FLORA: a novel method to predict protein function from structure in diverse superfamilies

Predicting protein function from structure remains an active area of interest, particularly for the structural genomics initiatives where a substantial number of structures are initially solved with little or no functional characterisation. Although global structure comparison methods can be used to transfer functional annotations, the relationship between fold and function is complex, particularly in functionally diverse superfamilies that have evolved through different secondary structure embellishments to a common structural core. The majority of prediction algorithms employ local templates built on known or predicted functional residues. Here, we present a novel method (FLORA) that automatically generates structural motifs associated with different functional sub-families (FSGs) within functionally diverse domain superfamilies. Templates are created purely on the basis of their specificity for a given FSG, and the method makes no prior prediction of functional sites, nor assumes specific physico-chemical properties of residues. FLORA is able to accurately discriminate between homologous domains with different functions and substantially outperforms (a 2–3 fold increase in coverage at low error rates) popular structure comparison methods and a leading function prediction method. We benchmark FLORA on a large data set of enzyme superfamilies from all three major protein classes (α, β, αβ) and demonstrate the functional relevance of the motifs it identifies. We also provide novel predictions of enzymatic activity for a large number of structures solved by the Protein Structure Initiative. Overall, we show that FLORA is able to effectively detect functionally similar protein domain structures by purely using patterns of structural conservation of all residues

Musculoskeletal symptoms of the upper extremities and the neck: A cross-sectional study on prevalence and symptom-predicting factors at visual display terminal (VDT) workstations

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to determine the prevalence and the predictors of musculoskeletal symptoms in the upper extremities and neck at visual display terminal (VDT) workstations.</p> <p>Methods</p> <p>In a cross-sectional study 1,065 employees working at VDT > 1 h/d completed a standardised questionnaire. Workstation conditions were documented in a standardised checklist, and a subgroup of 82 employees underwent a physical examination.</p> <p>Results</p> <p>Using the Nordic Questionnaire, the 12-month prevalence of symptoms of the neck, shoulder region, hand/wrist, or elbow/lower arm was 55%, 38%, 21%, and 15% respectively. The duration of VDT work had a significant impact on the frequency of neck symptoms in employees performing such work > 6 h/d.</p> <p>Conclusion</p> <p>With regard to musculoskeletal symptoms of the upper extremities, preventive measures at VDT workstations should be focused on neck and shoulder symptoms (e.g. ergonomic measures, breaks to avoid sitting over long periods).</p

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5?SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.© 2022. The Author(s)

Plasticity of BRCA2 Function in Homologous Recombination: Genetic Interactions of the PALB2 and DNA Binding Domains

The breast cancer suppressor BRCA2 is essential for the maintenance of genomic integrity in mammalian cells through its role in DNA repair by homologous recombination (HR). Human BRCA2 is 3,418 amino acids and is comprised of multiple domains that interact with the RAD51 recombinase and other proteins as well as with DNA. To gain insight into the cellular function of BRCA2 in HR, we created fusions consisting of various BRCA2 domains and also introduced mutations into these domains to disrupt specific protein and DNA interactions. We find that a BRCA2 fusion peptide deleted for the DNA binding domain and active in HR is completely dependent on interaction with the PALB2 tumor suppressor for activity. Conversely, a BRCA2 fusion peptide deleted for the PALB2 binding domain is dependent on an intact DNA binding domain, providing a role for this conserved domain in vivo; mutagenesis suggests that both single-stranded and double-stranded DNA binding activities in the DNA binding domain are required for its activity. Given that PALB2 itself binds DNA, these results suggest alternative mechanisms to deliver RAD51 to DNA. In addition, the BRCA2 C terminus contains both RAD51-dependent and -independent activities which are essential to HR in some contexts. Finally, binding the small peptide DSS1 is essential for activity when its binding domain is present, but not when it is absent. Our results reveal functional redundancy within the BRCA2 protein and emphasize the plasticity of this large protein built for optimal HR function in mammalian cells. The occurrence of disease-causing mutations throughout BRCA2 suggests sub-optimal HR from a variety of domain modulations

