A splicing factor that is inactivated during in vivo heat shock is functionally equivalent to the [U4/U6.U5] triple snRNP-specific proteins.

One of the consequences of the heat shock response in a shutdown of pre-mRNA splicing, a phenomenon that can be reproduced in extracts prepared from heat-shocked cells. The block in splicing occurs before the covalent modifications that generate spliced mRNA at the level of spliceosome formation. We have used extracts prepared from heat-shocked cells as a complementation system to characterize and partially purify a protein factor that is inactivated during the in vivo heat shock. The activity functions in the formation of the active spliceosome by assembling U4/U6 and U5 snRNPs into a triple snRNP particle.One of the consequences of the heat shock response in a shutdown of pre-mRNA splicing, a phenomenon that can be reproduced in extracts prepared from heat-shocked cells. The block in splicing occurs before the covalent modifications that generate spliced mRNA at the level of spliceosome formation. We have used extracts prepared from heat-shocked cells as a complementation system to characterize and partially purify a protein factor that is inactivated during the in vivo heat shock. The activity functions in the formation of the active spliceosome by assembling U4/U6 and U5 snRNPs into a triple snRNP particle

Anthropology, Brokerage and Collaboration in the development of a Tongan Public Psychiatry: Local Lessons for Global Mental Health

The Global Mental Health (GMH) movement has revitalised questions of the translatability of psychiatric concepts and the challenges of community engagement in countries where knowledge of the biomedical basis for psychiatric diagnosis is limited or challenged by local cultural codes. In Tonga, the local psychiatrist Dr Puloka has successfully established a publicly accessible psychiatry that has raised admission rates for serious mental illness and addressed some of the stigma attached to diagnosis. On the basis of historical analysis and ethnographic fieldwork with healers, doctors and patients since 1998, this article offers an ethnographic contextualization of the development and reception of three key interventions during the 1990s inspired by traditional healing and reliant on the translation of psychiatric terms and diagnosis. Dr Puloka’s use of medical anthropological and transcultural psychiatry research informed a community engaged brokerage between the implications of psychiatric nosologies and local needs. As such it reveals deficiencies in current polarised positions on the GMH project and offers suggestions to address current challenges of the Global Mental Health movement

Access, accountability, and the proliferation of psychological therapy:On the introduction of the IAPT initiative and the transformation of mental healthcare

Psychological therapy today plays a key role in UK public mental health. In large part, this has been through the development of the (specifically English) Improving Access to Psychological Therapies (IAPT) programme. Through IAPT, millions of citizens have encountered interventions such as cognitive behaviour therapy, largely for the treatment of depression and anxiety. This article interrogates how this national response to problems of mental ill-health – and the problematization itself – was developed, accounted for, and sustained. By imbricating economic expertise with accounts of mental ill-health and mechanisms of treatment, IAPT has revivified psychological framings of pathology and therapy. However, it has done so in ways that are more familiar within biomedical contexts (e.g. through recourse to randomized controlled trial studies). Today, the initiative is a principal player in relation to which other services are increasingly developed. Indeed, in many respects IAPT has transformed from content to context within UK public mental health (in a process of what I term ‘contextification’). By documenting these developments, this paper contributes to re-centring questions about the place and role of psychology in contemporary healthcare. Doing so helps to complicate assumptions about the dominance of linear forms of (de)biomedicalization in health-systems

Meaning in hoarding: perspectives of people who hoard on clutter, culture, and agency

Hoarding has become increasingly prominent in clinical practice and popular culture in recent years, giving rise to extensive research and commentary. Critical responses in the social sciences have criticised the cultural assumptions built in to the construct of ‘hoarding disorder’ and expressed fears that it may generate stigma outweighing its benefits; however, few of these studies have engaged directly with ‘hoarders’ themselves. This paper reports on in-depth, semi-structured interviews with ten individuals living in England, who received assessment and intervention for hoarding from Social Services. Their narratives drew on the cultural repertoire of values and discourses around waste and worth, the mediation of sociality and relationships through material objects, physical constraints on keeping order, and the role played by mental health. Analysing these perspectives anthropologically shows how dominant models of hoarding, such as the DSM-5 paradigm, potentially lend themselves to reductionist understandings that efface the meaning ‘hoarding’ may have and thereby deny agency to the person labelled as ‘hoarder’. More culturally informed analysis, by contrast, affords insights into the complex landscape of value, waste, social critique, emotion, interpersonal relationships and practical difficulties that may underlie hoarding cases, and points the way to more person-centred practice and analysis

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5\ub4-splice-site selection causing tissue-specific defects

\ua9 The Author(s) 2024.The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5’-splice site (5’SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5’SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches

Projects of devotion : energy exploration and moral ambition in the cosmoeconomy of oil and gas in the Western United States

This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 715146. The authors also acknowledge the funding received to carry out this research from the Leverhulme Trust (ECF‐2013‐177) and the British Academy (EN150010).This article considers how people working in the oil and gas industry in Colorado perceive their involvement in energy exploration in relation to broader understandings of devotion, compassion, and outreach. I argue that although their energy projects may appear to merely echo companies’ formal promotional pitches, the oil field and corporate actors’ own moral ambitions reveal more-than-human cosmoeconomic visions of oil’s potentiality. This article thus demonstrates how multiple and diverging ethical registers intersect and inform the valuation of oil.Publisher PDFPeer reviewe

Mapping the binding site of snurportin 1 on native U1 snRNP by cross-linking and mass spectrometry

Mass spectrometry allows the elucidation of molecular details of the interaction domains of the individual components in macromolecular complexes subsequent to cross-linking of the individual components. Here, we applied chemical and UV cross-linking combined with tandem mass-spectrometric analysis to identify contact sites of the nuclear import adaptor snurportin 1 to the small ribonucleoprotein particle U1 snRNP in addition to the known interaction of m3G cap and snurportin 1. We were able to define previously unknown sites of protein–protein and protein–RNA interactions on the molecular level within U1 snRNP. We show that snurportin 1 interacts with its central m3G-cap-binding domain with Sm proteins and with its extreme C-terminus with stem-loop III of U1 snRNA. The crosslinking data support the idea of a larger interaction area between snurportin 1 and U snRNPs and the contact sites identified prove useful for modeling the spatial arrangement of snurportin 1 domains when bound to U1 snRNP. Moreover, this suggests a functional nuclear import complex that assembles around the m3G cap and the Sm proteins only when the Sm proteins are bound and arranged in the proper orientation to the cognate Sm site in U snRNA