25 research outputs found

    A search for neutrino emission from the Fermi bubbles with the ANTARES telescope

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    Analysis of the Fermi-LAT data has revealed two extended structures above and below the Galactic Centre emitting gamma rays with a hard spectrum, the so-called Fermi bubbles. Hadronic models attempting to explain the origin of the Fermi bubbles predict the emission of high-energy neutrinos and gamma rays with similar fluxes. The ANTARES detector, a neutrino telescope located in the Mediterranean Sea, has a good visibility to the Fermi bubble regions. Using data collected from 2008 to 2011 no statistically significant excess of events is observed and therefore upper limits on the neutrino flux in TeV range from the Fermi bubbles are derived for various assumed energy cutoffs of the source

    Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

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    OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

    Large-scale ICU data sharing for global collaboration: the first 1633 critically ill COVID-19 patients in the Dutch Data Warehouse

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    Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

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    A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

    Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

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    To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

    Practical Equations for Three-Particle Scattering Calculations

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    Convergence of a neutron-deuteron multiple-scattering series

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    Levels of insulator-associated factors and Motif-1-binding protein are highest on unaffected genes.

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    <p><b>(A)</b> The median intensity for the insulator protein BEAF32 (BEAF_70 ChIP-chip) 500bp upstream and downstream of the TSS of paused genes with GAF-bound promoters separated into genes with significantly reduced promoter GRO-seq reads (Pause reduced, red line) and all other paused genes with GAF-bound promoters (Pause unchanged, gray line). The shaded areas represent the 10% and 90% confidence intervals. <b>(B)</b> The same plot as in A for the chromodomain protein Chriz (Chro(Chriz)BR ChIP-chip). <b>(C)</b> The median ChIP-seq reads for the transcription factor Motif-1-binding protein ChIP-seq dataset, plotted the same as A. <b>(D)</b> Fraction of paused genes with GAF-bound promoters overlapping with regions of enrichment for BEAF32 in BEAF_70 ChIP-chip dataset within 500bp of their TSS. <b>(E)</b> The same plot as in D for Chriz in the Chro(Chriz)BR dataset. <b>(F)</b> The same plot as in D for Motif-1-binding protein ChIP-seq dataset on their promoter.</p
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