An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows

An isotope dilution model to describe the partitioning of phenylalanine (PHE) and tyrosine (TYR) in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C] phenylalanine and [2,3,5,6-2H] tyrosine tracers. Model solutions described the extraction of PHE and TYR from the liver via the portal vein and hepatic artery. In addition, the exchange of free PHE and TYR between extracellular and intracellular pools was explained and the hydroxylation of PHE to TYR was estimated. The model was effective in providing information about the fates of PHE and TYR in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal

Meta-analysis of type 2 Diabetes in African Americans Consortium

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.Peer reviewe

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

GaInNAs semiconductor disk lasers as pump sources for Tm3+ (,Ho3+ )-doped glass, crystal and fibre lasers

We report the first use of a Semiconductor Disk Laser (SDL) as a pump source for ~2μm-emitting Tm3+ (,Ho3+)-doped dielectric lasers. The ~1213nm GaInNAs/GaAs SDL produces >1W of CW output power, a maximum power transfer net slope efficiency of 18.5%, and a full width half maximum wavelength tuning range of ~24nm. Free-running operation of a Tm3+-doped tellurite glass laser under 1213nm SDL pumping generated up to 60mW output power with 22.4% slope efficiency. Wavelength tunable output is also obtained from 1845 to 2043nm. Improved performance with output powers of ~200mW and a slope efficiency of ~35% are achieved by replacing the Tm3+-doped glass with a Tm3+-doped KYW active medium. Emission of a Tm3+,Ho3+-codoped tellurite glass laser is also reported with maximum output power of ~12mW and a ~7% slope efficiency. Finally, preliminary investigations of 1213nm-pumping of a Tm3+,Ho3+-codoped silica fibre laser lead to 36mW output power with ~19.3% slope efficiency

Current challenges for high-power semiconductor disk lasers

Here we review of high-power semiconductor disk lasers including thermal management issues and new results

Integrity of Electronic Patient Records

Part 4: Architecture, Security and InteroperabilityInternational audienceWe discuss a reference model for security measures to preserve integrity of information. Unlike traditional approaches which focus on an defensive approach to preserving integrity, we also present offensive measures to stimulate integrity of information, by providing feedback from usage. The reference model is used to analyze the security measures proposed in the design of the Dutch national Electronic Patient Dossier (EPD), in particular the projected application for medication records. We conclude that much of the defensive measures were covered, but that some offensive measures are lacking, in particular measures related to trust. This may have harmed adoption

ANCA-associated vasculitis is linked to carriage of the Z allele of {alpha}1 antitrypsin and its polymers.

Background Small studies have linked alpha 1 antitrypsin (alpha 1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Objective To test the validity and the mechanism of this association between alpha 1AT and AAV.Methods The distribution of alpha 1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. Results were compared between cases and controls using chi(2) tests. The serum and renal biopsies for alpha 1AT polymers were compared using the polymer-specific 2C1 antibody. The role of alpha 1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation.Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of alpha 1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of alpha 1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of alpha 1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse.Conclusions The Z but not the S deficiency allele is associated with AAV. Polymers of alpha 1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils