A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage.

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies

(Re)theorising laddish masculinities in higher education

In the context of renewed debates and interest in this area, this paper reframes the theoretical agenda around laddish masculinities in UK higher education, and similar masculinities overseas. These can be contextualised within consumerist neoliberal rationalities, the neoconservative backlash against feminism and other social justice movements, and the postfeminist belief that women are winning the ‘battle of the sexes’. Contemporary discussions of ‘lad culture’ have rightly centred sexism and men¹s violence against women: however, we need a more intersectional analysis. In the UK a key intersecting category is social class, and there is evidence that while working class articulations of laddism proceed from being dominated within alienating education systems, middle class and elite versions are a reaction to feeling dominated due to a loss of gender, class and race privilege. These are important differences, and we need to know more about the conditions which shape and produce particular performances of laddism, in interaction with masculinities articulated by other social groups. It is perhaps unhelpful, therefore, to collapse these social positions and identities under the banner of ‘lad culture’, as has been done in the past

Queer Asian Subjects: Transgressive Sexualities and Heteronormative Meanings

This special issue of Asian Studies Review explores comparatively the production and transformation of gender and sexual subjectivities across and beyond South and Southeast Asia. More specifically, papers in this special issue disclose the complex intersections of ethnicity, race, class, gender, religion and nationality through which sexual subjectivities are formed and subject positions inhabited within and across these regions. By tracing the transnational movement of people and the circulation of images and ideas, their appropriations and effects, the papers in this volume reveal mutable and multiple sexual subjectivities that are no longer fixed in place, even as state discourses, hegemonic meanings and individual actors work to attach specific meanings to particular bodies. In this special issue we ask, what are the effects of migration, forced and chosen, on forms and formulations of gender and sexuality for people's embodied and discursive entanglements? How do spatial and temporal, as well as religious, economic and political changes alter and foreclose some kinds of intimacies and subjectivities even as they open and enable others? What are the social and cultural processes through which heteronormativity is articulated, enforced, transgressed and challenged

Globalization and change among the hijras of South Asia

Drawing on the anthropological fieldwork of both authors, this article examines the hijras of India and Bangladesh, emphasizing the changes in their traditional religious and political roles and identities, from ancient times until the present. While the most popular common understanding of the hijras, who are found in India, Bangladesh, and Pakistan, is that of a third sex or third gender, they are now also characterized as transgender both within South Asia and internationally. Ancient Hindu mythology provides the basic context for the hijra role in South Asia, but Islam is also critical to their social organization, identities, and present culture. Culture contact predating today’s globalization has played an important role in hijra identity, beginning with their role as eunuchs in the Mughul Empire, through British colonialism, anthropological ethnography, and the internet and global social media. Hijra identity has now moved from an exclusive identification with the religious ritual of emasculation, to a global identity merging with LGBT activism. In addition, globally connected NGOS advocating human rights and HIV/AIDS related activism as well as transnational connections between hijras in South Asia and transgender groups in other parts of the world are now also central in hijra lives. In addition, partly through ethnography, gender theory, international tourism, and global media, the previously dominant binary Western sex/gender ideology is changing to a multiple and fluid gender ideology, both internationally and in South Asia. These global connections have resulted in increasing rights for hijras in India, Bangladesh, and Pakistan, including political, economic, and medical rights, through national legalization of hijras as a third gender

Pathophysiologic mechanisms of itch in bullous pemphigoid

One of the hallmarks of bullous pemphigoid (BP) is moderate to severe chronic itch. Managing this is difficult because little is known about the mechanisms of itch in BP. We sought to elucidate the pathophysiologic mechanisms of itch in BP. The expression of itch mediators in lesions of 24 patients with BP and 6 healthy individuals were examined through immunofluorescence staining. Furthermore, the expression of itch mediators and itch severity was correlated. Itch severity was correlated with eosinophils, substance P, neurokinin 1R, interleukin (IL) 31 receptor A, oncostatin M receptor-β, IL-13, periostin, and basophils. There was also a trend between itch severity and IL-31 expression. Most of the cells expressing IL-31 or neurokinin 1R were identified as eosinophils. Intraepidermal nerve fiber density was decreased. Other itch mediators, including mast cells, IL-4, thymic stromal lymphopoietin, transient receptor potential vanilloid 1 and ankyrin 1, and protease activated receptor 2 were not significantly correlated with itch severity. The relatively small sample size, the examination of protein expression exclusively through immunofluorescent analysis, and lack of functional assays in patients are the limitations. Multiple factors are involved in BP-associated itch, including eosinophils, substance P, neurokinin 1R, IL-31, IL-31 receptor A, oncostatin M receptor-β, IL-13, periostin, and basophils. They could be useful therapeutic targets