First-Step Mutations for Adaptation at Elevated Temperature Increase Capsid Stability in a Virus

The relationship between mutation, protein stability and protein function plays a central role in molecular evolution. Mutations tend to be destabilizing, including those that would confer novel functions such as host-switching or antibiotic resistance. Elevated temperature may play an important role in preadapting a protein for such novel functions by selecting for stabilizing mutations. In this study, we test the stability change conferred by single mutations that arise in a G4-like bacteriophage adapting to elevated temperature. The vast majority of these mutations map to interfaces between viral coat proteins, suggesting they affect protein-protein interactions. We assess their effects by estimating thermodynamic stability using molecular dynamic simulations and measuring kinetic stability using experimental decay assays. The results indicate that most, though not all, of the observed mutations are stabilizing

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Overlayer Formation As a Source of Stability in the N-Type Photoelectrochemical Cell the N-CdS/Fe(CN)64-/3-Cell

The stability of n-CdS in a Fe(CN64-/3- electrolyte is demonstrated to be due to the formation of a CdFe(CN62-/1-overlayer. Mediated hole transfer through the overlayer to solution Fe(CN64- competes with photoanodic decomposition of the electrode. The charge transfer energetics and kinetics of the overlayer are very sensitive to the supporting electrolyte cation. Variations in supporting electrolyte allow maximization of overlap between the semiconductor states and the filled levels of the surface CdFe(CN62/1 couple. This leads to enhanced energy conversion efficiencies and minimization of electrode decomposition. For the n-CdS electrode, a supporting electrolyte containing both K+ and Cs+ is found to maximize cell performance, A surface state responsible for deleterious electron transfer through the barrier is observed —600 mV positive of the conduction bandedge. Cells with monochromatic efficiencies in excess of 20% (488 nm) can be obtained by considering the CdFe(CN62-/1- overlayer properties

A decade of faculty development for health professions educators: lessons learned from the Macy Faculty Scholars Program

Abstract Faculty development (FD) programs are critical for providing the knowledge and skills necessary to drive positive change in health professions education, but they take many forms to attain the program goals. The Macy Faculty Scholars Program (MFSP), created by the Josiah Macy Jr. Foundation (JMJF) in 2010, intends to develop participants as leaders, scholars, teachers, and mentors. After a decade of implementation, an external review committee conducted a program evaluation to determine how well the program met its intended goals and defined options for ongoing improvement. The committee selected Stufflebeam’s CIPP (context, input, process, products) framework to guide the program evaluation. Context and input components were derived from the MFSP description and demographic data, respectively. Process and product components were obtained through a mixed-methods approach, utilizing both quantitative and qualitative data obtained from participant survey responses, and curriculum vitae (CV). The evaluation found participants responded favorably to the program and demonstrated an overall increase in academic productivity, most pronounced during the two years of the program. Mentorship, community of practice, and protected time were cited as major strengths. Areas for improvement included: enhancing the diversity of program participants, program leaders and mentors across multiple sociodemographic domains; leveraging technology to strengthen the MFSP community of practice; and improving flexibility of the program. The program evaluation results provide evidence supporting ongoing investment in faculty educators and summarizes key strengths and areas for improvement to inform future FD efforts for both the MFSP and other FD programs