In vivo manipulation of the extracellular matrix induces vascular regression in a basal chordate.

We investigated the physical role of the extracellular matrix (ECM) in vascular homeostasis in the basal chordate Botryllus schlosseri, which has a large, transparent, extracorporeal vascular network encompassing an area >100 cm2 We found that the collagen cross-linking enzyme lysyl oxidase is expressed in all vascular cells and that in vivo inhibition using β-aminopropionitrile (BAPN) caused a rapid, global regression of the entire network, with some vessels regressing >10 mm within 16 h. BAPN treatment changed the ultrastructure of collagen fibers in the vessel basement membrane, and the kinetics of regression were dose dependent. Pharmacological inhibition of both focal adhesion kinase (FAK) and Raf also induced regression, and levels of phosphorylated FAK in vascular cells decreased during BAPN treatment and FAK inhibition but not Raf inhibition, suggesting that physical changes in the vessel ECM are detected via canonical integrin signaling pathways. Regression is driven by apoptosis and extrusion of cells through the basal lamina, which are then engulfed by blood-borne phagocytes. Extrusion and regression occurred in a coordinated manner that maintained vessel integrity, with no loss of barrier function. This suggests the presence of regulatory mechanisms linking physical changes to a homeostatic, tissue-level response

Using Self-Affirmation to Increase Intellectual Humility in Debate

Intellectual humility, which entails openness to other views and a willingness to listen and engage with them, is crucial for facilitating civil dialogue and progress in debate between opposing sides. In the present research, we tested whether intellectual humility can be reliably detected in discourse and experimentally increased by a prior self-affirmation task. Three-hundred and three participants took part in 116 audio and video-recorded group discussions. Blind to condition, linguists coded participants’ discourse to create an intellectual humility score. As expected, the self-affirmation task increased the coded intellectual humility, as well as participants’ self-rated prosocial affect (e.g., empathy). Unexpectedly, the effect on prosocial affect did not mediate the link between experimental condition and intellectual humility in debate. Self-reported intellectual humility and other personality variables were uncorrelated with expert-coded intellectual humility. Implications of these findings for understanding the social psychological mechanisms underpinning intellectual humility are considered

Social science quantitative methods capacity building in Wales: ESRC/HEFCW scoping study

Previous research undertaken by the ESRC has revealed a “deficit” of quantitative social science researchers and identified that this should be tackled early in the academic life course. However, there is substantial heterogeneity across disciplines with previous studies indicating what while some subjects suffer serious deficits in quantitative methods research capacity, other disciplines such as economics and psychology are perceived to have strengths in quantitative methods training and research. There may be a particular problem in quantitative social science in Wales (possibly relating to the visible “Welsh deficit” in social science funding); however it is difficult to identify the configuration, strengths and weaknesses of quantitative social science in Wales from routine data. To provide more data on the current position of quantitative social science in Wales, and to identify potential ways forward to improve the situation in Wales, ESRC and HEFCW jointly funded this scoping study. The study mapped quantitative social science research (and training) expertise in Wales by undertaking an all-Wales questionnaire survey of social scientists in Higher Education Institutions in Wales. This was complemented by a number of semi-structured interviews with key stakeholders with an interest or expertise in quantitative social science research methods. A workshop including key stakeholders was then held to discuss the outcomes of the survey and interviews and recommendations for future action. This report presents the main findings of the study, which include the need for future actions to recognise the differences between disciplines, to not solely focus on advanced quantitative methods, and to be linked with wider initiatives to improve social science research methods training and capacity more generally. Many issues identified were not Wales specific and optimal solutions include increasing access to and participation in wider UK initiatives rather than solely Wales based actions. The report recommends the creation of a Centre in Wales to co-ordinate and deliver Wales-based solutions, link with UK initiatives and break down disciplinary and methodological barriers. Other recommendations address the deficit at different stages in the academic life course; undergraduate, postgraduate, post-doctoral and continued professional development, as well as suggestions for building wider quantitative capacity in Wales, monitoring and further research

Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing

Background: We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM). Methods and Results: We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing. Conclusions: Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

