BLM and RMI1 alleviate RPA inhibition of topoIIIα decatenase activity

RPA is a single-stranded DNA binding protein that physically associates with the BLM complex. RPA stimulates BLM helicase activity as well as the double Holliday junction dissolution activity of the BLM-topoisomerase IIIα complex. We investigated the effect of RPA on the ssDNA decatenase activity of topoisomerase IIIα. We found that RPA and other ssDNA binding proteins inhibit decatenation by topoisomerase IIIα. Complex formation between BLM, TopoIIIα, and RMI1 ablates inhibition of decatenation by ssDNA binding proteins. Together, these data indicate that inhibition by RPA does not involve species-specific interactions between RPA and BLM-TopoIIIα-RMI1, which contrasts with RPA modulation of double Holliday junction dissolution. We propose that topoisomerase IIIα and RPA compete to bind to single-stranded regions of catenanes. Interactions with BLM and RMI1 enhance toposiomerase IIIα activity, promoting decatenation in the presence of RPA

Methodological criteria for the assessment of moderators in systematic reviews of randomised controlled trials : a consensus study

Background: Current methodological guidelines provide advice about the assessment of sub-group analysis within RCTs, but do not specify explicit criteria for assessment. Our objective was to provide researchers with a set of criteria that will facilitate the grading of evidence for moderators, in systematic reviews. Method: We developed a set of criteria from methodological manuscripts (n = 18) using snowballing technique, and electronic database searches. Criteria were reviewed by an international Delphi panel (n = 21), comprising authors who have published methodological papers in this area, and researchers who have been active in the study of sub-group analysis in RCTs. We used the Research ANd Development/University of California Los Angeles appropriateness method to assess consensus on the quantitative data. Free responses were coded for consensus and disagreement. In a subsequent round additional criteria were extracted from the Cochrane Reviewers’ Handbook, and the process was repeated. Results: The recommendations are that meta-analysts report both confirmatory and exploratory findings for subgroups analysis. Confirmatory findings must only come from studies in which a specific theory/evidence based apriori statement is made. Exploratory findings may be used to inform future/subsequent trials. However, for inclusion in the meta-analysis of moderators, the following additional criteria should be applied to each study: Baseline factors should be measured prior to randomisation, measurement of baseline factors should be of adequate reliability and validity, and a specific test of the interaction between baseline factors and interventions must be presented. Conclusions: There is consensus from a group of 21 international experts that methodological criteria to assess moderators within systematic reviews of RCTs is both timely and necessary. The consensus from the experts resulted in five criteria divided into two groups when synthesising evidence: confirmatory findings to support hypotheses about moderators and exploratory findings to inform future research. These recommendations are discussed in reference to previous recommendations for evaluating and reporting moderator studies

Responsible management: Engaging moral reflexive practice through threshold concepts

YesIn this conceptual paper we argue that, to date, principles of responsible management have not impacted practice as anticipated because of a disconnect between knowledge and practice. This disconnect means that an awareness of ethical concerns, by itself, does not help students take personal responsibility for their actions. We suggest that an abstract knowledge of principles has to be supplemented by an engaged understanding of the responsibility of managers and leaders to actively challenge irresponsible practices. We argue that a form of moral reflexive practice drawing on an understanding of threshold concepts is central to responsible management, and provides a gateway to transformative learning. Our conceptual argument leads to implications for management and professional education

Slx8 removes Pli1-dependent protein-SUMO conjugates including SUMOylated Topoisomerase I to promote genome stability

Peer reviewedPublisher PD

Variability in the Effect of 5-HTTLPR on Depression in a Large European Population: The Role of Age, Symptom Profile, Type and Intensity of Life Stressors.

BACKGROUND: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. METHODS: In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. RESULTS: The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (</=30) individuals. LIMITATIONS: Our study is cross-sectional and applies self-report questionnaires. CONCLUSIONS: Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups

Force spectroscopy in studying infection

Biophysical force spectroscopy tools - for example optical tweezers, magnetic tweezers, atomic force microscopy, - have been used to study elastic, mechanical, conformational and dynamic properties of single biological specimens from single proteins to whole cells to reveal information not accessible by ensemble average methods such as X-ray crystallography, mass spectroscopy, gel electrophoresis and so on. Here we review the application of these tools on a range of infection-related questions from antibody-inhibited protein processivity to virus-cell adhesion. In each case we focus on how the instrumental design tailored to the biological system in question translates into the functionality suitable for that particular study. The unique insights that force spectroscopy has gained to complement knowledge learned through population averaging techniques in interrogating biomolecular details prove to be instrumental in therapeutic innovations such as those in structure-based drug design

Audiovisual Segregation in Cochlear Implant Users

It has traditionally been assumed that cochlear implant users de facto perform atypically in audiovisual tasks. However, a recent study that combined an auditory task with visual distractors suggests that only those cochlear implant users that are not proficient at recognizing speech sounds might show abnormal audiovisual interactions. The present study aims at reinforcing this notion by investigating the audiovisual segregation abilities of cochlear implant users in a visual task with auditory distractors. Speechreading was assessed in two groups of cochlear implant users (proficient and non-proficient at sound recognition), as well as in normal controls. A visual speech recognition task (i.e. speechreading) was administered either in silence or in combination with three types of auditory distractors: i) noise ii) reverse speech sound and iii) non-altered speech sound. Cochlear implant users proficient at speech recognition performed like normal controls in all conditions, whereas non-proficient users showed significantly different audiovisual segregation patterns in both speech conditions. These results confirm that normal-like audiovisual segregation is possible in highly skilled cochlear implant users and, consequently, that proficient and non-proficient CI users cannot be lumped into a single group. This important feature must be taken into account in further studies of audiovisual interactions in cochlear implant users

Small business owners' health and safety intentions: A cross-sectional survey

BACKGROUND: Little is known about the variables underlying small business owners' behavioural intentions toward workplace health and safety. This project explores the relationship between three mediating variables (Attitude Toward Safety, Subjective Norm and Perceived Behavioural Control) and owners' Intentions Toward Safety, following the Theory of Planned Behaviour. We also investigate the role of beliefs underlying each mediating variable. METHODS: Seven hundred businesses (5–50 employees) were randomly selected from 4084 eligible companies in a manufacturing business database (SIC codes 24 to 39). The 348 respondents are on average 51 yrs of age, 86% male, 96% white and have 2 to 4 years of post-secondary school. RESULTS: All three mediator variables are significantly correlated with Intentions Toward Safety; Attitude Toward Safety shows the strongest correlation, which is confirmed by path analysis. Owners with higher attitudes toward safety have a higher probability of believing that improving workplace health and safety will make employees' healthier and happier, show that they care, increase employee productivity, lower workers' compensation costs, increase product quality and lower costs. CONCLUSION: These results suggest that interventions aimed at increasing owners' health and safety intentions (and thus, behaviours) should focus on demonstrating positive employee health and product quality outcomes