Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway

Valine is one of the three branched-chain amino acids which undergoes oxidation within mitochondria. In this paper, we describe the current state of knowledge with respect to the enzymology of the valine oxidation pathway and the different disorders affecting oxidation

Association between polymorphisms in the coagulation factor VII gene and coronary heart disease risk in different ethnicities: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>Previous studies have examined the association between polymorphisms in the coagulation factor VII gene and the risk of coronary heart disease (CHD), but those studies have been inconclusive. This study was conducted to assess the associations between these polymorphisms and CHD and evaluated the associations in different ethnicities.</p> <p>Methods</p> <p>Literature-based searching was conducted to collect data and two methods, namely fixed-effects and random-effects, were performed to pool the odds ratio (OR), together with the 95% confidence interval (CI). Publication bias and between-study heterogeneity were also examined.</p> <p>Results</p> <p>Thirty-nine case-control studies of the three polymorphisms, R353Q (rs6046), HVR4 and -323Ins10 (rs36208070) in factor VII gene and CHD were enrolled in this meta-analysis, including 9,151 cases of CHD and 14,099 controls for R353Q, 2,863 cases and 2,727 controls for HVR4, and 2,862 cases and 4,240 controls for -323Ins10. Significant association was only found in Asian population for R353Q (Q vs R), with pooled OR of 0.70(95%CI: 0.55, 0.90). For the -323Ins10 polymorphism (10 vs 0), we found significant associations in both Asian and European populations, with pooled ORs of 0.74(95%CI: 0.61, 0.88) and 0.63(95%CI: 0.53, 0.74), respectively. Marginal significant association was found between HVR4 (H7 vs H5+H6) and CHD (OR = 0.88, 95% CI: 0.78, 1.00). There was no evidence of publication bias, but between-study heterogeneity was found in the analyses.</p> <p>Conclusions</p> <p>The -323Ins10 polymorphism in factor VII gene is significantly associated with CHD in both Asian and European populations, while R353Q polymorphism showed trend for association with CHD in Asians. Lack of association was found for HVR4 polymorphism. Further studies are needed to confirm the association, especially for -323Ins10 polymorphism.</p

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Public appraisal of government efforts and participation intent in medico-ethical policymaking in Japan: a large scale national survey concerning brain death and organ transplant

BACKGROUND: Public satisfaction with policy process influences the legitimacy and acceptance of policies, and conditions the future political process, especially when contending ethical value judgments are involved. On the other hand, public involvement is required if effective policy is to be developed and accepted. METHODS: Using the data from a large-scale national opinion survey, this study evaluates public appraisal of past government efforts to legalize organ transplant from brain-dead bodies in Japan, and examines the public's intent to participate in future policy. RESULTS: A relatively large percentage of people became aware of the issue when government actions were initiated, and many increasingly formed their own opinions on the policy in question. However, a significant number (43.3%) remained unaware of any legislative efforts, and only 26.3% of those who were aware provided positive appraisals of the policymaking process. Furthermore, a majority of respondents (61.8%) indicated unwillingness to participate in future policy discussions of bioethical issues. Multivariate analysis revealed the following factors are associated with positive appraisals of policy development: greater age; earlier opinion formation; and familiarity with donor cards. Factors associated with likelihood of future participation in policy discussion include younger age, earlier attention to the issue, and knowledge of past government efforts. Those unwilling to participate cited as their reasons that experts are more knowledgeable and that the issues are too complex. CONCLUSIONS: Results of an opinion survey in Japan were presented, and a set of factors statistically associated with them were discussed. Further efforts to improve policy making process on bioethical issues are desirable

The Staphylococcus aureus Response to Unsaturated Long Chain Free Fatty Acids: Survival Mechanisms and Virulence Implications

Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the σB and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids

Improving outcomes for people in mental health crisis: a rapid synthesis of the evidence for available models of care

BACKGROUND: Crisis Concordat was established to improve outcomes for people experiencing a mental health crisis. The Crisis Concordat sets out four stages of the crisis care pathway: (1) access to support before crisis point; (2) urgent and emergency access to crisis care; (3) quality treatment and care in crisis; and (4) promoting recovery. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of the models of care for improving outcomes at each stage of the care pathway. DATA SOURCES: Electronic databases were searched for guidelines, reviews and, where necessary, primary studies. The searches were performed on 25 and 26 June 2014 for NHS Evidence, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, and the Health Technology Assessment (HTA) and PROSPERO databases, and on 11 November 2014 for MEDLINE, PsycINFO and the Criminal Justice Abstracts databases. Relevant reports and reference lists of retrieved articles were scanned to identify additional studies. STUDY SELECTION: When guidelines covered a topic comprehensively, further literature was not assessed; however, where there were gaps, systematic reviews and then primary studies were assessed in order of priority. STUDY APPRAISAL AND SYNTHESIS METHODS: Systematic reviews were critically appraised using the Risk Of Bias In Systematic reviews assessment tool, trials were assessed using the Cochrane risk-of-bias tool, studies without a control group were assessed using the National Institute for Health and Care Excellence (NICE) prognostic studies tool and qualitative studies were assessed using the Critical Appraisal Skills Programme quality assessment tool. A narrative synthesis was conducted for each stage of the care pathway structured according to the type of care model assessed. The type and range of evidence identified precluded the use of meta-analysis. RESULTS AND LIMITATIONS: One review of reviews, six systematic reviews, nine guidelines and 15 primary studies were included. There was very limited evidence for access to support before crisis point. There was evidence of benefits for liaison psychiatry teams in improving service-related outcomes in emergency departments, but this was often limited by potential confounding in most studies. There was limited evidence regarding models to improve urgent and emergency access to crisis care to guide police officers in their Mental Health Act responsibilities. There was positive evidence on clinical effectiveness and cost-effectiveness of crisis resolution teams but variability in implementation. Current work from the Crisis resolution team Optimisation and RElapse prevention study aims to improve fidelity in delivering these models. Crisis houses and acute day hospital care are also currently recommended by NICE. There was a large evidence base on promoting recovery with a range of interventions recommended by NICE likely to be important in helping people stay well. CONCLUSIONS AND IMPLICATIONS: Most evidence was rated as low or very low quality, but this partly reflects the difficulty of conducting research into complex interventions for people in a mental health crisis and does not imply that all research was poorly conducted. However, there are currently important gaps in research for a number of stages of the crisis care pathway. Particular gaps in research on access to support before crisis point and urgent and emergency access to crisis care were found. In addition, more high-quality research is needed on the clinical effectiveness and cost-effectiveness of mental health crisis care, including effective components of inpatient care, post-discharge transitional care and Community Mental Health Teams/intensive case management teams. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013279. FUNDING: The National Institute for Health Research HTA programme

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development