Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin's favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities

Older employees' declining attitudes over 20 years and across classes

British employers, under increasing competitive pressures, and applying new technology and work organization, have sought to reduce labour costs, resulting in work intensification and precarity. Older employees as a result are exposed to work demands that conflict with expectations of favourable treatment in late career. National survey data for Britain in the years 1992, 2001, 2006 and 2012 demonstrate a decline in overall job attitude among older employees following the changed conditions of the 1990s and across the major recession that began in 2008. To assess whether this decline is unequally distributed, decomposition by socio-economic class is carried out. This shows that older employees in the ‘service class’ of managerial and professional employees are affected at least as much as older employees in intermediate and less-skilled classes, thus underlining the age effect and showing that ‘service-class’ employees are not invulnerable to a changing economic environment

Can differences in medical drug compliance between European countries be explained by social factors: analyses based on data from the European Social Survey, round 2

<p>Abstract</p> <p>Background</p> <p>Non-compliance with medication is a major health problem. Cultural differences may explain different compliance patterns. The size of the compliance burden and the impact of socio-demographic and socio-economic status within and across countries in Europe have, however, never been analysed in one survey. The aim of this study was to analyse 1) medical drug compliance in different European countries with respect to socio-demographic and socio-economic factors, and to examine 2) whether cross-national differences could be explained by these factors.</p> <p>Methods</p> <p>A multi-country interview survey <it>European Social Survey, Round 2 </it>was conducted in 2004/05 comprising questions about compliance with last prescribed drug. Non-compliance was classified as primary and secondary, depending whether the drug was purchased or not. Statistical weighting allowed for adjustment for national differences in sample mechanisms. A multiple imputation strategy was used to compensate for missing values. The analytical approach included multivariate and multilevel analyses.</p> <p>Results</p> <p>The survey comprised 45,678 participants. Response rate was 62.5% (range 43.6–79.1%). Reported compliance was generally high (82%) but the pattern of non-compliance showed large variation between countries. Some 3.2% did not purchase the most recently prescribed medicine, and 13.6% did not take the medicine as prescribed. Multiple regression analyses showed that each variable had very different and in some cases opposite impact on compliance within countries. The multilevel analysis showed that the variation between countries did not change significantly when adjusted for increasing numbers of covariates.</p> <p>Conclusion</p> <p>Reported compliance was generally high but showed wide variation between countries. Cross-national differences could, however, not be explained by the socio-demographic and socio-economic variables measured.</p

The impact of child soldiers on rebel groups’ fighting capacities

Several rebel groups actively recruit children to serve among their ranks. While this constitutes one of the most egregious violations of children’s rights, it remains unclear what impact recruited children have on the fighting capacities of these armed groups. The existing research suggests that, on the one hand, armed groups drafting children might also be militarily effective, since it is cheaper to provide for children, they are more obedient and aggressive than adults, and easily manipulable. On the other hand, children may negatively affect rebel groups’ fighting capacities as they are less proficient combatants than adults and often difficult to control. We add to this debate by systematically analyzing the quantitative evidence on the impact of child soldiers on rebel groups’ fighting capacities. Based on the analysis of newly compiled data on child recruitment by rebel groups between 1989 and 2010, our analyses show that children may actually increase rebel groups’ fighting capacities. That said, rebels’ ability to procure arms and the access to resources seem to be more important determinants of fighting capacity. The authors discuss these findings in light of policy implications and avenues for future research. </jats:p

Identity Formation in Adolescence: Change or Stability?

The aim of this five-wave longitudinal study of 923 early to middle adolescents (50.7% boys; 49.3% girls) and 390 middle to late adolescents (43.3% boys and 56.7% girls) is to provide a comprehensive view on change and stability in identity formation from ages 12 to 20. Several types of change and stability (i.e., mean-level change, rank-order stability, and profile similarity) were assessed for three dimensions of identity formation (i.e., commitment, in-depth exploration, and reconsideration), using adolescent self-report questionnaires. Results revealed changes in identity dimensions towards maturity, indicated by a decreasing tendency for reconsideration, increasingly more in-depth exploration, and increasingly more stable identity dimension profiles. Mean levels of commitment remained stable, and rank-order stability of commitment, in-depth exploration, and reconsideration did not change with age. Overall, girls were more mature with regard to identity formation in early adolescence, but boys had caught up with them by late adolescence. Taken together, our findings indicate that adolescent identity formation is guided by progressive changes in the way adolescents deal with commitments, rather than by changes in the commitments themselves

Robustness and uncertainties in global multivariate wind-wave climate projections

Understanding climate-driven impacts on the multivariate global wind-wave climate is paramount to effective offshore/coastal climate adaptation planning. However, the use of single-method ensembles and variations arising from different methodologies has resulted in unquantified uncertainty amongst existing global wave climate projections. Here, assessing the first coherent, community-driven, multi-method ensemble of global wave climate projections, we demonstrate widespread ocean regions with robust changes in annual mean significant wave height and mean wave period of 5–15% and shifts in mean wave direction of 5–15°, under a high-emission scenario. Approximately 50% of the world’s coastline is at risk from wave climate change, with ~40% revealing robust changes in at least two variables. Furthermore, we find that uncertainty in current projections is dominated by climate model-driven uncertainty, and that single-method modelling studies are unable to capture up to ~50% of the total associated uncertainty

The impact of positive psychological interventions on well-being in healthy elderly people

This systematic review aims to evaluate the impact of Positive Psychological Interventions (PPIs) on well-being in healthy older adults. Systematic review of PPIs obtained from three electronic databases (PsycINFO, Scopus, and Web of Science) was undertaken. Inclusion criteria were: that they were positive psychology intervention, included measurement of well-being, participants were aged over 60 years, and the studies were in English. The Cochrane Collaboration Guidelines dimensions of quality control, randomization, comparability, follow-up rate, dropout, blinding assessors are used to rate the quality of studies by two reviewers independently. The RE-AIM (Reach, Efficacy, Adoption, Implementation, and Maintenance) for evaluation of PPIs effectiveness was also applied. The final review included eight articles, each describing a positive psychological intervention study. The reminiscence interventions were the most prevalent type of PPIs to promote and maintain well-being in later life. Only two studies were rated as high quality, four were of moderate-quality and two were of low-quality. Overall results indicated that efficacy criteria (89%), reach criteria (85%), adoption criteria (73%), implementation criteria (67%), and maintenance criteria (4%) across a variety of RE-AIM dimensions. Directions for future positive psychological research related to RE-AIM, and implications for decision-making, are described