IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.

CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity

Sex Differences in Poststroke Cognitive Impairment : A Multicenter Study in 2343 Patients With Acute Ischemic Stroke

Funding Information: Dr Exalto is supported by Alzheimer Nederland WE.03-2019-15 and Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON 2018-28 & 2012-06). The Meta-VCI Map consortium is supported by Vici Grant 918.16.616 from The Netherlands Organisation for Health Research and Development (ZonMw) to Dr Biessels. Harmonization analyses were supported by a Rudolf Magnus Young Talent Fellowship from the University Medical Center Utrecht Brain Center to Dr Biesbroek. The CASPER cohort was supported by Maastricht University, Health Foundation Limburg, and Stichting Adriana van Rinsum-Ponsen. The CROMIS-2 cohort was funded by the UK Stroke Association and the British Heart Foundation (grant number TSA BHF 2009/01). The CU-STRIDE cohort was supported by the Health and Health Services Research Fund of the Food and Health Bureau of the Government of Hong Kong (grant number 0708041), the Lui Che Woo Institute of Innovative Medicine, and Therese Pei Fong Chow Research Center for Prevention of Dementia. The GRECogVASC cohort was funded by Amiens University Hospital and by a grant from the French Ministry of Health (grant number DGOS R1/2013/144). The MSS-2 cohort is funded by the Wellcome Trust (grant number WT088134/Z/09/A to Dr Wardlaw) and the Row Fogo Charitable Trust. The PROCRAS cohort was funded via ZonMW as part of the TopZorg project in 2015 (grant number 842003011). The CODECS cohort (ongoing) is supported by a grant from Stichting Coolsingel (grant number 514). The Bundang VCI and Hallym VCI cohort groups do not wish to report any relevant funding sources. At the time of contribution, Dr Hamilton was funded by the College of Medicine and Veterinary Medicine at the University of Edinburgh and was supported by the Wellcome Trust through the Translational Neuroscience PhD program at the University of Edinburgh. Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.Peer reviewedPublisher PD

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Measurement of CP observables in B± → D(⁎)K± and B± → D(⁎)π± decays

Measurements of CP observables in B ± →D (⁎) K ± and B ± →D (⁎) π ± decays are presented, where D (⁎) indicates a neutral D or D ⁎ meson that is an admixture of D (⁎)0 and D¯ (⁎)0 states. Decays of the D ⁎ meson to the Dπ 0 and Dγ final states are partially reconstructed without inclusion of the neutral pion or photon, resulting in distinctive shapes in the B candidate invariant mass distribution. Decays of the D meson are fully reconstructed in the K ± π ∓ , K + K − and π + π − final states. The analysis uses a sample of charged B mesons produced in pp collisions collected by the LHCb experiment, corresponding to an integrated luminosity of 2.0, 1.0 and 2.0 fb −1 taken at centre-of-mass energies of s=7, 8 and 13 TeV, respectively. The study of B ± →D ⁎ K ± and B ± →D ⁎ π ± decays using a partial reconstruction method is the first of its kind, while the measurement of B ± →DK ± and B ± →Dπ ± decays is an update of previous LHCb measurements. The B ± →DK ± results are the most precise to date

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are region

Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Several susceptibility loci for classical Hodgkin lymphoma (cHL) have been reported, however much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies (GWAS), a new GWAS, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all cHL at 6q22.33 (rs9482849, P=1.52 × 10-8) and for nodular sclerosis HL (NSHL) at 3q28 (rs4459895, P=9.43 × 10-17), 6q23.3 (rs6928977, P=4.62 × 10-55 11), 10p14 (rs3781093, P=9.49 × 10-13), 13q34 (rs112998813, P=4.58 × 10-8) and 16p13.13 (rs34972832, P=2.12 × 10-8). Additionally, independent loci within the HLA region are observed for NSHL (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity HL (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.In the United Kingdom, Bloodwise (LLR; 10021) provided principal funding for the study. Support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Lymphoma Research Trust is also acknowledged. A.S. is supported by a clinical fellowship from Cancer Research UK. For the UK-GWAS, sample and data acquisition were supported by Breast Cancer Now, the European Union and the Lymphoma Research Trust. The UK-GWAS made use of control genotyping data generated by the WTCCC. For further information, please visit the publishr's website

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for Cp

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype