Genome-wide characterization of genetic variants and putative regions under selection in meat and egg-type chicken lines

Abstract\ud \ud Background\ud Meat and egg-type chickens have been selected for several generations for different traits. Artificial and natural selection for different phenotypes can change frequency of genetic variants, leaving particular genomic footprints throghtout the genome. Thus, the aims of this study were to sequence 28 chickens from two Brazilian lines (meat and white egg-type) and use this information to characterize genome-wide genetic variations, identify putative regions under selection using Fst method, and find putative pathways under selection.\ud \ud \ud Results\ud A total of 13.93 million SNPs and 1.36 million INDELs were identified, with more variants detected from the broiler (meat-type) line. Although most were located in non-coding regions, we identified 7255 intolerant non-synonymous SNPs, 512 stopgain/loss SNPs, 1381 frameshift and 1094 non-frameshift INDELs that may alter protein functions. Genes harboring intolerant non-synonymous SNPs affected metabolic pathways related mainly to reproduction and endocrine systems in the white-egg layer line, and lipid metabolism and metabolic diseases in the broiler line. Fst analysis in sliding windows, using SNPs and INDELs separately, identified over 300 putative regions of selection overlapping with more than 250 genes. For the first time in chicken, INDEL variants were considered for selection signature analysis, showing high level of correlation in results between SNP and INDEL data. The putative regions of selection signatures revealed interesting candidate genes and pathways related to important phenotypic traits in chicken, such as lipid metabolism, growth, reproduction, and cardiac development.\ud \ud \ud Conclusions\ud In this study, Fst method was applied to identify high confidence putative regions under selection, providing novel insights into selection footprints that can help elucidate the functional mechanisms underlying different phenotypic traits relevant to meat and egg-type chicken lines. In addition, we generated a large catalog of line-specific and common genetic variants from a Brazilian broiler and a white egg layer line that can be used for genomic studies involving association analysis with phenotypes of economic interest to the poultry industry.CB received a fellowship from the program Science Without Borders - National Council for Scientific and Technological Development (CNPq, grant 370620/2013–5). GCMM and TFG received fellowships from São Paulo Research Foundation (FAPESP, grants 14/21380–9 and 15/00616–7). LLC is recipient of productivity fellowship from CNPq. This project was funded by São Paulo Research Foundation (FAPESP) - thematic project (2014/08704–0)

Access to weight reduction interventions for overweight and obese patients in UK primary care: population-based cohort study

OBJECTIVES: To investigate access to weight management interventions for overweight and obese patients in primary care. SETTING: UK primary care electronic health records. PARTICIPANTS: A cohort of 91 413 overweight and obese patients aged 30–100 years was sampled from the Clinical Practice Research Datalink (CPRD). Patients with body mass index (BMI) values ≥25 kg/m(2) recorded between 2005 and 2012 were included. BMI values were categorised using WHO criteria. INTERVENTIONS: Interventions for body weight management, including advice, referrals and prescription of antiobesity drugs, were evaluated. PRIMARY AND SECONDARY OUTCOME MEASURES: The rate of body weight management interventions and time to intervention were the main outcomes. RESULTS: Data were analysed for 91 413 patients, mean age 56 years, including 55 094 (60%) overweight and 36 319 (40%) obese, including 4099 (5%) with morbid obesity. During the study period, 90% of overweight patients had no weight management intervention recorded. Intervention was more frequent among obese patients, but 59% of patients with morbid obesity had no intervention recorded. Rates of intervention increased with BMI category. In morbid obesity, rates of intervention per 1000 patient years were: advice, 60.2 (95% CI 51.8 to 70.4); referral, 75.7 (95% CI 69.5 to 82.6) and antiobesity drugs 89.9 (95% CI 85.0 to 95.2). Weight management interventions were more often accessed by women, older patients, those with comorbidity and those in deprivation. Follow-up of body weight subsequent to interventions was infrequent. CONCLUSIONS: Limited evidence of weight management interventions in primary care electronic health records may result from poor recording of advice given, but may indicate a lack of patient access to appropriate body weight management interventions in primary care

Structure of granzyme C reveals an unusual mechanism of protease autoinhibition

Proteases act in important homeostatic pathways and are tightly regulated. Here, we report an unusual structural mechanism of regulation observed by the 2.5-Å X-ray crystal structure of the serine protease, granzyme C. Although the active-site triad residues adopt canonical conformations, the oxyanion hole is improperly formed, and access to the primary specificity (S1) pocket is blocked through a reversible rearrangement involving Phe-191. Specifically, a register shift in the 190-strand preceding the active-site serine leads to Phe-191 filling the S1 pocket. Mutation of a unique Glu–Glu motif at positions 192–193 unlocks the enzyme, which displays chymase activity, and proteomic analysis confirms that activity of the wild-type protease can be released through interactions with an appropriate substrate. The 2.5-Å structure of the unlocked enzyme reveals unprecedented flexibility in the 190-strand preceding the active-site serine that results in Phe-191 vacating the S1 pocket. Overall, these observations describe a broadly applicable mechanism of protease regulation that cannot be predicted by template-based modeling or bioinformatic approaches alone

The cost of additive manufacturing: machine productivity, economies of scale and technology-push

As part of the cosmos of digital fabrication technology, Additive Manufacturing (AM) systems are able to manufacture three-dimensional components and products directly from raw material and 3D design data. The layer-by-layer operating process of these systems does not require the use of tools, moulds or dies. Technology observers speculate that AM will have a profound economic impact on the manufacturing sector and indeed on wider society. By constructing a model of production cost for two different AM systems used commercially for the manufacture of end-use metal parts, Electron Beam Melting (EBM) and Direct Metal Laser Sintering (DMLS), this paper performs an inter-process comparison of cost performance. High specific costs, measured at £2.39 and £6.18 per cm3 of material deposited respectively, are identified as a central impediment to more widespread technology adoption of such additive systems. The research demonstrates differing levels of system productivity, suggesting that the observed deposition rates are not sufficient for the adoption of EBM and DMLS in high volume manufacturing applications. Despite the absence of amortisable tooling costs, the analysis also reveals that economies of scale are achievable in AM. The results reached are further discussed in the light of the varying strategic requirements posed by the market-pull and technology-push modes of innovation which are both found in the AM industry