BACKGROUND: Faculty vitality is integral to the endurance of higher education. Strengthening vitality is particularly important for mid-career faculty, who represent the largest and most productive segment, but also the most dissatisfied. While the mid-career phase is particularly vulnerable, the backdrop of academic medicine appears to be another factor that may put faculty at risk of attrition. To address these issues, Boston University School of Medicine initiated the Academy for Collaborative Innovation and Transformation (ACIT), a ten-month mid-career faculty development program consisting of six two-day interactive learning modules and multidisciplinary group projects. METHODS: This study is a mixed-methods evaluation of ACIT using a quasi-experimental design to assess the program's impact on faculty and institutional vitality. Pre-post surveys compared participants with a matched reference group. The quantitative data were augmented by interviews and focus groups with participants, senior leadership, department chairs, and ACIT staff members. RESULTS: At the program's conclusion, ACIT participants showed marked gains in knowledge, skills, attitudes, and connectivity when compared to the referents. Results also indicate that the program was largely successful in equipping participants to accomplish the four primary learning goals: to self-reflect and pursue an individual development plan; to connect longitudinally to one's peer cohort and to the larger organization; to collaborate effectively with colleagues across disciplines, sectors, and roles; and to enhance ability to implement transformative work. Lastly, the majority of didactic sessions were rated highly for both content areas and speakers, while the group projects and learning communities received mixed reviews. Based upon these results, recommendations were made to improve the design, execution, and costs of the program. CONCLUSION: Given that mid-career faculty development in academic medicine has not been extensively studied, this evaluation is able to provide a novel perspective to guide future initiatives aimed at this specific subset of higher education.

This dissertation explores tensions between individual freedom and institutional authority. Chapter one examines public perceptions of the legitimacy of "new frontier" public health measures. I present results from a national survey of 1,817 adults concerning the acceptability of public health interventions for noncommunicable diseases. We found that support for these interventions is high overall; strongly associated with race and political orientation; and tied to perceptions of democratic representation in policy making. There was much support for strategies that enable people to exercise healthful choices, but considerably less for more coercive measures. These findings suggest that the least coercive path will be the smoothest. Additionally, the findings underscore the need for policy makers to involve the public in decision making, understand the public's values, and communicate how policy decisions reflect this understanding.

A previous study identified Enterococcus faecalis as one of two bacteria known to have the selD gene and other selenium related genes without having the genes necessary to make selenocysteine or selenouridine. EF2570, a gene in the cluster, was later shown to be upregulated during biofilm formation and also responsible for a selenite- and molybdate-dependent increase in biofilm formation in vitro. The protein encoded was identified as a selenium dependent molybdenum hydroxylase (SDMH), enzymes that contain a labile selenium atom required for activity. While the process of inserting selenocysteine into a protein is well known, the process by which a SDMH acquires a labile selenium atom has not yet been described. To begin unraveling this pathway, the nifS-like EF2568 from the gene cluster will be characterized. Some NifS-like proteins have been shown to have selenocysteine lyase activity, providing a source of selenium for selenophosphate synthetase, the selD gene product. Study of EF2568 has shown that it specifically reacts with L-selenocysteine to form selenide and alanine with L-cysteine inhibiting the reaction. Guided by homology to the well-characterized human and E. coli NifS-like proteins, mutants of the active site and substrate discerning residues were also characterized for activity with L-selenocysteine and L-cysteine. While mutation of the residue at position 112 thought to be responsible for substrate specificity did not affect reactivity of the enzyme with L-cysteine, it did affect reactivity with L-selenocysteine. Studying the characteristics of this novel group II selenocysteine lyase will provide a foundation for studying the remaining pathway.

Cholera toxin (CT) moves from the cell surface to the endoplasmic reticulum (ER) where the catalytic CTA1 subunit separates from the holotoxin and unfolds due to its intrinsic thermal instability. Unfolded CTA1 then moves through an ER translocon pore to reach its cytosolic target. Due to the instability of CTA1, it must be actively refolded in the cytosol to achieve the proper conformation for modification of its G protein target. The cytosolic heat shock protein Hsp90 is involved with the ER-to-cytosol translocation of CTA1, yet the mechanistic role of Hsp90 in CTA1 translocation remains unknown. Potential post-translocation roles for Hsp90 in modulating the activity of cytosolic CTA1 are also unknown. Here, we show by isotope-edited Fourier transform infrared (FTIR) spectroscopy that Hsp90 induces a gain-of-structure in disordered CTA1 at physiological temperature. Only the ATP-bound form of Hsp90 interacts with disordered CTA1, and its refolding of CTA1 is dependent upon ATP hydrolysis. In vitro reconstitution of the CTA1 translocation event likewise required ATP hydrolysis by Hsp90. Surface plasmon resonance (SPR) experiments found that Hsp90 does not release CTA1, even after ATP hydrolysis and the return of CTA1 to a folded conformation. The interaction with Hsp90 allowed disordered CTA1 to attain an active state and did not prevent further stimulation of toxin activity by ADP-ribosylation factor 6, a host cofactor for CTA1. This activity is consistent with its role as a chaperone that refolds endogenous cytosolic proteins as part of a foldosome complex consisting of Hsp90, Hop, Hsp40, p23, and Hsc70. A role for Hsc70 in CT intoxication has not yet been established. Here, biophysical, biochemical, and cell-based assays demonstrate Hsp90 and Hsc70 play overlapping roles in the processing of CTA1. Using SPR we determined that Hsp90 and Hsc70 could bind independently to CTA1 at distinct locations with high affinity, even in the absence of the Hop linker. Studies using isotope-edited FTIR spectroscopy found that, like Hsp90, Hsc70 induces a gain-of-structure in unfolded CTA1. The interaction between CTA1 and Hsc70 is essential for intoxication, as an RNAi-induced loss of the Hsc70 protein generates a toxin-resistant phenotype. Further analysis using isotope-edited FTIR spectroscopy demonstrated that the addition of both Hsc70 and Hsp90 to unfolded CTA1 produced a gain-of-structure above that of the individual chaperones. Our data suggest that CTA1 translocation involves a ratchet mechanism which couples the Hsp90-mediated refolding of CTA1 with extraction from the ER. The subsequent binding of Hsc70 further refolds CTA1 in a manner not previously observed in foldosome complex formation. The interaction of CTA1 with these chaperones is essential to intoxication and this work elucidates details of the intoxication process not previously known.

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