Integration of disease-specific single nucleotide polymorphisms, expression quantitative trait loci and coexpression networks reveal novel candidate genes for type 2 diabetes.

Aims/hypothesisWhile genome-wide association studies (GWASs) have been successful in identifying novel variants associated with various diseases, it has been much more difficult to determine the biological mechanisms underlying these associations. Expression quantitative trait loci (eQTL) provide another dimension to these data by associating single nucleotide polymorphisms (SNPs) with gene expression. We hypothesised that integrating SNPs known to be associated with type 2 diabetes with eQTLs and coexpression networks would enable the discovery of novel candidate genes for type 2 diabetes.MethodsWe selected 32 SNPs associated with type 2 diabetes in two or more independent GWASs. We used previously described eQTLs mapped from genotype and gene expression data collected from 1,008 morbidly obese patients to find genes with expression associated with these SNPs. We linked these genes to coexpression modules, and ranked the other genes in these modules using an inverse sum score.ResultsWe found 62 genes with expression associated with type 2 diabetes SNPs. We validated our method by linking highly ranked genes in the coexpression modules back to SNPs through a combined eQTL dataset. We showed that the eQTLs highlighted by this method are significantly enriched for association with type 2 diabetes in data from the Wellcome Trust Case Control Consortium (WTCCC, p = 0.026) and the Gene Environment Association Studies (GENEVA, p = 0.042), validating our approach. Many of the highly ranked genes are also involved in the regulation or metabolism of insulin, glucose or lipids.Conclusions/interpretationWe have devised a novel method, involving the integration of datasets of different modalities, to discover novel candidate genes for type 2 diabetes

Yield anisotropy effects on buckling of circular tubes under bending

AbstractRelatively thin-walled tubes bent into the plastic range buckle by axial wrinkling. The wrinkles initially grow stably but eventually localize and cause catastrophic failure in the form of sharp local kinking. The onset of axial wrinkling was previously established by bifurcation analyses that use instantaneous deformation theory moduli. The curvatures at bifurcation were predicted accurately, but the wrinkle wavelengths were consistently longer than measured values. The subject is revisited with the aim of resolving this discrepancy. A set of new bending experiments is conducted on aluminum alloy tubes. The results are shown to be in line with previous ones. However, the tubes used were found to exhibit plastic anisotropy, which was measured and characterized through Hill’s quadratic anisotropic yield function. The anisotropy was incorporated in the flow theory used for prebuckling and postbuckling calculations as well as in the deformation theory used for bifurcation checks. With the anisotropy accounted for, calculated tube responses are found to be in excellent agreement with the measured ones while the predicted bifurcation curvatures and wrinkle wavelengths fall in line with the measurements also. The postbuckling response is established using a finite element model of a tube assigned an initial axisymmetric imperfection with the calculated wavelength. The response develops a limit moment that is followed by a sharp kink that grows while the overall moment drops. The curvature at the limit moment agrees well with the experimental onset of failure. From parametric studies of the various instabilities it is concluded that, for optimum predictions, anisotropy must be incorporated in both bifurcation buckling as well as in postbuckling calculations

Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36\u20130.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72\u20130.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57\u20130.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs

Greening an experiment for environmental chemistry: H2S capture with elemental recovery

An experiment is presented to demonstrate the production, capture, and electrochemical remediation of H2S in a closed syringe-based system. Final products are its pure constituent elements. This experiment is suitable for an environmental chemistry laboratory and it can be completed in 3- 4 h