Migration and Sexual Resocialisation: The Case of Central and East Europeans in London

Based upon a survey of more than three thousand respondents and forty in-depth interviews, the aim of this article is to examine the impact of migration on sexual resocialisation. In particular, we show how living in London influenced the attitudes of Central and East European migrants towards pre-marital sex and homosexuality. While the general acceptability of pre-marital sex was not affected by time spent in London, differences were noted in the meaning attached to sex outside marriage in the United Kingdom compared with Central and Eastern Europe. Particularly significant changes were observed in our respondents? attitudes towards homosexuality, with a greater liberalisation the result of extrication from mechanisms of social control, re-socialisation into new social norms regarding sex and sexuality, greater visibility of sexual difference in London and, in particular, inter-personal contacts with gays and lesbians. Limitations to the general liberalisation of attitudes were also noted

Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102–208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype–phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events

The Batten disease protein CLN3 is important for stress granules dynamics and translational activity

The assembly of membrane-less organelles such as stress granules (SGs) is emerging as central in helping cells rapidly respond and adapt to stress. Following stress sensing, the resulting global translational shutoff leads to the condensation of stalled mRNAs and proteins into SGs. By reorganizing cytoplasmic contents, SGs can modulate RNA translation, biochemical reactions, and signaling cascades to promote survival until the stress is resolved. While mechanisms for SG disassembly are not widely understood, the resolution of SGs is important for maintaining cell viability and protein homeostasis. Mutations that lead to persistent or aberrant SGs are increasingly associated with neuropathology and a hallmark of several neurodegenerative diseases. Mutations in CLN3 are causative of juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease affecting children also known as Batten disease. CLN3 encodes a transmembrane lysosomal protein implicated in autophagy, endosomal trafficking, metabolism, and response to oxidative stress. Using a HeLa cell model lacking CLN3, we now show that CLN3KO is associated with an altered metabolic profile, reduced global translation, and altered stress signaling. Furthermore, loss of CLN3 function results in perturbations in SG dynamics, resulting in assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1. With a growing interest in SG-modulating drugs for the treatment of neurodegenerative diseases, novel insights into the molecular basis of CLN3 Batten disease may reveal avenues for disease-modifying treatments for this debilitating childhood disease

Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.Includes Wellcome, BHF, MRC, BBSRC and NIHR

The nation and the family: the impact of national identification and perceived importance of family values on homophobic attitudes in Lithuania and Scotland

The meanings attached to the nation can be consequential for group members’ attitudes and beliefs. We examined how national identity definition can influence the extent of individuals’ homophobia with 159 Lithuanian and 176 Scottish university students who completed a questionnaire which measured their national identification, homophobia, and the extent to which they felt traditional family values were central to their nation’s identity. Consistent with nation-wide differences in the significance given to the family, Lithuanian participants perceived family values to be more important for their national identity and expressed higher levels of homophobia than did Scottish participants. Moreover, the relationship between level of national identification and homophobia was stronger in Lithuania than in Scotland. Analyses revealed that the perceived importance of family values helped explain the difference between homophobia levels in Lithuania and Scotland. In both sites we found an indirect effect of national identification on homophobia via the perceived importance of family values, but this effect was significantly stronger for Lithuanian participants. These findings illustrate the ways in which identification with the nation is relevant to attitudes concerning sexuality, and how this varies according to national context. Our work indicates that LGBT rights campaigns should be informed by the knowledge that homophobia may be perpetuated by national valorisation of the family

Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

<div><p>Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn’s disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.</p></div

Cultural difference on the table: food and drink and their role in multicultural team performance

Multicultural teams are increasingly common and provide a challenge to achieving the integration associated with greater effectiveness. The vague and abstract nature of many definitions of culture can make the difficulties in acknowledging and addressing difference challenging. This longitudinal study of a multicultural team follows the anthropological roots of cultural studies to focus on the material role of food and drink in team development. In an empirical, ethnographically oriented study of a culturally diverse work team over time, we explored the ways that food and drink acted as boundary objects in the processes of integration, differentiation and cultural adaptation and negotiation. By employing the lens of material culture, with its sensory nature and its associations with identity, we also highlight the complexity of cross-cultural interaction, with its possibilities of cooperation, learning, difficulties and resistance, and suggest that food and drink allow a grounded discussion of culture, accommodation and difference. We contribute to the multicultural team literature, emphasizing the roles of materiality, constrained choice and complexity, as well as how these are translated into performance by the generative mechanisms of agency in context. We also identify some specific contributions to practice arising from this research

From Computer Metaphor to Computational Modeling: The Evolution of Computationalism

In this paper, I argue that computationalism is a progressive research tradition. Its metaphysical assumptions are that nervous systems are computational, and that information processing is necessary for cognition to occur. First, the primary reasons why information processing should explain cognition are reviewed. Then I argue that early formulations of these reasons are outdated. However, by relying on the mechanistic account of physical computation, they can be recast in a compelling way. Next, I contrast two computational models of working memory to show how modeling has progressed over the years. The methodological assumptions of new modeling work are best understood in the mechanistic framework, which is evidenced by the way in which models are empirically validated. Moreover, the methodological and theoretical progress in computational neuroscience vindicates the new mechanistic approach to explanation, which, at the same time, justifies the best practices of computational modeling. Overall, computational modeling is deservedly successful in cognitive (neuro)science. Its successes are related to deep conceptual connections between cognition and computation. Computationalism is not only here to stay, it becomes stronger every year