Accumulation of rare coding variants in genes implicated in risk of human cleft lip with or without cleft palate.

Cleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 nonmalformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p = 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example, BHMT displayed a 10-fold increase in protein-altering variants in CLP cases (p = .03), including multiple case occurrences of a rare frameshift mutation (K400 fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B, BMP4, BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP

Shaped nozzles for cryogenic buffer gas beam sources

Cryogenic buffer gas beams are important sources of cold molecules. In this work we explore the use of a converging-diverging nozzle with a buffer-gas beam. We find that, under appropriate circumstances, the use of a nozzle can produce a beam with improved collimation, lower transverse temperatures, and higher fluxes per solid angle

Validation of the historical adulthood physical activity questionnaire (HAPAQ) against objective measurements of physical activity.

BACKGROUND: Lifetime physical activity energy expenditure (PAEE) is an important determinant of risk for many chronic diseases but remains challenging to measure. Previously reported historical physical activity (PA) questionnaires appear to be reliable, but their validity is less well established. METHODS: We sought to design and validate an historical adulthood PA questionnaire (HAPAQ) against objective PA measurements from the same individuals. We recruited from a population-based cohort in Cambridgeshire, UK, (Medical Research Council Ely Study) in whom PA measurements, using individually calibrated heart rate monitoring, had been obtained in the past, once between 1994 and 1996 and once between 2000 and 2002. 100 individuals from this cohort attended for interview. Historical PA within the domains of home, work, transport, sport and exercise was recalled using the questionnaire by asking closed questions repeated for several discrete time periods from the age of 20 years old to their current age. The average PAEE from the 2 periods of objective measurements was compared to the self-reported data from the corresponding time periods in the questionnaire. RESULTS: Significant correlations were observed between HAPAQ-derived and objectively measured total PAEE for both time periods (Spearman r = 0.44; P < 0.001). Similarly, self-reported time spent in vigorous PA was significantly correlated with objective measurements of vigorous PA (Spearman r = 0.40; P < 0.001). CONCLUSIONS: HAPAQ demonstrates convergent validity for total PAEE and vigorous PA. This instrument will be useful for ranking individuals according to their past PA in studies of chronic disease aetiology, where activity may be an important underlying factor contributing to disease pathogenesis.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Available carbon source influences the resistance of Neisseria meningitidis against complement

Neisseria meningitidis is an important cause of septicaemia and meningitis. To cause disease, the bacterium must acquire essential nutrients for replication in the systemic circulation, while avoiding exclusion by host innate immunity. Here we show that the utilization of carbon sources by N. meningitidis determines its ability to withstand complement-mediated lysis, through the intimate relationship between metabolism and virulence in the bacterium. The gene encoding the lactate permease, lctP, was identified and disrupted. The lctP mutant had a reduced growth rate in cerebrospinal fluid compared with the wild type, and was attenuated during bloodstream infection through loss of resistance against complement-mediated killing. The link between lactate and complement was demonstrated by the restoration of virulence of the lctP mutant in complement (C3−/−)-deficient animals. The underlying mechanism for attenuation is mediated through the sialic acid biosynthesis pathway, which is directly connected to central carbon metabolism. The findings highlight the intimate relationship between bacterial physiology and resistance to innate immune killing in the meningococcus

Electronic and bite angle effects in catalytic C-O bond cleavage of a lignin model compound using ruthenium xantphos complexes

The authors would like to thank the EPSRC (Global Engagement grant EP/K00445X/1 and critical mass grant EP/J018139/1) and the European Union (Marie Curie ITN ‘SuBiCat’ PITN-GA-2013-607044) for financial support. NMSF-Swansea and Mr. Stephen Boyer are kindly acknowledged for mass spectrometry and elemental analysis, respectively.Bite angle and electronic effects on the ruthenium-diphosphine catalysed ether bond cleavage of the lignin β-O-4 model compound 2-phenoxy-1-phenethanol were tested. Enhanced conversion of the substrate was observed with increasing σ-donor capacity of the ligands. Kinetic and thermodynamic data suggest oxidative addition of the dehydrogenated model compound to the diphosphine Ru(0) complex to be rate-limiting.PostprintPeer reviewe

Setting an International Research Agenda for Fear of Cancer Recurrence: an online delphi consensus study

