1,360 research outputs found

    The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket

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    P pili are hairlike polymeric structures that mediate binding of uropathogenic Escherichia coli to the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in-zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism

    A retrospective analysis of noise-induced hearing loss in the Dutch construction industry

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    Purpose Noise exposure is an important and highly prevalent occupational hazard in the construction industry. This study examines hearing threshold levels of a large population of Dutch construction workers and compares their hearing thresholds to those predicted by ISO-1999. Methods In this retrospective study, medical records of periodic occupational health examinations of 29,644 construction workers are analysed. Pure-tone audiometric thresholds of noise-exposed workers are compared to a non-exposed control group and to ISO-1999 predictions. Regression analyses are conducted to explore the relationship between hearing loss and noise intensity, noise exposure time and the use of hearing protection. Results Noise-exposed workers had greater hearing losses compared to their non-noise-exposed colleagues and to the reference population reported in ISO-1999. Noise exposure explained only a small proportion of hearing loss. When the daily noise exposure level rose from 80 dB(A) towards 96 dB(A), only a minor increase in hearing loss is shown. The relation of exposure time and hearing loss found was similar to ISO-1999 predictions when looking at durations of 10 years or more. For the first decade, the population medians show poorer hearing than predicted by ISO-1999. Discussion Duration of noise exposure was a better predictor than noise exposure levels, probably because of the limitations in noise exposure estimations. In this population, noise-induced hearing loss was already present at the beginning of employment and increased at the same rate as is predicted for longer exposure duration

    The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

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    Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

    The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa

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    BACKGROUND: The objective of this study was to document the clinical, laboratory and genetic features of galactosemia in patients from the Cape Town metropolitan region. METHODS: Diagnoses were based on thin layer chromatography for galactosuria/galactosemia and assays of erythrocyte galactose-1-phosphate uridyltransferase (GALT) and galactokinase activities. Patients were screened for the common S135L and Q188R transferase gene mutations, using PCR-based assays. Screening for the S135L mutation in black newborns was used to estimate the carrier rate for galactosemia in black South Africans. RESULTS: A positive diagnosis of galactosemia was made in 17 patients between the years 1980 to 2001. All had very low or absent galactose-1-phosphate uridyltransferase (GALT) activity, and normal galactokinase levels. The mean age at diagnosis was 5.1 months (range 4 days to 6.5 months). A review of 9 patients showed that hepatomegaly (9/9), and splenomegaly, failure to thrive, developmental delay, bilateral cataracts (6/9) were the most frequent features at diagnosis. Six had conjugated hyperbilirubinemia. Four experienced invasive E. coli infection before diagnosis. Ten patients were submitted to DNA analysis. All 4 black patients and 2 of mixed extraction were homozygous for the S135L allele, while all 3 white patients were homozygous for the Q188R allele. The remaining patient of mixed extraction was heterozygous for the Q188R allele. The estimated carrier frequency of the S135L mutation in 725 healthy black newborns was 1/60. CONCLUSIONS: In the absence of newborn screening the delay in diagnosis is most often unacceptably long. Also, carrier frequency data predict a galactosemia incidence of approximately 1/14 400 for black newborns in the Cape Metropole, which is much higher than the current detection rate. It is thus likely that many patients go undetected

    Oil Palm Research in Context: Identifying the Need for Biodiversity Assessment

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    Oil palm cultivation is frequently cited as a major threat to tropical biodiversity as it is centered on some of the world's most biodiverse regions. In this report, Web of Science was used to find papers on oil palm published since 1970, which were assigned to different subject categories to visualize their research focus. Recent years have seen a broadening in the scope of research, with a slight growth in publications on the environment and a dramatic increase in those on biofuel. Despite this, less than 1% of publications are related to biodiversity and species conservation. In the context of global vegetable oil markets, palm oil and soyabean account for over 60% of production but are the subject of less than 10% of research. Much more work must be done to establish the impacts of habitat conversion to oil palm plantation on biodiversity. Results from such studies are crucial for informing conservation strategies and ensuring sustainable management of plantations

    Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort

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    <p>Abstract</p> <p>Background</p> <p>Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk.</p> <p>Methods</p> <p>We sequenced the coding exons of 17 genes (<it>EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP </it>and <it>CREBBP</it>) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls) nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure.</p> <p>Results</p> <p>We identified 45 coding variants with frequencies β‰₯ 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (<it>NCOR2</it>: His52Arg, OR = 1.79; 95% CI, 1.05–3.05; <it>CALCOCO1</it>: Arg12His, OR = 2.29; 95% CI, 1.00–5.26). A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies.</p> <p>Conclusion</p> <p>Our findings suggest that common coding variation in these candidate genes do not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as inter-individual response to hormonal therapies used for cancer treatment and prevention.</p
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