Loss of Function and Inhibitory Effects of Human CSX/NKX2.5 Homeoprotein Mutations Associated with Congenital Heart Disease

CSX/NKX2.5 is an evolutionarily conserved homeodomain-containing (HD-containing) transcription factor that is essential for early cardiac development. Recently, ten different heterozygous CSX/NKX2.5 mutations were found in patients with congenital heart defects that are transmitted in an autosomal dominant fashion. To determine the consequence of these mutations, we analyzed nuclear localization, DNA binding, transcriptional activation, and dimerization of mutant CSX/NKX2.5 proteins. All mutant proteins were translated and located to the nucleus, except one splice-donor site mutant whose protein did not accumulate in the cell. All mutants that had truncation or missense mutations in the HD had severely reduced DNA binding activity and little or no transcriptional activation function. In contrast, mutants with intact HDs exhibit normal DNA binding to the monomeric binding site but had three- to ninefold reduction in DNA binding to the dimeric binding sites. HD missense mutations that preserved homodimerization ability inhibited the activation of atrial natriuretic factor by wild-type CSX/NKX2.5. Although our studies do not characterize the genotype-phenotype relationship of the ten human mutations, they identify specific abnormalities of CSX/NKX2.5 function essential for transactivation of target genes

Graph-based Features for Automatic Online Abuse Detection

While online communities have become increasingly important over the years, the moderation of user-generated content is still performed mostly manually. Automating this task is an important step in reducing the financial cost associated with moderation, but the majority of automated approaches strictly based on message content are highly vulnerable to intentional obfuscation. In this paper, we discuss methods for extracting conversational networks based on raw multi-participant chat logs, and we study the contribution of graph features to a classification system that aims to determine if a given message is abusive. The conversational graph-based system yields unexpectedly high performance , with results comparable to those previously obtained with a content-based approach

Tbx5 is Required for Avian and Mammalian Epicardial Formation and Coronary Vasculogenesis.

Rationale: Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ (PEO) impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and Tbx5\u27s role in mammalian coronary vasculogenesis, remains largely unknown. Objective: To evaluate the consequences of altered Tbx5 gene dosage during PEO and epicardial development in the embryonic chick and mouse. Methods and Results: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick PEO as well as proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/-)) impaired normal PEO cell development, inhibited epicardial and coronary blood vessel formation and altered developmental gene expression. The generation of epicardial-derived cells (EPDCs) and their migration into the myocardium was impaired between embryonic day (E) 13.5-15.5 in mutant hearts due to delayed epicardial attachment to the myocardium and subepicardial accumulation of EPDCs. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment, and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wildtype hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by HIF1α upregulation and increased binding of Hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity compared to wildtype mice. Conclusions: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and mouse coronary vascular formation

Associations of suffering with facets of health and well-being among working adults : longitudinal evidence from two samples

Bibliografia na końcu artykułuSuffering is an experiential state that every person encounters at one time or another, yet little is known about suffering and its consequences for the health and well‑being of nonclinical adult populations. In a pair of longitudinal studies, we used two waves of data from garment factory workers (Study 1 [T1: 2017, T2: 2019]: n = 344) and flight attendants (Study 2 [T1: 2017/2018, T2: 2020]: n = 1402) to examine the prospective associations of suffering with 16 outcomes across different domains of health and well‑being: physical health, health behavior, mental health, psychological well‑ being, character strengths, and social well‑being. The primary analysis involved a series of regression analyses in which each T2 outcome was regressed on overall suffering assessed at T1, adjusting for relevant sociodemographic characteristics and the baseline value (or close proxy) of the outcome assessed at T1. In Study 1, associations of overall suffering with worse subsequent health and well‑ being were limited to a single outcome on each of the domains of physical health and mental health. Overall suffering was more consistently related to worse subsequent health and well‑being in Study 2, with associations emerging for all but two outcomes. The pattern of findings for each study was largely similar when aspects of suffering were modeled individually, although associations for some aspects of suffering differed from those that emerged for overall suffering. Our findings suggest that suffering may have important implications for the health and well‑being of worker populations

The evolution of interdisciplinarity in physics research

Science, being a social enterprise, is subject to fragmentation into groups that focus on specialized areas or topics. Often new advances occur through cross-fertilization of ideas between sub-fields that otherwise have little overlap as they study dissimilar phenomena using different techniques. Thus to explore the nature and dynamics of scientific progress one needs to consider the large-scale organization and interactions between different subject areas. Here, we study the relationships between the sub-fields of Physics using the Physics and Astronomy Classification Scheme (PACS) codes employed for self-categorization of articles published over the past 25 years (1985-2009). We observe a clear trend towards increasing interactions between the different sub-fields. The network of sub-fields also exhibits core-periphery organization, the nucleus being dominated by Condensed Matter and General Physics. However, over time Interdisciplinary Physics is steadily increasing its share in the network core, reflecting a shift in the overall trend of Physics research.Comment: Published version, 10 pages, 8 figures + Supplementary Informatio

How should we measure psychological resilience in sport performers?

Psychological resilience is important in sport because athletes must constantly withstand a wide range of pressures to attain and sustain high performance. To advance psychologists’ understanding of this area, there exists an urgent need to develop a sport-specific measure of resilience. The purpose of this paper is to review psychometric issues in resilience research and to discuss the implications for sport psychology. Drawing on the wider general psychology literature to inform the discussion, the narrative is divided into three main sections relating to resilience and its assessment: adversity, positive adaptation, and protective factors. The first section reviews the different ways that adversity has been measured and considers the potential problems of using items with varying degrees of controllability and risk. The second section discusses the different approaches to assessing positive adaptation and examines the issue of circularity pervasive in resilience research. The final section explores the various issues related to the assessment of protective factors drawing directly from current measures of resilience in other psychology sub-disciplines. The commentary concludes with key recommendations for sport psychology researchers seeking to develop a measure of psychological resilience in athletes