Structure and Interactions of HIV-1 gp41 CHR-NHR Reverse Hairpin Constructs Reveal Molecular Determinants of Antiviral Activity.

Engineered reverse hairpin constructs containing a partial C-heptad repeat (CHR) sequence followed by a short loop and full-length N-heptad repeat (NHR) were previously shown to form trimers in solution and to be nanomolar inhibitors of HIV-1 Env mediated fusion. Their target is the in situ gp41 fusion intermediate, and they have similar potency to other previously reported NHR trimers. However, their design implies that the NHR is partially covered by CHR, which would be expected to limit potency. An exposed hydrophobic pocket in the folded structure may be sufficient to confer the observed potency, or they may exist in a partially unfolded state exposing full length NHR. Here we examined their structure by crystallography, CD and fluorescence, establishing that the proteins are folded hairpins both in crystal form and in solution. We examined unfolding in the milieu of the fusion reaction by conducting experiments in the presence of a membrane mimetic solvent and by engineering a disulfide bond into the structure to prevent partial unfolding. We further examined the role of the hydrophobic pocket, using a hairpin-small molecule adduct that occluded the pocket, as confirmed by X-ray footprinting. The results demonstrated that the NHR region nominally covered by CHR in the engineered constructs and the hydrophobic pocket region that is exposed by design were both essential for nanomolar potency and that interaction with membrane is likely to play a role in promoting the required inhibitor structure. The design concepts can be applied to other Class 1 viral fusion proteins.

Medical mentorship deconstructed: an analysis and structural recommendation for high value mentorship.

Background: Mentorship is an important component for young students interested in pursuing a career in medicine. In medically underserved areas, such as rural areas, mentorship can be sparse due to the lack of access to healthcare professionals. The purpose of this project was to gain an understanding of the mentorship received by practicing medical students. Methods: The authors conducted structured, one-on-one interviews with 10 current medical students about their perceptions and experiences with mentorship. Interviews were transcribed, coded, and analyzed for themes and subthemes. Results: Our findings revolve around three time periods of mentorship: 1) Before Obtaining a Mentor; 2) During the Mentorship; and 3) After the Mentorship.  In our findings we describe key characteristics such as professional development, personal qualities of the mentor, and professional and personal guidance as important components in guiding the mentee starting from the undergraduate level and continuing to their current level of education.  Conclusion: Interviewees' experiences with and perspectives on the mentorship they received were generally positive, though it was evident there are some aspects of the mentee-mentor relationship that can be improved. Building on the results obtained, setting expectations, providing mentor training, and pairing mentors/mentees from similar backgrounds are what we propose to create fulfilling and meaningful relationships between a mentee and mentor.

Women Leading Healthy Change: A Reciprocal Learning Experience for Women in the Sex Trade and Medical Students.

Introduction: Service learning can teach medical students about the social determinants of health and prepare them to better serve marginalized populations, while people in the sex trade can serve as effective educators for their peers and health professions trainees. However, service-learning projects involving medical students and people in the sex trade are currently rare. Methods: We modified a curriculum from an author's prior institution to provide a unique service-learning experience for medical students and peer health education for women in the sex trade in a new city and new context. Medical students partnered with a local community organization to implement a 10-week course on physical and mental health for women in the sex trade. Coled by a medical student and a woman who had utilized the community partner's services, the course's instructional methods included in-class demonstrations, group discussion, games, and worksheets. Results: Ten women participated in the course, and six medical students facilitated its implementation. The participants demonstrated increased knowledge in physical and mental health topics and reported being more comfortable speaking with health care providers. The coleaders developed skills and confidence to pursue additional leadership opportunities. The medical student coleader gained a better understanding of addiction and was more prepared to work with patients with substance use disorders. Discussion: This mutual learning experience was a valuable health education opportunity for a local underserved community and helped medical students understand the barriers women in the sex trade face when seeking health care and how physicians can better meet their needs.