Reconstruction of a pathway of antigen processing and class II MHC peptide capture

Endocytosed antigens are proteolytically processed and small amounts of peptides captured by class II MHC molecules. The details of antigen proteolysis, peptide capture and how destruction of T-cell epitopes is avoided are incompletely understood. Using the tetanus toxin antigen, we show that the introduction of 3-6 cleavage sites is sufficient to trigger a partially unfolded conformation able to bind to class II MHC molecules. The known locations of T-cell epitopes and protease cleavage sites predict that large domains of processed antigen (8-35kDa) are captured under these conditions. Remarkably, when antigen is bound to the B-cell antigen receptor (BCR), processing can trigger a concerted 'hand-over' reaction whereby BCR-associated processed antigen is captured by neighbouring class II MHC molecules. Early capture of minimally processed antigen and confinement of the processing and class II MHC loading reaction to the membrane plane may improve the likelihood of T-cell epitope survival in the class II MHC pathway and may help explain the reciprocal relationships observed between B- and T-cell epitopes in many protein antigens and autoantigen

Ubiquitin crosstalk connecting cellular processes

The polypeptide ubiquitin is used in many processes as different as endocytosis, multivesicular body formation, and regulation of gene transcription. Conjugation of a single ubiquitin moiety is typically used in these processes. A polymer of ubiquitin moieties is required for tagging proteins for proteasomal degradation. Besides its role in protein degradation, ubiquitin is also engaged as mono- or polymer in intracellular signalling and DNA repair. Since free ubiquitin is present in limiting amounts in cells, changes in the demands for ubiquitin in any of these processes is likely to indirectly affect other ubiquitin modifications. For example, proteotoxic stress strongly increases poly-ubiquitylated proteins at the cost of mono-ubiquitylated histones resulting in chromatin remodelling and altered transcription. Here we discuss the interconnection between ubiquitin-dependent processes and speculate on the functional significance of the ubiquitin equilibrium as a signalling route translating cellular stress into molecular responses

The impact of global health opportunities on residency selection

Abstract Background An increasing number of medical trainees across specialties desire and expect Global Health (GH) experiences during training. It is useful for residency programs to know the impact that offering GH opportunities has on resident recruitment. The study objectives were to explore the importance of GH opportunities in residency selection among fourth-year medical students, examine the relationship between interest in GH and career plans, and describe students’ perspectives on prior GH experiences. Methods The authors administered an electronic survey to all fourth-year medical students attending 12 different US institutions in February 2020. Data from the ten schools who were able to comply with the survey distribution methodology and with response rates above 25% were analyzed using descriptive statistics and Pearson’s correlation. Results A total of 707 fourth-year medical students from the included schools completed the survey out of 1554 possible students (46% response rate). One third of respondents ranked the presence of GH experiences in residency as moderately or very important and 26% felt that the presence of a formal GH curriculum was at least moderately important, with variation noted among specialties. After training, 65% of students envision practicing internationally in some capacity. A desire to care for underserved patients in their careers was significantly correlated with an interest in GH experiences during residency. Conclusions The opportunity to be involved in GH experiences during training can be an important factor for many medical students when considering residency choice, and the availability of these opportunities may be a valuable recruitment tool. Students valuing GH opportunities during residency are more interested in working with underserved populations in their future careers. </jats:sec

GHEARD: An Open-Access Modular Curriculum to Incorporate Equity, Anti-Racism, and Decolonization Training Into Global Health Education

Background: Global health (GH) interest is rising among graduate medical education (GME) trainees, yet GH engagement is marred by the impact of colonization or racism, and there remains a lack of training to confront these challenges. Objective: To develop a modular, open-access curriculum that provides training in decolonization for GH GME and evaluate its feasibility and impact on learners’ critical reflection on decolonization. Methods: From 2019 to 2022, 40 GH educators, including international and indigenous scholars from diverse organizations, created the Global Health Education for Equity, Anti-Racism, and Decolonization (GHEARD) curriculum. Using Kern’s 6 steps of curriculum development, critical gaps were identified and shaped into 8 modules, including a facilitator training module. Learning objectives and activities were developed using strategies grounded in transformative learning theory and trauma-informed educational approaches. The curriculum was peer-reviewed and piloted at multiple national conferences and institutions to assess feasibility and effectiveness in fostering critical reflection on decolonization. Results: Pilot testing demonstrated GME implementation feasibility. Based on initial educator feedback, facilitator tools and an implementation guide were incorporated to enhance usability. Nearly all (59 of 61) trainees felt GHEARD was effective or very effective in encouraging reflection on decolonization, and 72% (32 of 44) felt GHEARD encouraged reflection on motivations for engaging in GH. GHEARD was launched as a free online resource in June 2023 and garnered 3192 views by December 2024. Conclusions: To our knowledge, GHEARD is the first comprehensive decolonization curriculum designed specifically for GME. Program evaluation indicates GHEARD is feasible to implement and effective in promoting critical reflection on decolonization