Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe

The thermal emission of the exoplanets WASP-1b and WASP-2b

We present a comparative study of the thermal emission of the transiting exoplanets WASP-1b and WASP-2b using the Spitzer Space Telescope. The two planets have very similar masses but suffer different levels of irradiation and are predicted to fall either side of a sharp transition between planets with and without hot stratospheres. WASP-1b is one of the most highly irradiated planets studied to date. We measure planet/star contrast ratios in all four of the IRAC bands for both planets (3.6-8.0um), and our results indicate the presence of a strong temperature inversion in the atmosphere of WASP-1b, particularly apparent at 8um, and no inversion in WASP-2b. In both cases the measured eclipse depths favor models in which incident energy is not redistributed efficiently from the day side to the night side of the planet. We fit the Spitzer light curves simultaneously with the best available radial velocity curves and transit photometry in order to provide updated measurements of system parameters. We do not find significant eccentricity in the orbit of either planet, suggesting that the inflated radius of WASP-1b is unlikely to be the result of tidal heating. Finally, by plotting ratios of secondary eclipse depths at 8um and 4.5um against irradiation for all available planets, we find evidence for a sharp transition in the emission spectra of hot Jupiters at an irradiation level of 2 x 10^9 erg/s/cm^2. We suggest this transition may be due to the presence of TiO in the upper atmospheres of the most strongly irradiated hot Jupiters.Comment: 10 pages, submitted to Ap

Randomised trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients

Background: Mortality rates in the Intensive Care Unit and subsequent hospital mortality rates in the UK remain high. Infections in Intensive Care are associated with a 2–3 times increased risk of death. It is thought that under conditions of severe metabolic stress glutamine becomes "conditionally essential". Selenium is an essential trace element that has antioxidant and anti-inflammatory properties. Approximately 23% of patients in Intensive Care require parenteral nutrition and glutamine and selenium are either absent or present in low amounts. Both glutamine and selenium have the potential to influence the immune system through independent biochemical pathways. Systematic reviews suggest that supplementing parenteral nutrition in critical illness with glutamine or selenium may reduce infections and mortality. Pilot data has shown that more than 50% of participants developed infections, typically resistant organisms. We are powered to show definitively whether supplementation of PN with either glutamine or selenium is effective at reducing new infections in critically ill patients. Methods/design: 2 × 2 factorial, pragmatic, multicentre, double-blind, randomised controlled trial. The trial has an enrolment target of 500 patients. Inclusion criteria include: expected to be in critical care for at least 48 hours, aged 16 years or over, patients who require parenteral nutrition and are expected to have at least half their daily nutritional requirements given by that route. Allocation is to one of four iso-caloric, iso-nitrogenous groups: glutamine, selenium, both glutamine & selenium or no additional glutamine or selenium. Trial supplementation is given for up to seven days on the Intensive Care Unit and subsequent wards if practicable. The primary outcomes are episodes of infection in the 14 days after starting trial nutrition and mortality. Secondary outcomes include antibiotic usage, length of hospital stay, quality of life and cost-effectiveness. Discussion: To date more than 285 patients have been recruited to the trial from 10 sites in Scotland. Recruitment is due to finish in August 2008 with a further six months follow up. We expect to report the results of the trial in summer 2009. Trial registration: This trial is registered with the International Standard Randomised Controlled Trial Number system. ISRCTN87144826Not peer reviewedPublisher PD

Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain

<p>Abstract</p> <p>Background</p> <p>Variations in sortilin-related receptor (SORL1) expression and function have been implicated in Alzheimers Disease (AD). Here, to gain insights into SORL1, we evaluated SORL1 expression and splicing as a function of AD and AD neuropathology, neural gene expression and a candidate single nucleotide polymorphism (SNP).</p> <p>Results</p> <p>To identify SORL1 splice variants, we scanned each of the 46 internal SORL1 exons in human brain RNA samples and readily found SORL1 isoforms that lack exon 2 or exon 19. Quantification in a case-control series of the more abundant isoform lacking exon 2 (delta-2-SORL1), as well as the "full-length" SORL1 (FL-SORL1) isoform containing exon 2 showed that expression of FL-SORL1 was reduced in AD individuals. Moreover, FL-SORL1 was reduced in cognitively intact individuals with significant AD-like neuropathology. In contrast, the expression of the delta-2-SORL1 isoform was similar in AD and non-AD brains. The expression of FL-SORL1 was significantly associated with synaptophysin expression while delta-2-SORL1 was modestly enriched in white matter. Lastly, FL-SORL1 expression was associated with rs661057, a SORL1 intron one SNP that has been associated with AD risk. A linear regression analysis found that rs661057, synaptophysin expression and AD neuropathology were each associated with FL-SORL1 expression.</p> <p>Conclusion</p> <p>These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain.</p

