Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1.

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.This work was supported by the Wellcome Trust (098497/Z/ 12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (to I.S. Farooqi and L.R. Pearce), by the Medical Research Council Metabolic Diseases Unit and NIHR Cambridge Biomedical Research Centre (to I.S. Farooqi, I. Barroso, and S. O’Rahilly) and the Bernard Wolfe Health Neuroscience Fund (I.S. Farooqi); and by NIH grants RO1-DK54222 (to C. Carter-Su), RO1-DK065122 and RO1- DK073601 (to L. Rui), a predoctoral fellowship from the Systems and Integrative Biology Training Grant NIH–T32-GM008322 (to M.E. Doche) and a Rackham Merit Fellowship from the University of Michigan (to R. Joe). Confocal microscopy was performed using the Morphology and Image Analysis Core of the Michigan Diabetes Research Center (NIH grant P60-DK20572).This is the final published version distributed under a Creative Commons Attribution License, which can also be found on the publisher's website at: http://press.endocrine.org/doi/abs/10.1210/en.2014-1264?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubme

Acceleration of a Positron Bunch in a Hollow Channel Plasma

Plasmas are a compelling medium for particle acceleration owing to their natural ability to sustain electric fields that are orders of magnitude larger than those available in conventional radio-frequency accelerators. Plasmas are also unique amongst accelerator technologies in that they respond differently to beams of opposite charge. The asymmetric response of a plasma to highly-relativistic electron and positron beams arises from the fact that plasmas are composed of light, mobile electrons and heavy, stationary ions. Hollow channel plasma acceleration is a technique for symmetrizing the response of the plasma, such that it works equally well for high-energy electron and positron beams. In the experiment described here, we demonstrate the generation of a positron beam-driven wake in an extended, annular plasma channel, and acceleration of a second trailing witness positron bunch by the wake. The leading bunch excites the plasma wakefield and loses energy to the plasma, while the witness bunch experiences an accelerating field and gains energy, thus providing a proof-of-concept for hollow channel acceleration of positron beams. At a bunch separation of 330 um, the accelerating gradient is 70 MV/m, the transformer ratio is 0.55, and the energy transfer efficiency is 18% for a drive-to-witness beam charge ratio of 5:1

Male FFA

Table 1: Demographics, associated disorders, daily medications and laboratory profile of 33 male patients with FFA. Table 2: Clinical features of 33 male patients with FFA

Male FFA

Table 1: Demographics, associated disorders, daily medications and laboratory profile of 33 male patients with FFA. Table 2: Clinical features of 33 male patients with FFA

DLQI and LPPAI study

Participants' full data and statistical results

Variation of reproductive traits in Rhododendron ferrugineum L (Ericacene) populations along a successional gradient

International audienceSexual and vegetative reproduction in the alpine species Rhododendron ferrugineum was studied along a successional sequence (meadow --> open heathland --> closed heathland) at two sites and in a wet heathland. This study aims to determine (1) the characteristics of sexual reproduction in R. ferrugineum populations (2) when and how these populations develop layering (adventitious rooting) and (3) whether reproductive traits and reproductive strategies develop relative to the degree of population closure and maturity. The variables used to describe sexual reproduction were inflorescence density (per m(2) of Rhododendron cover), number of flowers per inflorescence and per m(2) of Rhododendron cover, and seeds production (per fruit and m(2) of Rhododendron cover). Flowering and fruiting phenologies were also recorded. For describing clonal development, we investigated layering variables such as length and annual growth rate of prostrate stems, rooting occurence and ramet density. The results show that the direction toward which the clones extend is mainly determinated by the topography, and that layering steadily increases with increasing population closure and maturity. Reproductive potential of R. ferrugineum is enormous (0.4-2.4 million seeds m(-2)) but reproductive effort remains low with respect to total biomass of seeds (3-21 g m(-2)). Reproductive effort of R. ferrugineum populations could be reduced as a counterpart of layering development only when the shrub draws more matter and energy in layering stems than aerial stems. The variations reproductive traits observed on our sites could be due to primarily to phenotypic response to variable microhabitat features, rather than to genetically deterministic processes

Breeding system in an alpine species: Rhododendron ferrugineum L (Ericaceae) in the French northern Alps

International audienceThe breeding system of the alpine shrub Rhododendron ferrugineum was studied at two sites of a population (site L and site H) in the French Alps. The aims were to estimate the degree of selfing and (or) outcrossing and to determine if floral traits (including floral morphology, pollen to ovule ratio, stigma receptivity) may be related to the breeding system of the shrub. First, floral traits (corolla length and anther, and style heights) were measured, the number of pollen tetrads and ovules were counted, and the date of stigma receptivity and anther dehiscence were recorded. Second, five pollinations treatments (unmanipulated flowers, natural selfing, hand selfing, natural outcrossing, and hand outcrossing) were performed on 35 randomly chosen individuals in each site, and after each treatment the number of seeds per fruit was recorded. The results demonstrate that Rhododendron ferrugineum is self-compatible (self-compatibility index = 0.95 and 0.97; auto-fertility index = 0.92 and 0.98; selfing rate = 0.24 and 0.11 at sites L and H, respectively). Indices values are not significantly different between the two sites and facultatively xenogamous (pollen to ovule ratio = 669.5 +/- 280.5 and 845.2 +/- 246.9 at sites L and H, respectively)

Stamen dimorphism in Rhododendron ferrugineum (Ericaceae): Development and function

Times Cited: 6 Cited Reference Count: 42International audienceThe function of stamen dimorphism in the breeding system of the alpine shrub Rhododendron ferrugineum was studied in two populations in the French Alps. This species has pentameric flowers with two whorls of stamens: an inner whorl of Ave long stamens and an outer whorl of short stamens. We studied the development of stamens from buds to mature flowers (measurement of the filament, anther, and style lengths at five successive phenological stages) and compared the size and position of reproductive organs at maturity in control and partially emasculated flowers (removal of long-level stamens) to determine whether the presence of long-level stamens constitutes a constraint for the development of the short-level ones. Stamen dimorphism can be observed early in stamen development, from the bud stage of the year prior to flowering. At this early stage, meiosis had already occurred. Emasculation of the long-level stamens induced the short-level ones to grow longer than in normal conditions. We also performed seven pollination treatments on ten randomly chosen individuals in each population, and the number of seeds following each treatment was recorded. Results from these treatments showed that R. ferrugineum produced spontaneous selfed seeds in the absence of pollinators. However, no seed was produced when short-level stamens were emasculated and pollinators excluded, suggesting that long-level stamens are not responsible for selfing in the absence of pollinators and that reproductive assurance is promoted by short-level stamens