > A was found exclusively in long survivors (3/25) and rs4808092:G > A exclusively in short survivors (4/25). These findings were not replicated in a Dutch sample. In conclusion, population specific rare variants of UNC13A may modulate survival in ALS

Association between statin use after diagnosis of esophageal cancer and survival: a population-based cohort study

Background & Aims: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), commonly prescribed to prevent cardiovascular disease, promote apoptosis and limit proliferation of esophageal cancer cell lines. We investigated whether statin use following diagnosis of esophageal cancer is associated with reduced esophageal cancer-specific and all-cause mortality.  Methods: We identified a cohort of 4445 men and women in the United Kingdom diagnosed with esophageal cancer from January 2000 through November 2009 using the General Practice Research Database. The National Cancer Registry and Office of National Statistics datasets respectively established the histologic subtype and cancer-specific mortality. Cox proportional hazard regression analysis with time-dependent exposures estimated the association between statin use after diagnosis and esophageal cancer-specific and all-cause mortality.  Results: The median survival time of the entire cohort was 9.2 months (inter-quartile range [IQR], 3.7–23.2 months). Among subjects who used statins after diagnosis of esophageal cancer, the median survival time was 14.9 months (IQR, 7.1–52.3) compared to 8.1 months for non-users (IQR, 3.3–20). In the entire cohort, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44–0.86) and all-cause mortality (HR, 0.67; 95% CI, 0.58–0.77). In patients with esophageal adenocarcinoma, statin use after diagnosis was associated with decreased risk of esophageal cancer-specific mortality (HR, 0.61; 95% CI 0.38–0.96) and all-cause mortality (HR, 0.63; 95% 0.43–0.92). This effect was not observed in patients with esophageal squamous cell carcinoma. There was no evidence for effect modification of these associations with statin use before cancer diagnosis.  Conclusions: In a large population-based cohort, statin use after diagnosis of esophageal adenocarcinoma, but not esophageal squamous cell carcinoma, was associated with reduced esophageal cancer-specific and all-cause mortality

Pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in obesity and diabetes, and is rapidly becoming the most common cause of liver disease in Western countries. Indeed, NAFLD is now recognized to be the aetiology in many cases previously labelled as cryptogenic cirrhosis

Ultra-red Galaxies Signpost Candidate Protoclusters at High Redshift

We present images obtained with LABOCA of a sample of 22 galaxies selected via their red Herschel SPIRE colors. We aim to see if these luminous, rare, and distant galaxies are signposting dense regions in the early universe. Our 870 μm survey covers an area of ≈1 deg2 down to an average rms of $3.9\,\mathrm{mJy}\,{\mathrm{beam}}^{-1}$, with our five deepest maps going ≈2× deeper still. We catalog 86 dusty star-forming galaxies (DSFGs) around our "signposts," detected above a significance of 3.5σ. This implies a ${100}_{-30}^{+30} \%$ overdensity of ${S}_{870}\gt 8.5\,\mathrm{mJy}$ (or {L}_{\mathrm{FIR}}=6.7\times {10}^{12}\mbox{--}2.9\times {10}^{13}\,{L}_{\odot }) DSFGs, excluding our signposts, when comparing our number counts to those in "blank fields." Thus, we are 99.93% confident that our signposts are pinpointing overdense regions in the universe, and ≈95% [50%] confident that these regions are overdense by a factor of at least ≥1.5 × [2×]. Using template spectral energy distributions (SEDs) and SPIRE/LABOCA photometry, we derive a median photometric redshift of z = 3.2 ± 0.2 for our signposts, with an inter-quartile range of z = 2.8–3.6, somewhat higher than expected for ~850 μm selected galaxies. We constrain the DSFGs that are likely responsible for this overdensity to within $| {\rm{\Delta }}z| \leqslant 0.65$ of their respective signposts. These "associated" DSFGs are radially distributed within (physical) distances of 1.6 ± 0.5 Mpc from their signposts, have median star formation rates (SFRs) of $\approx (1.0\pm 0.2)\times {10}^{3}\,{M}_{\odot }\,{\mathrm{yr}}^{-1}$ (for a Salpeter stellar inital mass function) and median gas reservoirs of $\sim 1.7\times {10}^{11}\,{M}_{\odot }$. These candidate protoclusters have average total SFRs of at least $\approx (2.3\pm 0.5)\times {10}^{3}\,{M}_{\odot }\,{\mathrm{yr}}^{-1}$ and space densities of ~9 × 10−7 Mpc−3, consistent with the idea that their constituents may evolve to become massive early-type galaxies in the centers of the rich galaxy clusters we see today

HI in the Outskirts of Nearby Galaxies

The HI in disk galaxies frequently extends beyond the optical image, and can trace the dark matter there. I briefly highlight the history of high spatial resolution HI imaging, the contribution it made to the dark matter problem, and the current tension between several dynamical methods to break the disk-halo degeneracy. I then turn to the flaring problem, which could in principle probe the shape of the dark halo. Instead, however, a lot of attention is now devoted to understanding the role of gas accretion via galactic fountains. The current $\rm \Lambda$ cold dark matter theory has problems on galactic scales, such as the core-cusp problem, which can be addressed with HI observations of dwarf galaxies. For a similar range in rotation velocities, galaxies of type Sd have thin disks, while those of type Im are much thicker. After a few comments on modified Newtonian dynamics and on irregular galaxies, I close with statistics on the HI extent of galaxies.Comment: 38 pages, 17 figures, invited review, book chapter in "Outskirts of Galaxies", Eds. J. H. Knapen, J. C. Lee and A. Gil de Paz, Astrophysics and Space Science Library, Springer, in pres

Cosmological parameters from SDSS and WMAP

We measure cosmological parameters using the three-dimensional power spectrum P(k) from over 200,000 galaxies in the Sloan Digital Sky Survey (SDSS) in combination with WMAP and other data. Our results are consistent with a ``vanilla'' flat adiabatic Lambda-CDM model without tilt (n=1), running tilt, tensor modes or massive neutrinos. Adding SDSS information more than halves the WMAP-only error bars on some parameters, tightening 1 sigma constraints on the Hubble parameter from h~0.74+0.18-0.07 to h~0.70+0.04-0.03, on the matter density from Omega_m~0.25+/-0.10 to Omega_m~0.30+/-0.04 (1 sigma) and on neutrino masses from <11 eV to <0.6 eV (95%). SDSS helps even more when dropping prior assumptions about curvature, neutrinos, tensor modes and the equation of state. Our results are in substantial agreement with the joint analysis of WMAP and the 2dF Galaxy Redshift Survey, which is an impressive consistency check with independent redshift survey data and analysis techniques. In this paper, we place particular emphasis on clarifying the physical origin of the constraints, i.e., what we do and do not know when using different data sets and prior assumptions. For instance, dropping the assumption that space is perfectly flat, the WMAP-only constraint on the measured age of the Universe tightens from t0~16.3+2.3-1.8 Gyr to t0~14.1+1.0-0.9 Gyr by adding SDSS and SN Ia data. Including tensors, running tilt, neutrino mass and equation of state in the list of free parameters, many constraints are still quite weak, but future cosmological measurements from SDSS and other sources should allow these to be substantially tightened.Comment: Minor revisions to match accepted PRD version. SDSS data and ppt figures available at http://www.hep.upenn.edu/~max/sdsspars.htm

Effects of mineralogy, chemistry and physical properties of basalts on carbon capture potential and plant-nutrient element release via enhanced weathering