Determinants of job satisfaction: a European comparison of self-employed and paid employees

The job satisfaction of self-employed and paid-employed workers is analyzed using the European Community Household Panel for the EU-15 covering the years 1994-2001. We distinguish between two types of job satisfaction: job satisfaction in terms of type of work and job satisfaction in terms of job security. Findings from our generalized ordered logit regressions indicate that self-employed individuals as compared to paid employees are more likely to be satisfied with their present jobs in terms of type of work and less likely to be satisfied in terms of job security. The findings also provide many insights into the determinants of the two types of job satisfaction for both self-employed and paid-employed workers

Patterns of Diversity in Soft-Bodied Meiofauna: Dispersal Ability and Body Size Matter

Background: Biogeographical and macroecological principles are derived from patterns of distribution in large organisms, whereas microscopic ones have often been considered uninteresting, because of their supposed wide distribution. Here, after reporting the results of an intensive faunistic survey of marine microscopic animals (meiofauna) in Northern Sardinia, we test for the effect of body size, dispersal ability, and habitat features on the patterns of distribution of several groups.Methodology/Principal Findings: As a dataset we use the results of a workshop held at La Maddalena (Sardinia, Italy) in September 2010, aimed at studying selected taxa of soft-bodied meiofauna (Acoela, Annelida, Gastrotricha, Nemertodermatida, Platyhelminthes and Rotifera), in conjunction with data on the same taxa obtained during a previous workshop hosted at Tjärnö (Western Sweden) in September 2007. Using linear mixed effects models and model averaging while accounting for sampling bias and potential pseudoreplication, we found evidence that: (1) meiofaunal groups with more restricted distribution are the ones with low dispersal potential; (2) meiofaunal groups with higher probability of finding new species for science are the ones with low dispersal potential; (3) the proportion of the global species pool of each meiofaunal group present in each area at the regional scale is negatively related to body size, and positively related to their occurrence in the endobenthic habitat.Conclusion/Significance: Our macroecological analysis of meiofauna, in the framework of the ubiquity hypothesis for microscopic organisms, indicates that not only body size but mostly dispersal ability and also occurrence in the endobenthic habitat are important correlates of diversity for these understudied animals, with different importance at different spatial scales. Furthermore, since the Western Mediterranean is one of the best-studied areas in the world, the large number of undescribed species (37%) highlights that the census of marine meiofauna is still very far from being complete

Partner relationship satisfaction and maternal emotional distress in early pregnancy

<p>Abstract</p> <p>Background</p> <p>Recognition of maternal emotional distress during pregnancy and the identification of risk factors for this distress are of considerable clinical- and public health importance. The mental health of the mother is important both for herself, and for the physical and psychological health of her children and the welfare of the family. The first aim of the present study was to identify risk factors for maternal emotional distress during pregnancy with special focus on partner relationship satisfaction. The second aim was to assess interaction effects between relationship satisfaction and the main predictors.</p> <p>Methods</p> <p>Pregnant women enrolled in the Norwegian Mother and Child Cohort Study (n = 51,558) completed a questionnaire with questions about maternal emotional distress, relationship satisfaction, and other risk factors. Associations between 37 predictor variables and emotional distress were estimated by multiple linear regression analysis.</p> <p>Results</p> <p>Relationship dissatisfaction was the strongest predictor of maternal emotional distress (β = 0.25). Other predictors were dissatisfaction at work (β = 0.11), somatic disease (β = 0.11), work related stress (β = 0.10) and maternal alcohol problems in the preceding year (β = 0.09). Relationship satisfaction appeared to buffer the effects of frequent moving, somatic disease, maternal smoking, family income, irregular working hours, dissatisfaction at work, work stress, and mother's sick leave (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>Dissatisfaction with the partner relationship is a significant predictor of maternal emotional distress in pregnancy. A good partner relationship can have a protective effect against some stressors.</p