10 research outputs found

    Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes.

    Get PDF
    The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a-GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations

    Residents' Attitude, Knowledge, and Perceived Preparedness Toward Caring for Patients from Diverse Sociocultural Backgrounds

    No full text
    Purpose: Training residents to deliver care to increasingly diverse patients in the United States is an important strategy to help alleviate racial and ethnic disparities in health outcomes. Cross-cultural care training of residents continues to present challenges. This study sought to explore the associations among residents' cross-cultural attitudes, preparedness, and knowledge about disparities to better elucidate possible training needs. Methods: This cross-sectional study used web-based questionnaires from 2013 to 2014. Eighty-four internal medicine residency programs with 954 residents across the United States participated. The main outcome was perceived preparedness to care for sociocultural diverse patients. Key Results: Regression analysis showed attitude toward cross-cultural care (beta coefficient [β]=0.57, 95% confidence interval [CI]: 0.49–0.64, p<0.001) and report of serving a large number of racial/ethnic minorities (β=0.90, 95% CI: 0.56–1.24, p<0.001), and low-socioeconomic status patients (β=0.74, 95% CI: 0.37–1.10, p<0.001) were positively associated with preparedness. Knowledge of disparities was poor and did not differ significantly across postgraduate year (PGY)-1, PGY-2, and PGY-3 residents (mean scores: 56%, 58%, and 55%, respectively; p=0.08). Conclusion: Residents' knowledge of health and healthcare disparities is poor and does not improve during training. Residents' preparedness to provide cross-cultural care is directly associated with their attitude toward cross-cultural care and their level of exposure to patients from diverse sociocultural backgrounds. Future studies should examine the role of residents' cross-cultural care-related attitudes on their ability to care for diverse patients

    Large-scale replication and heterogeneity in Parkinson disease genetic loci.

    Get PDF
    OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity

    Feminist Perspectives in Sociological Research

    No full text

    Same data, different analysts: variation in effect sizes due to analytical decisions in ecology and evolutionary biology

    Get PDF
    Gould E, Fraser H, Parker T, et al. Same data, different analysts: variation in effect sizes due to analytical decisions in ecology and evolutionary biology. 2023.Although variation in effect sizes and predicted values among studies of similar phenomena is inevitable, such variation far exceeds what might be produced by sampling error alone. One possible explanation for variation among results is differences among researchers in the decisions they make regarding statistical analyses. A growing array of studies has explored this analytical variability in different (mostly social science) fields, and has found substantial variability among results, despite analysts having the same data and research question. We implemented an analogous study in ecology and evolutionary biology, fields in which there have been no empirical exploration of the variation in effect sizes or model predictions generated by the analytical decisions of different researchers. We used two unpublished datasets, one from evolutionary ecology (blue tit, Cyanistes caeruleus, to compare sibling number and nestling growth) and one from conservation ecology (Eucalyptus, to compare grass cover and tree seedling recruitment), and the project leaders recruited 174 analyst teams, comprising 246 analysts, to investigate the answers to prespecified research questions. Analyses conducted by these teams yielded 141 usable effects for the blue tit dataset, and 85 usable effects for the Eucalyptus dataset. We found substantial heterogeneity among results for both datasets, although the patterns of variation differed between them. For the blue tit analyses, the average effect was convincingly negative, with less growth for nestlings living with more siblings, but there was near continuous variation in effect size from large negative effects to effects near zero, and even effects crossing the traditional threshold of statistical significance in the opposite direction. In contrast, the average relationship between grass cover and Eucalyptus seedling number was only slightly negative and not convincingly different from zero, and most effects ranged from weakly negative to weakly positive, with about a third of effects crossing the traditional threshold of significance in one direction or the other. However, there were also several striking outliers in the Eucalyptus dataset, with effects far from zero. For both datasets, we found substantial variation in the variable selection and random effects structures among analyses, as well as in the ratings of the analytical methods by peer reviewers, but we found no strong relationship between any of these and deviation from the meta-analytic mean. In other words, analyses with results that were far from the mean were no more or less likely to have dissimilar variable sets, use random effects in their models, or receive poor peer reviews than those analyses that found results that were close to the mean. The existence of substantial variability among analysis outcomes raises important questions about how ecologists and evolutionary biologists should interpret published results, and how they should conduct analyses in the future
    corecore