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Antgen processing involves the generation of peptides from cytosolic proteins and their transport into the endoplasmic reticulum where they associate with major histocompatibility complex (MHC) class I molecules. Two genes have been identified in the MHC class II region, RING4 and RING11 in humans, which are believed to encode the peptide transport proteins. Attention is now focused on how the transporters are provided with peptides. The proteasome, a large complex of subunits with multiple proteolytic activities, is a candidate for this function. Recently we reported a proteasome-related sequence, RING10, mapping between the transporter genes. Here we describe a second human proteasome-like gene, RING12, immediately centromeric of the RING4 locus. Therefore RING12, 4, 10 and 11 form a tightly linked cluster of interferon-inducible genes within the MHC with an essential role in antigen processing.

RNA splicing shapes neuronal identity and disease risk, yet current maps lack the developmental resolution and depth to resolve this complexity. Here, we integrate deep long-read RNA sequencing and proteomics in iPSC-derived cortical neurons to generate a high-resolution proteogenomic atlas of human neuron development. We identify 182,371 mRNA isoforms (over half previously unknown) and provide direct peptide evidence for the translation of hundreds of novel protein-coding sequences. Population genetics demonstrates that variants affecting novel exons and splice sites are under negative selection, underscoring the potential significance of these isoforms. During neuronal maturation, we observe that ASD risk genes undergo dynamic isoform switching, including microexon inclusion and intron retention, that remodel key protein domains and regulatory regions. Furthermore, we uncover widespread, long-range coordination between splicing and polyadenylation. Finally, our atlas enables variant reinterpretation in ASD, highlighting the value of an isoform-centric view for interpreting pathogenic variation in neurodevelopment.

The atomic-resolution structural information that X-ray crystallography can provide on the binding interface between a Fab and its cognate antigen is highly valuable for understanding the mechanism of interaction. However, many Fab:antigen complexes are recalcitrant to crystallisation, making the endeavour a significant effort with no guarantee of success. Consequently, there have been significant steps taken to increase the likelihood of Fab:antigen complex crystallisation by altering the Fab framework. In this investigation, we applied the surface entropy reduction strategy coupled with phage-display technology to identify a set of surface substitutions that improve the propensity of a human Fab framework to crystallise. In addition, we showed that combining these surface substitutions with previously reported Crystal Kappa and elbow substitutions results in a striking improvement in Fab and Fab:antigen complex crystallisability, revealing a synergistic relationship between these sets of substitutions. Through comprehensive Fab and Fab:antigen complex crystallisation screenings followed by structure determination and analysis, we defined the roles that each of these substitutions play in facilitating crystallisation and how they complement each other in the process.Competing Interest StatementThe authors have declared no competing interest.

This research aims to explore teachers' views and beliefs with regard to drama as they attempt to define their subject and discuss its content. It examines the debates of the major theorists for drama, including Heathcote and Hornbrook, and considers the views and beliefs of teachers in the field to see which models of learning are reflected in their teaching. Teachers are required to teach drama to English National Curriculum objectives at Key Stage Three, where drama is not regarded us U discrete subject, but is subsumed under English Attainment Target One, 'Speaking and Listening'. At Key Stage Four, drama is regarded as a separate subject from English, where it is taught according to specific Drama GCSE syllabuses. The question is whether teachers ' beliefs about the content, learning and assessment of drama complement the National Curriculum objectives in Key Stages Three and Four. Consequently, further investigation is carried out with regard to which orientation to content, learning and assessment is reflected by the National Curriculum. Teachers ' beliefs concerning subject content, learning and assessment are considered generally us well as with explicit regard to drama teaching itself; to see whether there is a mismatch between the views embodied by the major theorists, teachers' beliefs and the National Curriculum.

Infection with human papillomavirus (HPV) serotypes 16 and 18 in men who have sex with men is a cause of considerable morbidity associated with anal intraepithelial neoplasia. This study shows that the HPV vaccine decreases the risk of HPV-associated anal disease. Anal cancer is biologically similar to cervical cancer, including having a causal relationship with human papillomavirus (HPV) infection. 1 Although HPV type 6 (HPV-6) or HPV type 11 (HPV-11) alone is rarely causal, the proportion of anal cancers associated with infection with HPV type 16 (HPV-16) or HPV type 18 (HPV-18) is as high as or higher than the proportion of cervical cancers. 1 Just as cervical cancer is preceded by high-grade cervical intraepithelial neoplasia (grade ≥2), anal cancer is preceded by high-grade anal intraepithelial neoplasia (grade 2 or 3). 2 – 4 Although not yet formally demonstrated, prevention or treatment of high-grade anal . . .

Standing outside the [Dylan Just] home on Ball Street, Mr. [Jack Leroux] said [Nathan], 11, and Dylan, 9, were \"active young boys who lived to play with their friends.\" Dylan brought [Jason Deane Michael MacCormack], 9, and Nathan brought his best buddy, 11- year-old Jason. At the same time, the telephone at Queen's Ward School was ringing constantly, said principal Norm Dodgson. Jason and Nathan were starting grade 6, and Dylan was to enter grade 4 at the school.

BackgroundSystematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health.ObjectiveThe My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU).MethodsMYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11–14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included.FindingsAnalysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI −0.05 to 0.06) for risk for depression; 0.02 (−0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (−0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed.ConclusionsFindings do not support the superiority of SBMT over TAU in promoting mental health in adolescence.Clinical implicationsThere is need to ask what works, for whom and how, as well as considering key contextual and implementation factors.Trial registrationCurrent controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

The national screening programme guidance for Abdominal Aortic Aneurysm (AAA) in England states that men with small AAAs will exit surveillance after 15 years. This study explored the informed preferences of men for AAA surveillance. A Deliberative Engagement Session was conducted in two workshops comprising 30 men in AAA surveillance and six of their family members. The workshops consisted of measurement of men's knowledge and preferences pre- and post-deliberation, presentations by experts, and deliberation by men and their family members, in terms of knowledge sharing and discussion. Before deliberation, only two of the 30 men in the session were aware of the existence of an exit strategy from AAA surveillance, and their knowledge levels about AAA were poor. Post-deliberation, knowledge levels increased from a median score of 6 (IQR 4 to 7) to a median score of 8 (IQR 8 to 9) correct answers to 11 multiple-choice questions about AAA and AAA screening (p < 0.001). Men in the session identified rate of growth of AAA, size of AAA, health issues that may make surgery risky, and the views of healthcare professionals as important factors to consider in any exit strategy. Most men in the session preferred a strategy whereby they were not discharged from surveillance but had longer intervals between scans (two yearly rather than yearly). Discussion revealed the importance to men and family members of the reassurance surveillance offered to them. In terms of how decisions should be made regarding exit, men in this session wanted to have estimates of the risks of different options, to discuss exit with a Nurse Specialist, and that the patient should decide. Based on informed preferences, men in this Deliberative Engagement Session preferred longer intervals between scans rather than exiting surveillance because of the reassurance offered by surveillance.

People who overdose on opioids when they are alone or unmonitored are at heightened risk of death as other people do not know they should provide an emergency response. Wearable technology provides an opportunity to continuously measure respiratory function and ultimately send an alert if respiratory depression occurs. This study evaluates the feasibility and acceptability of PneumoWave DC in UK homeless hostels or supported accommodation settings (equivalent to Housing First in the USA) for individuals at high risk of opioid overdose. The PneumoWave system consists of a wearable biosensor that is affixed to the chest and records chest motion and which, in future, could potentially provide early detection of respiratory depression and trigger overdose response. RESCU-2 is a non-randomised, observational trial conducted in supported accommodation facilities across the UK. 50 participants who currently use opioids and live in homeless hostels in England and Scotland will wear the PneumoWave biosensor for varying periods to collect data over 2,000 participant-days. The biosensor will be linked via Bluetooth to a hub for continuous respiratory data collection. Self-reported drug use during the trial will be measured using drug diaries. Quantitative acceptability data will be measured using structured satisfaction surveys, while qualitative acceptability data will be obtained from interviews and focus groups with both residents and staff. Statistical analysis will include descriptive evaluation of feasibility outcomes, while qualitative data will undergo thematic analysis. The primary objectives of the study are: 1) feasibility of the study protocol within the hostel setting; 2) acceptability and usability of the device among people who use opioids and live in hostels; 3) acceptability of the device among staff who work in hostels and respond to overdose events. Primary outcomes are recruitment, total hours of usable data collected and successful recording of key outcome measures, among others. Trial registration: ISRCTN12060022. Findings will inform the feasibility of future integration of chest biosensor technology into hostel settings, assessing participant adherence, usability, and acceptability among people who use substances and staff. Insights gained will support the design of future trials and further development of remote monitoring technologies for overdose prevention and response strategies.

Background The NHS Abdominal Aortic Aneurysm (AAA) Screening Programme in England screens men aged 65. Men with small aneurysms enter annual surveillance. The current ‘exit strategy’ is to leave surveillance after 15 years if the aneurysm remains small. Objectives The aim was to explore the views of clinicians, men in surveillance and their family members about exiting surveillance. Design A sequential study involving a Clinical Stakeholder Workshop to explore clinicians' views about factors that should be considered in any exit strategy, followed by a qualitative interview study to explore the views of men in surveillance and family members. Methods A Clinical Stakeholder Workshop with 15 clinicians in the United Kingdom. Semi‐structured interviews with 22 men in surveillance and 5 of their family members from a single regional screening provider. Data were collected from January 2023 to April 2024. Framework Analysis was used. Results Clinicians wanted an exit strategy to reduce unnecessary surveillance. They were concerned about the ethics of men attending for surveillance when they were not healthy enough for future treatment. They identified the need for a ‘low risk strategy’ for men with a low risk of future AAA rupture and a ‘poor health strategy’ so men could leave surveillance if they became too ill to attend surveillance or for future surgery. Men and their family members were less welcoming of an exit strategy because they valued the reassurance offered by surveillance. They also had an ethical concern about being removed from surveillance based on age. Some men proposed a reduction in the frequency of surveillance as an alternative to exit. Both clinicians and men valued shared decision‐making for exit from surveillance, whilst recognising that this needed to occur in the context of limited resources within the NHS screening programme. Conclusions Although clinicians and patients had conflicting views about the need for an exit strategy from AAA surveillance, they agreed that shared decision‐making was key to any exit strategy. Patient or Public Contribution This paper presents the perspectives of men with experience of abdominal aortic aneurysm (AAA) surveillance, and some of their family members. One member of the research team, who is also a co‐author on this paper, is a man who was diagnosed with an AAA. He actively contributed to the design and delivery of the study as co‐applicant on the funding grant. He also attended monthly project meetings where decisions were made about how best to conduct the research. We set up a new Patient and Public Involvement (PPI) Panel made up of men who had experienced AAA screening, including four who were diagnosed with AAA. This panel met eight times throughout the project to ensure that the interview invitations and the topic guide were appropriate; to interpret the findings; and to advise on dissemination strategies.