GUP1 and its close homologue GUP2, encoding multi-membrane-spanning proteins involved in active glycerol uptake in Saccharomyces cerevisiae

Many yeast species can utilise glycerol, both as sole carbon source and as an osmolyte. In Saccharomyces cerevisiae, physiological studies have previously shown the presence of an active uptake system driven by electrogenic proton symport. We have used transposon mutagenesis to isolate mutants affected in the transport of glycerol into the cell. Here we present the identification of YGL084c, encoding a multi-membrane-spanning protein, as being essential for proton symport of glycerol into Saccharomyces cerevisiae. The gene is named GUP1 (Glycerol UPtake) and is important for growth on glycerol as carbon and energy source, as well as for osmotic protection by added glycerol, of a strain deficient in glycerol production. Another ORF, YPL189w, presenting a high degree of homology to YGL084c, similarly appears to be involved in active glycerol uptake in salt-containing glucose-based media in strains deficient in glycerol production. Analogously, this gene is named GUP2. To our knowledge, this is the first report on a gene product involved in active transport of glycerol in yeasts. Mutations with the same phenotypes occurred in two other open reading frames of previously unknown function, YDL074c and YPL180w.Comunidade Europeia (CE) - contract BIO4-CT95-0161

Throat related symptoms and voice: development of an instrument for self assessment of throat-problems

<p>Abstract</p> <p>Background</p> <p>Symptoms from throat (sensation of globus; frequent throat clearing; irritated throat) are common in patients referred to voice clinics and to ENT specialists. The relation to symptoms of voice discomfort is unclear and in some cases patients do not have voice problems at all. Instruments for patients' self-reporting of symptoms, and assessment of handicap, such as the Voice Handicap Index (VHI), are in common use in voice clinics. Symptoms from throat are however only marginally covered. Purpose: To develop and evaluate an instrument that could make the patients' estimation of symptoms from the throat possible. Further to facilitate the consideration of the relation between throat- and voice problems with the Throat subscale together with a Swedish translation of the Voice Handicap Index. Finally to try the VHI with the Throat subscale: the VHI-T, for test-retest reliability and validity.</p> <p>Methods</p> <p>A subscale with 10 throat related items was developed for appliance with the VHI. The VHI was translated to Swedish and retranslated to English. The questionnaire was tried in two phases on a total of 23+144 patients and 12+58 voice healthy controls. The reliability was calculated with Cronbach's alpha, ICC and Pearson's correlation coefficient. The validity was estimated by independent T-test.</p> <p>Results</p> <p>The difference in VHI-T scores between the patients and the voice-healthy controls was significant (<it>p </it>= < 0,01) and there was a good correlation of the test- retest occasions. The reliability testing of the entire questionnaire showed an alpha value of <it>r </it>= 0,90 and that for the Throat subscale separately a value of <it>r </it>= 0,87 which shows a high degree of reliability.</p> <p>Conclusions</p> <p>For the estimation of self-perceived throat and voice problems the scale on throat related problems together with the present Swedish translation of the Voice Handicap Index, (VHI) the VHI-Throat, proves to be a valid and reliable instrument. The throat subscale seems to help revealing a category of symptoms that are common in our patients. These are symptoms that have not earlier been possible to cover with the questionnaires designed for use in the voice clinic.</p

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study.

OBJECTIVES: To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. DESIGN: Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. SETTING: 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. PARTICIPANTS: A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor. RESULTS: Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10-68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture. CONCLUSIONS: This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk

Weekly Intra-Amniotic IGF-1 Treatment Increases Growth of Growth-Restricted Ovine Fetuses and Up-Regulates Placental Amino Acid Transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway

Association of vitamin D status with arterial blood pressure and hypertension risk:A mendelian randomisation study

Background:Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods: In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108 173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings: In phenotypic analyses (up to n=49 363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, -0·12 mm Hg, 95% CI -0·20 to -0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97-0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, -0·02 mm Hg, -0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146 581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of -0·10 mm Hg in systolic blood pressure (-0·21 to -0·0001; p=0·0498) and a change of -0·08 mm Hg in diastolic blood pressure (-0·15 to -0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142 255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96-0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of -0·29 mm Hg in diastolic blood pressure (-0·52 to -0·07; p=0·01), a change of -0·37 mm Hg in systolic blood pressure (-0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87-0·97; p=0·002). Interpretation: Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study. </p

