Measurements of charmless B⁰s meson decays at LHCb

Using 3 fbˉ1 of proton-proton collisions, collected at centre-of-mass energies of √s = 7 and 8 TeV by the LHCb detector, several measurements of charmless B⁰s meson decays are made. A search is also performed for a highly suppressed B⁰ decay. First, the branching fraction of the B0⁰s→ ØØ decay is measured to be B(B⁰s→ ØØ) = (1:84 ± 0:05(stat) ± 0:07(syst) ± 0:11(fs=fd) ± 0:12(norm))X10ˉ⁵; where the third and fourth uncertainties arise from the fragmentation fraction fs/fd and the branching fraction of the normalisation mode. This represents a factor of five reduction in the statistical uncertainty compared to the previous best measurement. An upper limit on the branching fraction of the mode B⁰→ ØØ is set at B(B⁰→ ØØ) < 2:8 X 10ˉ⁸ (90% CL): This is a factor of seven improvement over the previous best measurement. An amplitude analysis of the B⁰s→ ØK+Kˉ decay is performed, wherein first observations of the decay modes B⁰s→ Øf´2(1525) and B⁰s→ ØØ(1680) are made. The branching fraction of the B⁰s→ Øf´2(1525) decay is measured to be B(B⁰s→ Øf´2 (1525)) = (1:63 ± 0:18(stat) ± 0:12(syst) ± 0:29(model) ± 0:17(norm)) X 10ˉ⁶; where the 'model' uncertainty arises from the choice of amplitude model. The longitudinal polarisation fraction of the decay B⁰s→ Øf´2(1525) is measured to be F0 = (86:6 ± 3:4 ± 0:8 ± 2:0 (model))%

Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy.

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) in mammalian nitric oxide signaling. We determined structures of full-length Manduca sexta sGC in both inactive and active states using cryo-electron microscopy. NO and the sGC-specific stimulator YC-1 induce a 71° rotation of the heme-binding β H-NOX and PAS domains. Repositioning of the β H-NOX domain leads to a straightening of the coiled-coil domains, which, in turn, use the motion to move the catalytic domains into an active conformation. YC-1 binds directly between the β H-NOX domain and the two CC domains. The structural elongation of the particle observed in cryo-EM was corroborated in solution using small angle X-ray scattering (SAXS). These structures delineate the endpoints of the allosteric transition responsible for the major cyclic GMP-dependent physiological effects of NO

Young people’s priorities for the self-management of distress after stoma surgery due to inflammatory bowel disease: a consensus study using online nominal group technique

Abstract Introduction: The aim of this study was to gain consensus among young people with a stoma due to inflammatory bowel disease (IBD) on the priorities for the content of an intervention for the self-management of stoma-related distress. The current identification and management of distress in young people with a stoma is often sub-optimal in clinical settings and there is a need for improved support resources.Methods: Two consensus group meetings were carried out via online video conferencing, using Nominal Group Technique. Participants generated, rated on a Likert scale and discussed, topics for inclusion in a future self-management intervention.Results: Nineteen young people, aged 19-33, with a stoma due to IBD took part in one of two group meetings. Participants were located across England, Scotland, and Northern Ireland. Twenty-nine topics were generated by participants, seven of which reached consensus of &gt;80%, that is, a mean of &gt;5.6 on a 7-point Likert scale. These were: receiving advice from young people with lived experience of stoma surgery; advice on/ addressing concerns about romantic relationships, sex and intimacy; information about fertility and pregnancy related to stoma surgery; stoma ‘hacks’, e.g. useful everyday tips regarding clothing, making bag changes easier etc.; reflecting on and recognising own emotional response to surgery; tips on managing the stoma during the night; and processing trauma related to the illness and surgery journey.Conclusions: Findings extend previous research on young people’s experiences of stoma surgery, by generating consensus on young peoples’ priorities for managing distress related to surgery and living with a stoma. These priorities include topics not previously reported in the literature, including the need for information about fertility and pregnancy. Findings will inform the development of a self-management resource for young people with an IBD stoma and have relevance for the clinical management of stoma-related distress in this population.<br/

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P &lt; 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

'It's just superstition I suppose ... I've always done something on game day': The construction of everyday life on a university basketball team

Research in sport has tended to focus on ‘spectacular’ or ‘extra-ordinary’ experiences, at the expense of discussing how particular phenomena are embedded in everyday life. Drawing on ethnographic research with a university basketball team in the North of England, this article considers the meanings that amateur players attach to basketball and how such meanings go beyond their participation in competitive games. Analysis reveals the rhythms and rituals which are hugely important in determining the players’ sense of self. It also highlights the carnivalesque celebrations which allow the players to temporarily disrupt the status quo and experiment with alternative identities. In conclusion, it is argued that the meaning of sport should not be seen as rigid, determining and predictable, but rather a creative experience that is largely dependent on the subjective appropriation of time and place

The National COVID Cohort Collaborative (N3C): Rationale, design, infrastructure, and deployment.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) poses societal challenges that require expeditious data and knowledge sharing. Though organizational clinical data are abundant, these are largely inaccessible to outside researchers. Statistical, machine learning, and causal analyses are most successful with large-scale data beyond what is available in any given organization. Here, we introduce the National COVID Cohort Collaborative (N3C), an open science community focused on analyzing patient-level data from many centers. MATERIALS AND METHODS: The Clinical and Translational Science Award Program and scientific community created N3C to overcome technical, regulatory, policy, and governance barriers to sharing and harmonizing individual-level clinical data. We developed solutions to extract, aggregate, and harmonize data across organizations and data models, and created a secure data enclave to enable efficient, transparent, and reproducible collaborative analytics. RESULTS: Organized in inclusive workstreams, we created legal agreements and governance for organizations and researchers; data extraction scripts to identify and ingest positive, negative, and possible COVID-19 cases; a data quality assurance and harmonization pipeline to create a single harmonized dataset; population of the secure data enclave with data, machine learning, and statistical analytics tools; dissemination mechanisms; and a synthetic data pilot to democratize data access. CONCLUSIONS: The N3C has demonstrated that a multisite collaborative learning health network can overcome barriers to rapidly build a scalable infrastructure incorporating multiorganizational clinical data for COVID-19 analytics. We expect this effort to save lives by enabling rapid collaboration among clinicians, researchers, and data scientists to identify treatments and specialized care and thereby reduce the immediate and long-term impacts of COVID-19