To induce central T-cell tolerance, medullary thymic epithelial cells (mTEC) collectively express most protein-coding genes, thereby presenting an extensive library of tissue-restricted antigens (TRAs). To resolve mTEC diversity and whether promiscuous gene expression (PGE) is stochastic or coordinated, we sequenced transcriptomes of 6,894 single mTEC, enriching for 1,795 rare cells expressing either of two TRAs, TSPAN8 or GP2. Transcriptional heterogeneity allowed partitioning of mTEC into 15 reproducible subpopulations representing distinct maturational trajectories, stages and subtypes, including novel mTEC subsets, such as chemokine-expressing and ciliated TEC, which warrant further characterisation. Unexpectedly, 50 modules of genes were robustly defined each showing patterns of co-expression within individual cells, which were mainly not explicable by chromosomal location, biological pathway or tissue specificity. Further, TSPAN8+ and GP2+ mTEC were randomly dispersed within thymic medullary islands. Consequently, these data support observations that PGE exhibits ordered co-expression, although mechanisms underlying this instruction remain biologically indeterminate. Ordered co-expression and random spatial distribution of a diverse range of TRAs likely enhance their presentation and encounter with passing thymocytes, while maintaining mTEC identity

Using Self-Affirmation to Increase Intellectual Humility in Debate

Intellectual humility, which entails openness to other views and a willingness to listen and engage with them, is crucial for facilitating civil dialogue and progress in debate between opposing sides. In the present research, we tested whether intellectual humility can be reliably detected in discourse and experimentally increased by a prior self-affirmation task. Three-hundred and three participants took part in 116 audio and video-recorded group discussions. Blind to condition, linguists coded participants’ discourse to create an intellectual humility score. As expected, the self-affirmation task increased the coded intellectual humility, as well as participants’ self-rated prosocial affect (e.g., empathy). Unexpectedly, the effect on prosocial affect did not mediate the link between experimental condition and intellectual humility in debate. Self-reported intellectual humility and other personality variables were uncorrelated with expert-coded intellectual humility. Implications of these findings for understanding the social psychological mechanisms underpinning intellectual humility are considered

Social science quantitative methods capacity building in Wales: ESRC/HEFCW scoping study

Previous research undertaken by the ESRC has revealed a “deficit” of quantitative social science researchers and identified that this should be tackled early in the academic life course. However, there is substantial heterogeneity across disciplines with previous studies indicating what while some subjects suffer serious deficits in quantitative methods research capacity, other disciplines such as economics and psychology are perceived to have strengths in quantitative methods training and research. There may be a particular problem in quantitative social science in Wales (possibly relating to the visible “Welsh deficit” in social science funding); however it is difficult to identify the configuration, strengths and weaknesses of quantitative social science in Wales from routine data. To provide more data on the current position of quantitative social science in Wales, and to identify potential ways forward to improve the situation in Wales, ESRC and HEFCW jointly funded this scoping study. The study mapped quantitative social science research (and training) expertise in Wales by undertaking an all-Wales questionnaire survey of social scientists in Higher Education Institutions in Wales. This was complemented by a number of semi-structured interviews with key stakeholders with an interest or expertise in quantitative social science research methods. A workshop including key stakeholders was then held to discuss the outcomes of the survey and interviews and recommendations for future action. This report presents the main findings of the study, which include the need for future actions to recognise the differences between disciplines, to not solely focus on advanced quantitative methods, and to be linked with wider initiatives to improve social science research methods training and capacity more generally. Many issues identified were not Wales specific and optimal solutions include increasing access to and participation in wider UK initiatives rather than solely Wales based actions. The report recommends the creation of a Centre in Wales to co-ordinate and deliver Wales-based solutions, link with UK initiatives and break down disciplinary and methodological barriers. Other recommendations address the deficit at different stages in the academic life course; undergraduate, postgraduate, post-doctoral and continued professional development, as well as suggestions for building wider quantitative capacity in Wales, monitoring and further research

First virtual international congress on cellular and organismal stress responses, november 5–6, 2020

Members of the Cell Stress Society International (CSSI), Patricija van Oosten-Hawle (University of Leeds, UK), Mehdi Mollapour (SUNY Upstate Medical University, USA), Andrew Truman (University of North Carolina at Charlotte, USA) organized a new virtual meeting format which took place on November 5–6, 2020. The goal of this congress was to provide an international platform for scientists to exchange data and ideas among the Cell Stress and Chaperones community during the Covid-19 pandemic. Here we will highlight the summary of the meeting and acknowledge those who were honored by the CSSI

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements