Medical students’ characteristics as predictors of career practice location: retrospective cohort study tracking graduates of Nepal’s first medical college

Objective: To determine, in one low income country (Nepal), which characteristics of medical students are associated with graduate doctors staying to practise in the country or in its rural areas. Design: Observational cohort study. Setting: Medical college registry, with internet, phone, and personal follow-up of graduates. Participants: 710 graduate doctors from the first 22 classes (1983-2004) of Nepal’s first medical college, the Institute of Medicine. Main outcome measures: Career practice location (foreign or in Nepal; in or outside of the capital city Kathmandu) compared with certain pre-graduation characteristics of medical student. Results: 710 (97.7%) of the 727 graduates were located: 193 (27.2%) were working in Nepal in districts outside the capital city Kathmandu, 261 (36.8%) were working in Kathmandu, and 256 (36.1%) were working in foreign countries. Of 256 working abroad, 188 (73%) were in the United States. Students from later graduating classes were more likely to be working in foreign countries. Those with pre-medical education as paramedics were twice as likely to be working in Nepal and 3.5 times as likely to be in rural Nepal, compared with students with a college science background. Students who were academically in the lower third of their medical school class were twice as likely to be working in rural Nepal as those from the upper third. In a regression analysis adjusting for all variables, paramedical background (odds ratio 4.4, 95% confidence interval 1.7 to 11.6) was independently associated with a doctor remaining in Nepal. Rural birthplace (odds ratio 3.8, 1.3 to 11.5) and older age at matriculation (1.1, 1.0 to 1.2) were each independently associated with a doctor working in rural Nepal. Conclusions: A cluster of medical students’ characteristics, including paramedical background, rural birthplace, and lower academic rank, was associated with a doctor remaining in Nepal and with working outside the capital city of Kathmandu. Policy makers in medical education who are committed to producing doctors for underserved areas of their country could use this evidence to revise their entrance criteria for medical school

Oct1 and OCA-B are selectively required for CD4 memory T cell function

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory

Oct1 and OCA-B are selectively required for CD4 memory T cell function

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4⁺ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4⁺ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ~50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4⁺ T cell memory

Dynamic regulatory network controlling T_H17 cell differentiation

Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4(+) T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation