A New Way of Evaluating Effectiveness of URM Summer Pipeline Programs.

PURPOSE: Many academic medical centers fund educational opportunities (pipeline programs) for students who are underrepresented in medicine (URM). However, there is a sparsity of published literature on pipeline programs and an even smaller body of published literature that investigates program effectiveness. METHODS: In a retrospective cohort study (n=12) of the Provost's Summer Mentorship Program-Medicine (SMPM), we evaluated students' rating of program effectiveness, students' rating of the program's impact on their mindsets, and SAT scores. Several program mindsets, including sense of belonging (inclusiveness) in the health professions and connection to mentors in the medical field, reflect common barriers that prevent URM students from pursuing careers in medicine as outlined in pipeline literature. We describe program effectiveness using mean and median ratings of SMPM effectiveness, ratings of mindsets, and SAT scores. We used Wilcoxon Rank Sum to assess pre and post program differences in ratings of mindsets and SAT scores. RESULTS: SMPM was effective for learners. The overall mean rating for SMPM effectiveness was 4.27. Mindsets for confidence, interest, sense of belonging, college mentorship, and physician mentorship were statistically different from the start to the end of SMPM (p<0.05), with mean improvement of about 34%, 41%, 44%, 180%, and 140% respectively. The mean pre and post SMPM SAT scores as well as 4-month follow-up SAT mean scores were 713 (SD:155), 813 (SD:83), and 1058 (SD:147), respectively. There was a statistically significant difference between all three SAT scores (p<0.05). CONCLUSION: In addition to providing educational support, our pipeline program effectively increased students' sense of belonging in the medical field and their connections to physician mentors, which are two common barriers for URM students who are interested in medicine.

Probing the antigenicity of hepatitis C virus envelope glycoprotein complex by high-throughput mutagenesis.

The hepatitis C virus (HCV) envelope glycoproteins E1 and E2 form a non-covalently linked heterodimer on the viral surface that mediates viral entry. E1, E2 and the heterodimer complex E1E2 are candidate vaccine antigens, but are technically challenging to study because of difficulties in producing natively folded proteins by standard protein expression and purification methods. To better comprehend the antigenicity of these proteins, a library of alanine scanning mutants comprising the entirety of E1E2 (555 residues) was created for evaluating the role of each residue in the glycoproteins. The mutant library was probed, by a high-throughput flow cytometry-based assay, for binding with the co-receptor CD81, and a panel of 13 human and mouse monoclonal antibodies (mAbs) that target continuous and discontinuous epitopes of E1, E2, and the E1E2 complex. Together with the recently determined crystal structure of E2 core domain (E2c), we found that several residues in the E2 back layer region indirectly impact binding of CD81 and mAbs that target the conserved neutralizing face of E2. These findings highlight an unexpected role for the E2 back layer in interacting with the E2 front layer for its biological function. We also identified regions of E1 and E2 that likely located at or near the interface of the E1E2 complex, and determined that the E2 back layer also plays an important role in E1E2 complex formation. The conformation-dependent reactivity of CD81 and the antibody panel to the E1E2 mutant library provides a global view of the influence of each amino acid (aa) on E1E2 expression and folding. This information is valuable for guiding protein engineering efforts to enhance the antigenic properties and stability of E1E2 for vaccine antigen development and structural studies.

Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design.

Hepatitis C virus infects nearly 3% of the world's population and is often referred as a silent epidemic. It is a leading cause of liver cirrhosis and hepatocellular carcinoma in endemic countries. Although antiviral drugs are now available, they are not readily accessible to marginalized social groups and developing nations that are disproportionally impacted by HCV. To stop the HCV pandemic, a vaccine is needed. Recent advances in HCV research have provided new opportunities for studying HCV neutralizing antibodies and their subsequent use for rational vaccine design. It is now recognized that neutralizing antibodies to conserved antigenic sites of the virus can cross-neutralize diverse HCV genotypes and protect against infection in vivo. Structural characterization of the neutralizing epitopes has provided valuable information for design of candidate immunogens.