Awareness and knowledge of sexually transmitted diseases (STDs) among school-going adolescents in Europe: a systematic review of published literature

Samkange-Zeeb FN, Spallek L, Zeeb H. Awareness and knowledge of sexually transmitted diseases (STDs) among school-going adolescents in Europe: a systematic review of published literature. BMC public health. 2011;11(1): 727.BACKGROUND: Sexually transmitted diseases (STDs) are a major health problem affecting mostly young people, not only in developing, but also in developed countries.We conducted this systematic review to determine awareness and knowledge of school-going male and female adolescents in Europe of STDs and if possible, how they perceive their own risk of contracting an STD. Results of this review can help point out areas where STD risk communication for adolescents needs to be improved. METHODS: Using various combinations of the terms "STD", "HIV", "HPV", "Chlamydia", "Syphilis", "Gonorrhoea", "herpes", "hepatitis B", "knowledge", "awareness", and "adolescents", we searched for literature published in the PubMed database from 01.01.1990 up to 31.12.2010. Studies were selected if they reported on the awareness and/or knowledge of one or more STD among school-attending adolescents in a European country and were published in English or German. Reference lists of selected publications were screened for further publications of interest. Information from included studies was systematically extracted and evaluated. RESULTS: A total of 15 studies were included in the review. All were cross-sectional surveys conducted among school-attending adolescents aged 13 to 20 years. Generally, awareness and knowledge varied among the adolescents depending on gender.Six STDs were focussed on in the studies included in the review, with awareness and knowledge being assessed in depth mainly for HIV/AIDS and HPV, and to some extent for chlamydia. For syphilis, gonorrhoea and herpes only awareness was assessed. Awareness was generally high for HIV/AIDS (above 90%) and low for HPV (range 5.4%-66%). Despite knowing that use of condoms helps protect against contracting an STD, some adolescents still regard condoms primarily as an interim method of contraception before using the pill. CONCLUSION: In general, the studies reported low levels of awareness and knowledge of sexually transmitted diseases, with the exception of HIV/AIDS. Although, as shown by some of the findings on condom use, knowledge does not always translate into behaviour change, adolescents' sex education is important for STD prevention, and the school setting plays an important role. Beyond HIV/AIDS, attention should be paid to infections such as chlamydia, gonorrhoea and syphilis

Immunity to HIV-1 Is Influenced by Continued Natural Exposure to Exogenous Virus

Unprotected sexual intercourse between individuals who are both infected with HIV-1 can lead to exposure to their partner's virus, and potentially to super-infection. However, the immunological consequences of continued exposure to HIV-1 by individuals already infected, has to our knowledge never been reported. We measured T cell responses in 49 HIV-1 infected individuals who were on antiretroviral therapy with suppressed viral loads. All the individuals were in a long-term sexual partnership with another HIV-1 infected individual, who was either also on HAART and suppressing their viral loads, or viremic (>9000 copies/ml). T cell responses to HIV-1 epitopes were measured directly ex-vivo by the IFN-γ enzyme linked immuno-spot assay and by cytokine flow cytometry. Sexual exposure data was generated from questionnaires given to both individuals within each partnership. Individuals who continued to have regular sexual contact with a HIV-1 infected viremic partner had significantly higher frequencies of HIV-1-specific T cell responses, compared to individuals with aviremic partners. Strikingly, the magnitude of the HIV-1-specific T cell response correlated strongly with the level and route of exposure. Responses consisted of both CD4+ and CD8+ T cell subsets. Longitudinally, decreases in exposure were mirrored by a lower T cell response. However, no evidence for systemic super-infection was found in any of the individuals. Continued sexual exposure to exogenous HIV-1 was associated with increased HIV-1-specific T cell responses, in the absence of systemic super-infection, and correlated with the level and type of exposure