Ambient air quality in the Kathmandu Valley, Nepal, during the pre-monsoon: Concentrations and sources of particulate matter and trace gases

The Kathmandu Valley in Nepal is a bowl-shaped urban basin that experiences severe air pollution that poses health risks to its 3.5 million inhabitants. As part of the Nepal Ambient Monitoring and Source Testing Experiment (NAMaSTE), ambient air quality in the Kathmandu Valley was investigated from 11 to 24 April 2015, during the premonsoon season. Ambient concentrations of fine and coarse particulate matter (PM2:5 and PM10, respectively), online PM1, inorganic trace gases (NH3, HNO3, SO2, and HCl), and carbon-containing gases (CO2, CO, CH4, and 93 nonmethane volatile organic compounds; NMVOCs) were quantified at a semi-urban location near the center of the valley. Concentrations and ratios of NMVOC indicated origins primarily from poorly maintained vehicle emissions, biomass burning, and solvent/gasoline evaporation. During those 2 weeks, daily average PM2:5 concentrations ranged from 30 to 207 μ g m-3, which exceeded the World Health Organization 24 h guideline by factors of 1.2 to 8.3. On average, the nonwater mass of PM2:5 was composed of organic matter (48 %), elemental carbon (13 %), sulfate (16 %), nitrate (4 %), ammonium (9 %), chloride (2 %), calcium (1 %), magnesium (0.05 %), and potassium (1 %). Large diurnal variability in temperature and relative humidity drove corresponding variability in aerosol liquid water content, the gas-aerosol phase partitioning of NH3, HNO3, and HCl, and aerosol solution pH. The observed levels of gas-phase halogens suggest that multiphase halogen-radical chemistry involving both Cl and Br impacted regional air quality. To gain insight into the origins of organic carbon (OC), molecular markers for primary and secondary sources were quantified. Levoglucosan (averaging 1230±1154 ng m-3), 1,3,5-triphenylbenzene (0:8± 0:6 ng m-3), cholesterol (2:9±6:6 ng m-3), stigmastanol (1.0 ±0:8 ng m-3), and cis-pinonic acid (4:5 ± 1:9 ng m-3) indicate contributions from biomass burning, garbage burning, food cooking, cow dung burning, and monoterpene secondary organic aerosol, respectively. Drawing on source profiles developed in NAMaSTE, chemical mass balance (CMB) source apportionment modeling was used to estimate contributions to OC from major primary sources including garbage burning (18 ± 5 %), biomass burning (17 ± 10 %) inclusive of open burning and biomass-fueled cooking stoves, and internal-combustion (gasoline and diesel) engines (18±9 %). Model sensitivity tests with newly developed source profiles indicated contributions from biomass burning within a factor of 2 of previous estimates but greater contributions from garbage burning (up to three times), indicating large potential impacts of garbage burning on regional air quality and the need for further evaluation of this source. Contributions of secondary organic carbon (SOC) to PM2:5 OC included those originating from anthropogenic precursors such as naphthalene (10 ± 4 %) and methylnaphthalene (0:3 ± 0:1 %) and biogenic precursors for monoterpenes (0:13 ± 0:07 %) and sesquiterpenes (5 ± 2 %). An average of 25 % of the PM2.5 OC was unapportioned, indicating the presence of additional sources (e.g., evaporative and/or industrial emissions such as brick kilns, food cooking, and other types of SOC) and/or underestimation of the contributions from the identified source types. The source apportionment results indicate that anthropogenic combustion sources (including biomass burning, garbage burning, and fossil fuel combustion) were the greatest contributors to PM2:5 and, as such, should be considered primary targets for controlling ambient PM pollution

Galaxy Zoo: CANDELS barred discs and bar fractions

The formation of bars in disc galaxies is a tracer of the dynamical maturity of the population. Previous studies have found that the incidence of bars in discs decreases from the local Universe to z ~ 1, and by z > 1 simulations predict that bar features in dynamically mature discs should be extremely rare. Here, we report the discovery of strong barred structures in massive disc galaxies at z ~ 1.5 in deep rest-frame optical images from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. From within a sample of 876 disc galaxies identified by visual classification in Galaxy Zoo, we identify 123 barred galaxies. Selecting a subsample within the same region of the evolving galaxy luminosity function (brighter than L*), we find that the bar fraction across the redshift range 0.5 ≤ z ≤ 2 (fbar = 10.7+6.3 -3.5 per cent after correcting for incompleteness) does not significantly evolve.We discuss the implications of this discovery in the context of existing simulations and our current understanding of the way disc galaxies have evolved over the last 11 billion yearsPeer reviewedFinal Accepted Versio

Profiles of Global Gene Expression in Ionizing-Radiation–Damaged Human Diploid Fibroblasts Reveal Synchronization behind the G(1) Checkpoint in a G(0)-like State of Quiescence

Cell cycle arrest and stereotypic transcriptional responses to DNA damage induced by ionizing radiation (IR) were quantified in telomerase-expressing human diploid fibroblasts. Analysis of cytotoxicity demonstrated that 1.5 Gy IR inactivated colony formation by 40–45% in three fibroblast lines; this dose was used in all subsequent analyses. Fibroblasts exhibited > 90% arrest of progression from G(2) to M at 2 hr post-IR and a similarly severe arrest of progression from G(1) to S at 6 and 12 hr post-IR. Normal rates of DNA synthesis and mitosis 6 and 12 hr post-IR caused the S and M compartments to empty by > 70% at 24 hr. Global gene expression was analyzed in IR-treated cells. A microarray analysis algorithm, EPIG, identified nine IR-responsive patterns of gene expression that were common to the three fibroblast lines, including a dominant p53-dependent G(1) checkpoint response. Many p53 target genes, such as CDKN1A, GADD45, BTG2, and PLK3, were significantly up-regulated at 2 hr post-IR. Many genes whose expression is regulated by E2F family transcription factors, including CDK2, CCNE1, CDC6, CDC2, MCM2, were significantly down-regulated at 24 hr post-IR. Numerous genes that participate in DNA metabolism were also markedly repressed in arrested fibroblasts apparently as a result of cell synchronization behind the G(1) checkpoint. However, cluster and principal component analyses of gene expression revealed a profile 24 hr post-IR with similarity to that of G(0) growth quiescence. The results reveal a highly stereotypic pattern of response to IR in human diploid fibroblasts that reflects primarily synchronization behind the G(1) checkpoint but with prominent induction of additional markers of G(0) quiescence such as GAS1

Gravity wave analogs of black holes

It is demonstrated that gravity waves of a flowing fluid in a shallow basin can be used to simulate phenomena around black holes in the laboratory. Since the speed of the gravity waves as well as their high-wavenumber dispersion (subluminal vs. superluminal) can be adjusted easily by varying the height of the fluid (and its surface tension) this scenario has certain advantages over the sonic and dielectric black hole analogs, for example, although its use in testing quantum effects is dubious. It can be used to investigate the various classical instabilities associated with black (and white) holes experimentally, including positive and negative norm mode mixing at horizons. PACS: 04.70.-s, 47.90.+a, 92.60.Dj, 04.80.-y.Comment: 14 pages RevTeX, 5 figures, section VI modifie

Bacteroides fragilis outer membrane vesicles preferentially activate innate immune receptors compared to their parent bacteria

The release of bacterial membrane vesicles (BMVs) has become recognized as a key mechanism used by both pathogenic and commensal bacteria to activate innate immune responses in the host and mediate immunity. Outer membrane vesicles (OMVs) produced by Gram-negative bacteria can harbor various immunogenic cargo that includes proteins, nucleic acids and peptidoglycan, and the composition of OMVs strongly influences their ability to activate host innate immune receptors. Although various Gram-negative pathogens can produce OMVs that are enriched in immunogenic cargo compared to their parent bacteria, the ability of OMVs produced by commensal organisms to be enriched with immunostimulatory contents is only recently becoming known. In this study, we investigated the cargo associated with OMVs produced by the intestinal commensal Bacteroides fragilis and determined their ability to activate host innate immune receptors. Analysis of B. fragilis OMVs revealed that they packaged various biological cargo including proteins, DNA, RNA, lipopolysaccharides (LPS) and peptidoglycan, and that this cargo could be enriched in OMVs compared to their parent bacteria. We visualized the entry of B. fragilis OMVs into intestinal epithelial cells, in addition to the ability of B. fragilis OMVs to transport bacterial RNA and peptidoglycan cargo into Caco-2 epithelial cells. Using HEK-Blue reporter cell lines, we identified that B. fragilis OMVs could activate host Toll-like receptors (TLR)-2, TLR4, TLR7 and nucleotide-binding oligomerization domain-containing protein 1 (NOD1), whereas B. fragilis bacteria could only induce the activation of TLR2. Overall, our data demonstrates that B. fragilis OMVs activate a broader range of host innate immune receptors compared to their parent bacteria due to their enrichment of biological cargo and their ability to transport this cargo directly into host epithelial cells. These findings indicate that the secretion of OMVs by B. fragilis may facilitate immune crosstalk with host epithelial cells at the gastrointestinal surface and suggests that OMVs produced by commensal bacteria may preferentially activate host innate immune receptors at the mucosal gastrointestinal tract