Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy

A growing line of evidence indicates dysfunctional ubiquitin-proteasome system (UPS) in cardiac diseases. Anti-hypertrophic effects and improved cardiac function have been reported after treatment with proteasome inhibitors in experimental models of cardiac hypertrophy. Here we tested whether proteasome inhibition could also reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C. At 7 weeks of age, homozygous mice (KI) have +39% higher left ventricular mass and -29% lower fractional area shortening (FAS) than wild-type (WT) mice. Both groups were treated with epoxomicin (0.5 mg/kg/day) or vehicle for 1 week via osmotic minipumps. Epoxomicin inhibited the chymotrypsin-like activity by ~50% in both groups. All parameters of cardiac hypertrophy (including the fetal gene program) were not affected by epoxomicin treatment in both groups. In contrast, FAS was +12% and 35% higher in epoxomicin-treated than vehicle-treated WT and KI mice, respectively. To identify which genes or pathways could be involved in this positive effect, we performed a transcriptome analysis in KI and WT neonatal cardiac myocytes, treated or not with the proteasome inhibitor MG132 (1 {mu}M, 24 h). This revealed 103 genes (4-fold difference; 5% FDR) which are commonly regulated in both KI and WT cardiac myocytes. Thus, even in genetically-modified mice with manifest HCM, proteasome inhibition showed beneficial effects, at least with regard to cardiac function. Targeting the UPS in cardiac diseases remains therefore a therapeutic option

Unravelling social constructionism

Social constructionist research is an area of rapidly expanding influence that has brought together theorists from a range of different disciplines. At the same time, however, it has fuelled the development of a new set of divisions. There would appear to be an increasing uneasiness about the implications of a thoroughgoing constructionism, with some regarding it as both theoretically parasitic and politically paralysing. In this paper I review these debates and clarify some of the issues involved. My main argument is that social constructionism is not best understood as a unitary paradigm and that one very important difference is between what Edwards (1997) calls its ontological and epistemic forms. I argue that an appreciation of this distinction not only exhausts many of the disputes that currently divide the constructionist community, but also takes away from the apparent radicalism of much of this work

Human uniqueness explored from the uniquely human perspective: Epistemological and methodological challenges

Exploring human uniqueness encounters fundamental challenges because we can approach this endeavour only from within our uniquely human perspective. The intrinsic presumptions that this involves may entail two types of anthropocentric, ethnocentric, and egocentric biases, which can influence research on both epistemological and methodological levels. Their impact may be particularly pronounced if quests for the origins of human sociality are based only on our knowledge about humans. Tomasello's (2019) research demonstrates that the comparative study of humans and nonhuman species offers unique opportunities to explore forms of social cooperation, underlying cognitive and meta‐cognitive abilities as well as pathways in their ontological and (possible) phylogenetic development. It also shows that comparative approaches are essential to unravel the ways in which humans are indeed unique. But species comparisons are challenged by the need to consider inherent trade‐offs between achieving operational comparability in empirical studies and establishing ecological validity for the species compared—challenges, which analogously occur in comparisons across human cultures as well. This shows that comparative research can also contribute meaningfully to methodology development in psychology

Rigor and Ethics in the World of Big-team Qualitative Data: Experiences From Research in International Development

In the large international projects where many qualitative researchers work, generating qualitative Big Data, data sharing represents the status quo. This is rarely acknowledged, even though the ethical implications are considerable and span both process and product. I argue that big-team qualitative researchers can strengthen claims to rigor in analysis (the product) by drawing on a growing body of knowledge about how to do credible secondary analysis. Since this necessitates a full account of how the research and the analysis are done (the process), I consider the structural disincentives for providing these. Debates around credibility and rigor are not new to qualitative research in international development, but they intensify when new actors such as program evaluators and quantitative researchers use qualitative methods on a large scale. In this context, I look at the utility of guidelines used by these actors to ensure the quality of qualitative research. I ask whether these offer pragmatic suggestions to improve its quality, recognizing the common and hierarchized separation between the generation and interpretation of data, or conversely, whether they set impossible standards and fail to recognize the differences between and respective strengths of qualitative and quantitative research

How to humiliate and shame: A reporter's guide to the power of the mugshot

This is an Author's Accepted Manuscript of an article published in Social Semiotics, 24(1), 56-87, 2014, copyright Taylor & Francis, available online at: http://www.tandfonline.com/The judicial photograph – the “mugshot” – is a ubiquitous and instantly recognisable form, appearing in the news media, on the internet, on book covers, law enforcement noticeboards and in many other mediums. This essay attempts to situate the mugshot in a historical and theoretical context to explain the explicit and implicit meaning of the genre as it has developed, focussing in particular on their use in the UK media in late modernity. The analysis is based on the author's reflexive practice as a journalist covering crime in the national news media for 30 years and who has used mugshots to illustrate stories for their explicit and specific content. The author argues that the visual limitations of the standardised “head and shoulders” format of the mugshot make it a robust subject for analysing the changing meaning of images over time. With little variation in the image format, arguments for certain accreted layers of signification are easier to make. Within a few years of the first appearance of the mugshot form in the mid-19th century, it was adopted and adapted as a research tool by scientists and criminologists. While the positivist scientists claimed empirical objectivity we can now see that mugshots played a part in the construction of subjective notions of “the other”, “the lesser” or “sub-human” on the grounds of class, race and religion. These dehumanising ideas later informed the theorists and bureaucrats of National Socialist ideology from the 1920s to 1940s. The author concludes that once again the mugshot has become, in certain parts of the media, a signifier widely used to exclude or deride certain groups. In late modernity, the part of the media that most use mugshots – the tabloid press and increasingly tabloid TV – is part of a neo-liberal process that, in a conscious commercial appeal to the paying audience, seeks to separate rather than unify wider society

Maternal deaths in Pakistan : intersection of gender, class and social exclusion.

Background: A key aim of countries with high maternal mortality rates is to increase availability of competent maternal health care during pregnancy and childbirth. Yet, despite significant investment, countries with the highest burdens have not reduced their rates to the expected levels. We argue, taking Pakistan as a case study, that improving physical availability of services is necessary but not sufficient for reducing maternal mortality because gender inequities interact with caste and poverty to socially exclude certain groups of women from health services that are otherwise physically available. Methods: Using a critical ethnographic approach, two case studies of women who died during childbirth were pieced together from information gathered during the first six months of fieldwork in a village in Northern Punjab, Pakistan. Findings: Shida did not receive the necessary medical care because her heavily indebted family could not afford it. Zainab, a victim of domestic violence, did not receive any medical care because her martial family could not afford it, nor did they think she deserved it. Both women belonged to lower caste households, which are materially poor households and socially constructed as inferior. Conclusions: The stories of Shida and Zainab illustrate how a rigidly structured caste hierarchy, the gendered devaluing of females, and the reinforced lack of control that many impoverished women experience conspire to keep women from lifesaving health services that are physically available and should be at their disposal

School violence, school differences and school discourses

This article highlights one strand of a study which investigated the concept of the violenceresilient school. In six inner-city secondary schools, data on violent incidents in school and violent crime in the neighbourhood were gathered, and compared with school practices to minimise violence, accessed through interviews. Some degree of association between the patterns of behaviour and school practices was found: schools with a wider range of wellconnected practices seemed to have less difficult behaviour. Interviews also showed that the different schools had different organisational discourses for construing school violence, its possible causes and the possible solutions. Differences in practices are best understood in connection with differences in these discourses. Some of the features of school discourses are outlined, including their range, their core metaphor and their silences. We suggest that organisational discourse is an important concept in explaining school effects and school differences, and that improvement attempts could have clearer regard to this concept