RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF

Testing the role of circadian genes in conferring risk for psychiatric disorders

Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of

Thermal Adaptation and Diversity in Tropical Ecosystems: Evidence from Cicadas (Hemiptera, Cicadidae)

The latitudinal gradient in species diversity is a central problem in ecology. Expeditions covering approximately 16°54′ of longitude and 21°4′ of latitude and eight Argentine phytogeographic regions provided thermal adaptation data for 64 species of cicadas. We test whether species diversity relates to the diversity of thermal environments within a habitat. There are general patterns of the thermal response values decreasing in cooler floristic provinces and decreasing maximum potential temperature within a habitat except in tropical forest ecosystems. Vertical stratification of the plant communities leads to stratification in species using specific layers of the habitat. There is a decrease in thermal tolerances in species from the understory communities in comparison to middle level or canopy fauna. The understory Herrera umbraphila Sanborn & Heath is the first diurnally active cicada identified as a thermoconforming species. The body temperature for activity in H. umbraphila is less than and significantly different from active body temperatures of all other studied species regardless of habitat affiliation. These data suggest that variability in thermal niches within the heterogeneous plant community of the tropical forest environments permits species diversification as species adapt their physiology to function more efficiently at temperatures different from their potential competitors

Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study

The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examination) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were assessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evidence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

Epidemiology of invasive group B streptococcal disease in infants from urban area of South China, 2011–2014

YesBackground: Group B Streptococcus (GBS) is a leading cause of morbidity and mortality in infants in both developed and developing countries. To our knowledge, only a few studies have been reported the clinical features, treatment and outcomes of the GBS disease in China. The severity of neonatal GBS disease in China remains unclear. Population-based surveillance in China is therefore required. Methods: We retrospectively collected data of <3 months old infants with culture-positive GBS in sterile samples from three large urban tertiary hospitals in South China from Jan 2011 to Dec 2014. The GBS isolates and their antibiotic susceptibility were routinely identified in clinical laboratories in participating hospitals. Serotyping and multi-locus sequence typing (MLST) were also conducted for further analysis of the neonatal GBS disease. Results: Total 70 cases of culture-confirmed invasive GBS infection were identified from 127,206 live births born in studying hospitals, giving an overall incidence of 0.55 per 1000 live births (95% confidence interval [CI] 0.44–0.69). They consisted of 49 with early-onset disease (EOD, 0.39 per 1000 live births (95% CI 0.29–0.51)) and 21 with late-onset disease (LOD, 0.17 per 1000 live births (95% CI 0.11–0.25)). The incidence of EOD increased significantly over the studying period. Five infants (4 EOD and 1 LOD) died before discharge giving a mortality rate of 7.1% and five infants (7.1%, 2 EOD and 3 LOD) had neurological sequelae. Within 68 GBS isolates from GBS cases who born in the studying hospitals or elsewhere, serotype III accounted for 77.9%, followed by Ib (14.7%), V (4.4%), and Ia (2.9%). MLST analysis revealed the presence of 13 different sequence types among the 68 GBS isolates and ST-17 was the most frequent sequence type (63.2%). All isolates were susceptible to penicillin, ceftriaxone, vancomycin and linezolid, while 57.4% and 51.5% were resistant to erythromycin and clindamycin, respectively. Conclusions: This study gains the insight into the spectrum of GBS infection in south China which will facilitate the development of the guidance for reasonable antibiotics usage and will provide evidence for the implementation of potential GBS vaccines in the future.Supported by medical and health science and technology projects of Health and Family Planning Commission of Guangzhou Municipality (grant number 20151A010034) and Guangdong provincial science and technology planning projects (grant number 2014A020212520)

The dependence of dijet production on photon virtuality in ep collisions at HERA

The dependence of dijet production on the virtuality of the exchanged photon, Q^2, has been studied by measuring dijet cross sections in the range 0 < Q^2 < 2000 GeV^2 with the ZEUS detector at HERA using an integrated luminosity of 38.6 pb^-1. Dijet cross sections were measured for jets with transverse energy E_T^jet > 7.5 and 6.5 GeV and pseudorapidities in the photon-proton centre-of-mass frame in the range -3 < eta^jet <0. The variable xg^obs, a measure of the photon momentum entering the hard process, was used to enhance the sensitivity of the measurement to the photon structure. The Q^2 dependence of the ratio of low- to high-xg^obs events was measured. Next-to-leading-order QCD predictions were found to generally underestimate the low-xg^obs contribution relative to that at high xg^obs. Monte Carlo models based on leading-logarithmic parton-showers, using a partonic structure for the photon which falls smoothly with increasing Q^2, provide a qualitative description of the data.Comment: 35 pages, 6 eps figures, submitted to Eur.Phys.J.

Wolbachia in the flesh: symbiont intensities in germ-line and somatic tissues challenge the conventional view of Wolbachia transmission routes

Symbionts can substantially affect the evolution and ecology of their hosts. The investigation of the tissue-specific distribution of symbionts (tissue tropism) can provide important insight into host-symbiont interactions. Among other things, it can help to discern the importance of specific transmission routes and potential phenotypic effects. The intracellular bacterial symbiont Wolbachia has been described as the greatest ever panzootic, due to the wide array of arthropods that it infects. Being primarily vertically transmitted, it is expected that the transmission of Wolbachia would be enhanced by focusing infection in the reproductive tissues. In social insect hosts, this tropism would logically extend to reproductive rather than sterile castes, since the latter constitute a dead-end for vertically transmission. Here, we show that Wolbachia are not focused on reproductive tissues of eusocial insects, and that non-reproductive tissues of queens and workers of the ant Acromyrmex echinatior, harbour substantial infections. In particular, the comparatively high intensities of Wolbachia in the haemolymph, fat body, and faeces, suggest potential for horizontal transmission via parasitoids and the faecal-oral route, or a role for Wolbachia modulating the immune response of this host. It may be that somatic tissues and castes are not the evolutionary dead-end for Wolbachia that is commonly thought

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente