Structural atlas of a human gut crassvirus

CrAssphage and related viruses of the order Crassvirales (hereafter referred to as crassviruses) were originally discovered by cross-assembly of metagenomic sequences. They are the most abundant viruses in the human gut, are found in the majority of individual gut viromes, and account for up to 95% of the viral sequences in some individuals 1-4. Crassviruses are likely to have major roles in shaping the composition and functionality of the human microbiome, but the structures and roles of most of the virally encoded proteins are unknown, with only generic predictions resulting from bioinformatic analyses 4,5. Here we present a cryo-electron microscopy reconstruction of Bacteroides intestinalis virus ΦcrAss001 6, providing the structural basis for the functional assignment of most of its virion proteins. The muzzle protein forms an assembly about 1 MDa in size at the end of the tail and exhibits a previously unknown fold that we designate the 'crass fold', that is likely to serve as a gatekeeper that controls the ejection of cargos. In addition to packing the approximately 103 kb of virus DNA, the ΦcrAss001 virion has extensive storage space for virally encoded cargo proteins in the capsid and, unusually, within the tail. One of the cargo proteins is present in both the capsid and the tail, suggesting a general mechanism for protein ejection, which involves partial unfolding of proteins during their extrusion through the tail. These findings provide a structural basis for understanding the mechanisms of assembly and infection of these highly abundant crassviruses

Exploring the effect of implementation and context on a stepped-wedge randomised controlled trial of a vital sign triage device in routine maternity care in low-resource settings

© 2019 The Author(s). Background: Interventions aimed at reducing maternal mortality are increasingly complex. Understanding how complex interventions are delivered, to whom, and how they work is key in ensuring their rapid scale-up. We delivered a vital signs triage intervention into routine maternity care in eight low- and middle-income countries with the aim of reducing a composite outcome of morbidity and mortality. This was a pragmatic, hybrid effectiveness-implementation stepped-wedge randomised controlled trial. In this study, we present the results of the mixed-methods process evaluation. The aim was to describe implementation and local context and integrate results to determine whether differences in the effect of the intervention across sites could be explained. Methods: The duration and content of implementation, uptake of the intervention and its impact on clinical management were recorded. These were integrated with interviews (n = 36) and focus groups (n = 19) at 3 months and 6-9 months after implementation. In order to determine the effect of implementation on effectiveness, measures were ranked and averaged across implementation domains to create a composite implementation strength score and then correlated with the primary outcome. Results: Overall, 61.1% (n = 2747) of health care providers were trained in the intervention (range 16.5% to 89.2%) over a mean of 10.8 days. Uptake and acceptability of the intervention was good. All clusters demonstrated improved availability of vital signs equipment. There was an increase in the proportion of women having their blood pressure measured in pregnancy following the intervention (79.2% vs. 97.6%; OR 1.30 (1.29-1.31)) and no significant change in referral rates (3.7% vs. 4.4% OR 0.89; (0.39-2.05)). Availability of resources and acceptable, effective referral systems influenced health care provider interaction with the intervention. There was no correlation between process measures within or between domains, or between the composite score and the primary outcome. Conclusions: This process evaluation has successfully described the quantity and quality of implementation. Variation in implementation and context did not explain differences in the effectiveness of the intervention on maternal mortality and morbidity. We suggest future trials should prioritise in-depth evaluation of local context and clinical pathways. Trial registration: Trial registration: ISRCTN41244132. Registered on 2 Feb 2016

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Study of Beauty Hadron Decays into Pairs of Charm Hadrons

First observations of the decays A(b)(0) -> A(c)(+)D((s))(-) are reported using data corresponding to an integrated luminosity of 3 fb(-1) collected at 7 and 8 TeV center-of- ass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(B-s(0) -> D+Ds-) is made and a search is performed for the decays B-0((s)) -> A(c)(+)A(c)(-). The results obtained are B(A(b)(0) -> A(c)(+)D(-))/B(A(b)(0) -> A(c)(+)D(s)(-)) = 0.042 +/- 0.003 (stat) +/- 0.003 (syst), [B(A(b)(0) -> A(c)(+)D(s)(-))/B((B) over bar (0) -> D+Ds-)]/[B(A(b)(0) -> A(c)(+)pi(-))/B((B) over bar (0) -> D+pi(-))] = 0.96 +/- 0.02 (stat) +/- 0.06 (syst), B(B-s(0) -> D+Ds-)/B((B) over bar (0) -> D+Ds-) = 0.038 +/- 0.004 (stat) +/- (syst), B((B) over bar (0) -> A(c)(+)A(c)(-))/B((B) over bar (0) -> D+Ds-) A(c)(+)A(c)(-)) /B(B-s(0) -> D+Ds-) < 0.30[95% C.L.]. Measurement of the mass of the A(b)(0) baryon relative to the (B) over bar (0) meson gives M(A(b)(0)) ¿ M((B) over bar (0)) = 339.72 +/- 0.24 (stat) +/- 0.18 (syst) MeV/c(2). This result provides the most precise measurement of the mass of the A(b)(0) baryon to date

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Study of beauty hadron decays into pairs of harm hadrons

First observations of the decays Λ0b→Λ+cD−(s) are reported using data corresponding to an integrated luminosity of 3  fb−1 collected at 7 and 8 TeV center-of-mass energies in proton-proton collisions with the LHCb detector. In addition, the most precise measurement of the branching fraction B(B0s→D+D−s) is made and a search is performed for the decays B0(s)→Λ+cΛ−c. The results obtained are B(Λ0b→Λ+cD−)/B(Λ0b→Λ+cD−s)=0.042±0.003(stat)±0.003(syst),[B(Λ0b→Λ+cD−s)B(B¯0→D+D−s)]/[B(Λ0b→Λ+cπ−)B(B¯0→D+π−)]=0.96±0.02(stat)±0.06(syst),B(B0s→D+D−s)/B(B¯0→D+D−s)=0.038±0.004(stat)±0.003(syst),B(B¯0→Λ+cΛ−c)/B(B¯0→D+D−s)&#60;0.0022[95%  C.L.],B(B0s→Λ+cΛ−c)/B(B0s→D+D−s)&#60;0.30[95%  C.L.]. Measurement of the mass of the Λ0b baryon relative to the B¯0 meson gives M(Λ0b)−M(B¯0)=339.72±0.24(stat)±0.18(syst)  MeV/c2. This result provides the most precise measurement of the mass of the Λ0b baryon to date

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe