A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

A high-resolution three-dimensional reconstruction of a fossil forest (Upper Jurassic Shishugou Formation, Junggar Basin, Northwest China)

This study focuses on the three-dimensional (3D) reconstruction of an Late Jurassic fossil forest based on a fossil assemblage located in the Shishugou Formation near Jiangjunmiao, north-eastern Junggar Basin, Xinjiang Uygur Autonomous Region, Northwest China. On the basis of tree stumps found in growth position together with published data on megaplant fossils, seeds and spores, a highresolution digital computer model, including different forest layers, was developed. In a study area of 31,500 m, 65 tree stumps with diameters between 0.2 and 2.9 m were mapped and subsequently used for the 3D reconstruction. The forest grew under moist conditions, probably close to the banks of an anastomosing river and consisted primarily of conifers, in particular Araucariaceae. Even though the tree density of the forest is only 22 trees/ha, the 3D reconstruction indicates a relatively closed canopy. Megaplant fossils and spores also show evidence for the presence of Angiopteris, Osmunda and Coniopteris, which were then used to reconstruct the understory of the forest. The trees were modelled in three different growth stages, representing young, older and mature trees, respectively. The growth parameters of individual trees and ferns were randomized in order to avoid duplications within the reconstruction. Detailed textures of leaves, fronds and bark were created to give the plants a more realistic appearance than that in previously published 3D reconstructions of fossil forest assemblages. Estimations of net biomass (approximately 9 tons/ha), annual biomass production and a calculation of nearest neighbour index (0.86) suggest an open forest with spatially distributed trees

Assays for insulin and insulin-like activity based on adipocytes.

Data from the metabolic assays (and signaling assays; see below) are calculated as stimulation factor above basal activity (absence of insulin/compound/drug candidate) for processes stimulated (e.g., lipogenesis, glucose transport, and GLUT4 translocation) or as difference between the basal and insulin/compound/drug candidate-induced values for processes downregulated (e.g., lipolysis). In each case, these data, which reflect the responsiveness of the metabolic effector system studied toward the respective stimulus (insulin/compound/drug candidate), are normalized to the basal (set at 0 %) and maximal insulin action (set at 100 %; elicited by maximally effective concentration of insulin). For characterization of the sensitivity of the metabolic effector system toward the respective stimulus, effective concentrations for the induction of 150 % (or higher) of the basal activity (set at 100 %) can be given. These so-called EC150-values facilitate the insulin-independent comparison of the relative potency of the insulin-like activity between compounds/drug candidates, in general, and in particular for those frequently observed stimuli, which do not elicit the same maximal response in % stimulation or inhibition and/or fail to approach the maximal insulin response