People's differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found ...evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal-numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal-numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer's disease and schizophrenia.
PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small ...biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other ...psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.
We present a sample of low-resolution 5-38 km Spitzer IRS spectra of the inner few square kiloparsecs of 59 nearby galaxies spanning a large range of star formation properties. A robust method for ...decomposing mid-infrared galaxy spectra is described and used to explore the behavior of PAH emission and the prevalence of silicate dust extinction. Evidence for silicate extinction is found in6 of the sample, at strengths that indicate that most normal galaxies undergo A sub(V) 3 mag averaged over then-centers. The contribution of PAH emission to the total infrared power is found to peak near 10% and extend up to 620% and is suppressed at metallicities Z Z /4, as well as in low-luminosity AGN environments. Strong interband PAH feature strength variations (2-5 times) are observed, with the presence of a weak AGN and, to a lesser degree, increasing metallicity shifting power to the longer wavelength bands. A peculiar PAH emission spectrum with markedly diminished 5-8 km features arises among the sample solely in systems with relatively hard radiation fields harboring low-luminosity AGNs. The AGNs may modify the emitting grain distribution and provide the direct excitation source of the unusual PAH emission, which cautions against using absolute PAH strength to estimate star formation rates in systems harboring active nuclei. Alternatively, the low star formation intensity often associated with weak AGNs may affect the spectrum. The effect of variations in the mid-infrared spectrum on broadband infrared surveys is modeled and points to more than a factor of 2 uncertainty in results that assume a fixed PAH emission spectrum, for redshifts z = 0-2.5.
Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin’s effects on food intake are ...mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp−/−;Npy−/− and Mc3r−/−;Mc4r−/− double knockout mice as well as Npy−/− and Agrp−/− single knockout mice with either ghrelin or an orally active nonpeptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. Although deletion of either NPY or AgRP caused only a modest or nondetectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.
We present accurate resolved WISE photometry of galaxies in the combined SINGS and KINGFISH sample. The luminosities in the W3 12 m and W4 23 m bands are calibrated to star formation rates (SFRs) ...derived using the total infrared luminosity, avoiding UV/optical uncertainties due to dust extinction corrections. The W3 relation has a 1 scatter of 0.15 dex that is over nearly 5 orders of magnitude in SFR and 12 m luminosity, and a range in host stellar mass from dwarfs (107 ) to (1011.5 ) galaxies. In the absence of deep silicate absorption features and powerful active galactic nuclei, we expect this to be a reliable SFR indicator chiefly due to the broad nature of the W3 band. By contrast, the W4 SFR relation shows more scatter (1 dex). Both relations show reasonable agreement with radio-continuum-derived SFRs and excellent accordance with so-called "hybrid" H + 24 m and FUV+24 m indicators. Moreover, the WISE SFR relations appear to be insensitive to the metallicity range in the sample. We also compare our results with IRAS-selected luminous infrared galaxies, showing that the WISE relations maintain concordance, but systematically deviate for the most extreme galaxies. Given the all-sky coverage of WISE and the performance of the W3 band as an SFR indicator, the SFR relation could be of great use to studies of nearby galaxies and forthcoming large-area surveys at optical and radio wavelengths.
The applications of Western/immunoblotting (WB) techniques have reached multiple layers of the scientific community and are now considered routine procedures in the field of physiology. This is none ...more so than in relation to skeletal muscle physiology (i.e., resolving the mechanisms underpinning adaptations to exercise). Indeed, the inclusion of WB data is now considered an essential aspect of many such physiological publications to provide mechanistic insight into regulatory processes. Despite this popularity, and due to the ubiquitous and relatively inexpensive availability of WB equipment, the quality of WB in publications and subsequent analysis and interpretation of the data can be variable, perhaps resulting in spurious conclusions. This may be due to poor laboratory technique and/or lack of comprehension of the critical steps involved in WB and what quality control procedures should be in place to ensure robust data generation. The present review aims to provide a detailed description and critique of WB procedures and technicalities, from sample collection through preparation, blotting and detection, to analysis of the data collected. We aim to provide the reader with improved expertise to critically conduct, evaluate, and troubleshoot the WB process, to produce reproducible and reliable blots.
Context. Deep far-infrared (FIR) cosmological surveys are known to be affected by source confusion, causing issues when examining the main sequence (MS) of star forming galaxies. In the past this has ...typically been partially tackled by the use of stacking. However, stacking only provides the average properties of the objects in the stack. Aims. This work aims to trace the MS over 0.2 ≤ z < 6.0 using the latest de-blended Herschel photometry, which reaches ≈10 times deeper than the 5σ confusion limit in SPIRE. This provides more reliable star formation rates (SFRs), especially for the fainter galaxies, and hence a more reliable MS. Methods. We built a pipeline that uses the spectral energy distribution (SED) modelling and fitting tool CIGALE to generate flux density priors in the Herschel SPIRE bands. These priors were then fed into the de-blending tool XID+ to extract flux densities from the SPIRE maps. In the final step, multi-wavelength data were combined with the extracted SPIRE flux densities to constrain SEDs and provide stellar mass (M⋆) and SFRs. These M⋆ and SFRs were then used to populate the SFR-M⋆ plane over 0.2 ≤ z < 6.0. Results. No significant evidence of a high-mass turn-over was found; the best fit is thus a simple two-parameter power law of the form log(SFR) = αlog(M⋆) − 10.5 + β. The normalisation of the power law increases with redshift, rapidly at z ≲ 1.8, from 0.58 ± 0.09 at z ≈ 0.37 to 1.31 ± 0.08 at z ≈ 1.8. The slope is also found to increase with redshift, perhaps with an excess around 1.8 ≤ z < 2.9. Conclusions. The increasing slope indicates that galaxies become more self-similar as redshift increases. This implies that the specific SFR of high-mass galaxies increases with redshift, from 0.2 to 6.0, becoming closer to that of low-mass galaxies. The excess in the slope at 1.8 ≤ z < 2.9, if present, coincides with the peak of the cosmic star formation history.
In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of surveillance, the virus spread worldwide to ...30 countries (as of May 11) by human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5 of 6. This virus has the potential to develop into the first influenza pandemic of the twenty-first century. Here we use evolutionary analysis to estimate the timescale of the origins and the early development of the S-OIV epidemic. We show that it was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. A phylogenetic estimate of the gaps in genetic surveillance indicates a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. Furthermore, the unsampled history of the epidemic means that the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic, despite the fact that we included a panel of closely related and previously unpublished swine influenza isolates. Our results highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.
Abstract
Chemically peculiar stars in dwarf galaxies provide a window for exploring the birth environment of stars with varying chemical enrichment. We present a chemical abundance analysis of the ...brightest star in the newly discovered ultra-faint dwarf galaxy candidate Tucana III. Because it is particularly bright for a star in an ultra-faint Milky Way (MW) satellite, we are able to measure the abundance of 28 elements, including 13 neutron-capture species. This star, DES J235532.66−593114.9 (DES J235532), shows a mild enhancement in neutron-capture elements associated with the
r
-process and can be classified as an
r
-I star. DES J235532 is the first
r
-I star to be discovered in an ultra-faint satellite, and Tuc III is the second extremely low-luminosity system found to contain
r
-process enriched material, after Reticulum II. Comparison of the abundance pattern of DES J235532 with
r
-I and
r
-II stars found in other dwarf galaxies and in the MW halo suggests a common astrophysical origin for the neutron-capture elements seen in all
r
-process enhanced stars. We explore both internal and external scenarios for the
r
-process enrichment of Tuc III and show that with abundance patterns for additional stars, it should be possible to distinguish between them.
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