Mafic igneous rocks, such as basalt, are composed of abundant calcium- and magnesium-rich silicate minerals widely proposed to be suitable for scalable carbon dioxide removal (CDR) by enhanced rock weathering (ERW). Here, we report a detailed characterization of the mineralogy, chemistry, particle size and surface area of six mined basalts being used in large-scale ERW field trials. We use 1-D reactive transport modelling (RTM) of soil profile processes to simulate inorganic CDR potential via cation flux (Mg2+, Ca2+, K+ and Na+) and assess the release of the essential plant nutrients phosphorus (P) and potassium (K) for a typical clay-loam agricultural soil. The basalts are primarily composed of pyroxene and plagioclase feldspar (up to 71 wt%), with accessory olivine, quartz, glass and alkali feldspar. Mean crushed particle size varies by a factor of 10, owing to differences in the mining operations and grinding processes. RTM simulations, based on measured mineral composition and N2-gas BET specific surface area (SSA), yielded potential CDR values of between c. 1.3 and 8.5 t CO2 ha−1 after 15 years following a baseline application of 50 t ha−1 basalt. The RTM results are comparative for the range of inputs that are described and should be considered illustrative for an agricultural soil. Nevertheless, they indicate that increasing the surface area for slow-weathering basalts through energy intensive grinding prior to field application in an ERW context may not be warranted in terms of additional CDR gains. We developed a function to convert CDR based on widely available and easily measured rock chemistry measures to more realistic determinations based on mineralogy. When applied to a chemistry dataset for >1300 basalt analyses from 25 large igneous provinces, we simulated cumulative CDR potentials of up to c. 8.5 t CO2 ha−1 after 30 years of weathering, assuming a single application of basalt with a SSA of 1 m2 g−1. Our RTM simulations suggest that ERW with basalt releases sufficient phosphorus (P) to substitute for typical arable crop P-fertiliser usage in Europe and the USA offering potential to reduce demand for expensive rock-derived P

A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease

The interpretation of non-coding variants still constitutes a major challenge in the application of whole-genome sequencing in Mendelian disease, especially for single-nucleotide and other small non-coding variants. Here we present Genomiser, an analysis framework that is able not only to score the relevance of variation in the non-coding genome, but also to associate regulatory variants to specific Mendelian diseases. Genomiser scores variants through either existing methods such as CADD or a bespoke machine learning method and combines these with allele frequency, regulatory sequences, chromosomal topological domains, and phenotypic relevance to\ua0discover variants associated to specific Mendelian disorders. Overall, Genomiser is able to identify causal regulatory variants as the\ua0top candidate in 77% of simulated whole genomes, allowing effective detection and discovery of regulatory variants in Mendelian disease

Measurement of the p-pbar -> Wgamma + X cross section at sqrt(s) = 1.96 TeV and WWgamma anomalous coupling limits

The WWgamma triple gauge boson coupling parameters are studied using p-pbar -> l nu gamma + X (l = e,mu) events at sqrt(s) = 1.96 TeV. The data were collected with the DO detector from an integrated luminosity of 162 pb^{-1} delivered by the Fermilab Tevatron Collider. The cross section times branching fraction for p-pbar -> W(gamma) + X -> l nu gamma + X with E_T^{gamma} > 8 GeV and Delta R_{l gamma} > 0.7 is 14.8 +/- 1.6 (stat) +/- 1.0 (syst) +/- 1.0 (lum) pb. The one-dimensional 95% confidence level limits on anomalous couplings are -0.88 < Delta kappa_{gamma} < 0.96 and -0.20 < lambda_{gamma} < 0.20.Comment: Submitted to Phys. Rev. D Rapid Communication

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s} = 1.96 TeV using Kinematic Characteristics of Lepton + Jets Events

We present a measurement of the top quark pair ttbar production cross section in ppbar collisions at a center-of-mass energy of 1.96 TeV using 230 pb**{-1} of data collected by the DO detector at the Fermilab Tevatron Collider. We select events with one charged lepton (electron or muon), large missing transverse energy, and at least four jets, and extract the ttbar content of the sample based on the kinematic characteristics of the events. For a top quark mass of 175 GeV, we measure sigma(ttbar) = 6.7 {+1.4-1.3} (stat) {+1.6- 1.1} (syst) +/-0.4 (lumi) pb, in good agreement with the standard model prediction.Comment: submitted to Phys.Rev.Let