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permissionBackground: Fear of cancer recurrence (FCR) is common amongst cancer survivors. There is rapidly growing research interest in FCR but a need to prioritise research to address the most pressing clinical issues and reduce duplication and fragmentation of effort. This study aimed to establish international consensus among clinical and academic FCR experts regarding priorities for FCR research. Methods: Members of the International Psycho-oncology Society (IPOS) Fear of Cancer Recurrence Special Interest Group (FORwards) were invited to participate in an online Delphi study. Research domains identified in Round 1 were presented and discussed at a focus group (Round 2) to consolidate the domains and items prior to presentation in further survey rounds (Round 3) aimed at gaining consensus on research priorities of international significance. Results: Thirty four research items were identified in Round 1 and 33 of the items were consolidated into 6 overarching themes through a focus group discussion with FCR experts. The 33 research items were presented in subsequent rounds of the delphi technique. Twenty one participants contributed to delphi round 1, 16 in round 2 and 25 and 29 participants for subsequent delphi rounds. Consensus was reached for 27 items in round 3.1. A further 4 research items were identified by panellists and included in round 3.2. After round 3.2, 35 individual research items were ratified by the panellists. Given the high levels of consensus and stability between rounds no further rounds were conducted. Overall intervention research was considered the most important focus for FCR research. Panellists identified models of care that facilitate greater access to FCR treatment and evaluation of the effectiveness of FCR interventions in real world settings as the two research items of highest priority. Defining the mechanisms of action and active components across FCR/P interventions, was the third highest priority identified. Conclusions: The findings of this study outline a research agenda for international FCR research. Intervention research to identify models of care that increase access to treatment, are based on a flexible approach based on symptom severity and can be delivered within routine clinical care, were identified as research areas to prioritise. Greater understanding of the active components and mechanisms of action of existing FCR interventions will facilitate increased tailoring of interventions to meet patient need

Evaluating a process of academic detailing in primary care: an educational programme for acute kidney injury

BackgroundPrimary care has a significant role in AKI management: two-thirds of AKI originates in the community. Through academic detailing (an evidence-based educational approach) we aimed to implement and measure the effect of a primary care-based education programme based around academic detailing and peer-reviewed audit.MethodsThe education programme took place across a large clinical commissioning group (CCG) consisting of 55 primary care practices. All 55 practices participated in large group teaching sessions, 25 practices participated in academic detailing and 28 of the remaining 30 practices performed internal AKI audit. Over a 12 month period, an educational programme was delivered consisting of large group teaching sessions followed by either academic detailing sessions or self-directed AKI audit activity. Academic detailing sessions consisted of a short presentation by a consultant nephrologist followed by discussion of cases. Qualitative feedback was collected from all participants at peer review sessions. Web-based, CCG-wide questionnaires assessed baseline and post-intervention knowledge levels.ResultsNine hundred ninety-six individuals completed the questionnaires (556 at baseline, 440 at 1 yr., 288 participated in both). Exposure to AKI teaching, self-reported awareness and confidence levels were higher in the second questionnaire. There was a significant increase in the percentage of correct answers before and after the intervention (55.6 ± 21% versus 87.5 ± 20%,

Analisis dan Perancangan Sistem Akuntansi dengan Model Driven Development (MDD) Pada Konveksi Anemarie

Informasi Akuntansi merupakan salah satu alat untuk mengambil keputusan dalam perusahaan.Sistem Informasi Akuntansi dapat memberikan kemudahan dalam menghasilkan informasi yang akurat, tepat waktu dapat dipahami dan teruji.Selain itu, sistem informasi akuntansi dapat memudahkan siklus operasional perusahaan baik dari pembelian, produksi, sampai penjualan.Maka dari uraian itu, peneliti ingin menganalisis dan merancang sistem informasi akuntansi pada usaha yang tidak memiliki sistem informasi akuntansi dan masih melakukan pencatatan secara manual. Peneliti menggunakan data sistem akuntansi Konveksi Anemarie periode April 2017 dan Model Driven Development untuk merancang Sistem Informasi Akuntansi konveksi Anemarie. Hasil pengembangan Sistem Informasi Akuntansi dengan Model Driven Development ini ialah Desain Model Data dengan Entity Relathionship diagram baik secara keseluruhan maupun per subsistem, Desain model Proses dengan Data Flow Diagram, dan desain model output dengan pembuatan interface dari form yang dibutuhka