Computational spatiotemporal analysis identifies WAVE2 and cofilin as joint regulators of costimulation-mediated T cell actin dynamics

Fluorescence microscopy is one of the most important tools in cell biology research and it provides spatial and temporal information to investigate regulatory systems inside cells. This technique can generate data in the form of signal intensities at thousands of positions resolved inside individual live cells; however, given extensive cell-to-cell variation, methods do not currently exist to assemble these data into three- or four-dimensional maps of protein concentration that can be compared across different cells and conditions. Here, we have developed one such method and applied it to investigate actin dynamics in T cell activation. Antigen recognition in T cells by the T cell receptor (TCR) is amplified by engagement of the costimulatory receptor CD28 and we have determined how CD28 modulates actin dynamics. We imaged actin and eight core actin regulators under conditions where CD28 in the context of a strong TCR signal was engaged or blocked to yield over a thousand movies. Our computational analysis identified diminished recruitment of the activator of actin nucleation WAVE2 and the actin severing protein cofilin to F-actin as the dominant difference upon costimulation blockade. Reconstitution of WAVE2 and cofilin activity restored the defect in actin signaling dynamics upon costimulation blockade. Thus we have developed and validated an approach to quantify protein distributions in time and space for analysis of complex regulatory systems

Managing authenticity and performance in Gulag tourism, Kazakhstan

To date, there has been limited research concerning the methodology and approach to Gulag heritage and how it has been memorialised and commodified for tourism purposes. The recent cultural commodification of the Soviet past and the development of participatory visitor experiences at Gulag museums in Kazakhstan necessitate to advance understandings of the roles authenticity and performance play in the management of Gulag museum practices in the country. Using a qualitative case study research approach based on a combination of semi-structured interviews with stakeholders involved in the development of Gulag tourism including senior management of museums, museum guides, policy-makers, tourism operators, local NGOs and experts in Soviet Gulag heritage, direct observations and qualitative document analysis of two Gulag museums and sites in Kazakhstan, the commodification and management of Soviet Gulag heritage is explored. Results reveal that beyond objects on display and images regarded as interpretive illustrations that allow visitors to connect with the past and verify history, dioramas and staged performances re-enacting various elements of the Gulag life are used as immersive and emotional tools to accentuate the ‘dark’ atmosphere of the epoch and induce a more impactful and participatory visitor experience. The findings contribute to literature on authenticity and performance in Gulag tourism by examining the delicate question of the extent to which stakeholders involved in the management of the Gulag tragedy can offer meaningful visitor experiences that are historically accurate and protect the dignity of the victims while adapting to the dynamic roles of museums as heritage and education sites

Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort

Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question “Would you consider yourself a risk taker?” Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders

Dark tourism and world heritage sites: a delphi study of stakeholder perceptions of the development of dark tourism products

Dark tourism has attracted increasing academic attention, but the extent to which it exists as a separate form of tourism from heritage tourism is not yet clear. Despite the growth of UNESCO World Heritage Site designations, little research has considered the relationship between dark tourism and World Heritage Sites. Because the development of dark tourism is beset with ethical concerns, heritage professionals can have negative perceptions about the acceptability or attractiveness of it for the sites that they are involved in managing. This research used a qualitative Delphi Panel method to evaluate stakeholder perceptions of the potential development of dark tourism to the Greenwich Maritime World Heritage Site in London, United Kingdom. The findings show that stakeholders are broadly supportive of tourism to the site and positive about future tourism growth. Despite this, they did not support the development of dark tourism to the site because it was perceived as inauthentic, tacky and sensationalist. In order to address this issue, recommendations are made that future attempts to develop dark tourism at WHS should involve enhancing the knowledge of stakeholders about dark tourism, and of the resources within their sites that could be included in a dark tourism offer to tourists

The genomic basis of mood instability:identification of 46 loci in 363,705 UK Biobank participants, genetic correlation with psychiatric disorders, and association with gene expression and function

Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health

Kazakhstan Gulag heritage: dark tourism and selective interpretation

Kazakhstan holds some of the most significant Gulag heritage sites; however, tourism research remains limited. This article introduces analysis of contrasting sites and considers how some have been developed and others ignored. Selectivity in interpretation is linked to societal amnesia and the collective trauma experienced by the population of Kazakhstan. The article reaffirms the politicization of heritage in this emergent nation

The Future of World Heritage and the Emergence of Transnational Heritage Regimes

Archaeological Heritage Managemen