Structural and Kinetics Studies of the Enzyme Dihydropteroate Synthase and the Implications for Antibiotic Resistance

The goal of this study is to develop small molecule inhibitors of DHPS for the treatment of a variety of infectious diseases. According to the World Health Organization (WHO), infectious diseases kill more than 13 million people worldwide every year making it the second leading cause of death behind cardiovascular disease. The sulfonamide class of drugs has been in use since the 1930’s to treat many infectious agents and act by targeting the enzyme dihydropteroate synthase (DHPS) of the prokaryotic and lower eukaryotic folate pathway. DHPS is an ideal drug target because humans do not synthesize folate de novo and is a well validated system. However, the emergence of bacterial resistance has limited the efficacy of sulfonamides, and an increasing trend in drug resistance has heightened the need for development of new therapeutics. Although drug resistance has severely limited the clinical use of sulfonamides, the folate pathway, and DHPS in particular, remain an ideal target for therapeutic development. This is due to the fact that DHPS accommodates two substrates, para-aminobenzoic acid (pABA) and 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPPP), which bind to separate and distinct regions of the protein. Sulfonamides act by binding the pABA pocket composed largely of dynamic loop regions which fold in upon substrate binding to complete the active site. In contrast, the pterin pocket is a highly conserved, rigid binding site, and is predicted to be more suitable for the development of small molecule inhibitors. Therefore, we propose targeting the pterin binding site as a means of developing novel small molecule inhibitors of DHPS. The advantages of this method are that pterin binds to a distinct region of DHPS separate from the pABA binding site and removed from areas known to accommodate sulfonamide resistance. In addition, it provides a novel approach to exploit a well validated drug target. We hypothesize that pterin-based compounds will provide a new class of antibiotics that will overcome the problems of drug resistance and provide novel therapeutics for a broad spectrum of infectious diseases

A non-precious metal hydrogen catalyst in a commercial polymer electrolyte membrane electrolyser.

We demonstrate the translation of a low-cost, non-precious metal cobalt phosphide (CoP) catalyst from 1 cm2 lab-scale experiments to a commercial-scale 86 cm2 polymer electrolyte membrane (PEM) electrolyser. A two-step bulk synthesis was adopted to produce CoP on a high-surface-area carbon support that was readily integrated into an industrial PEM electrolyser fabrication process. The performance of the CoP was compared head to head with a platinum-based PEM under the same operating conditions (400 psi, 50 °C). CoP was found to be active and stable, operating at 1.86 A cm-2 for >1,700 h of continuous hydrogen production while providing substantial material cost savings relative to platinum. This work illustrates a potential pathway for non-precious hydrogen evolution catalysts developed in past decades to translate to commercial applications

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Feminist Pedagogy in Our Classrooms and Our Communities

Please click the links below to view more information about each presentation. “‘The Feminist History Your Momma Never Taught You’ and its Necessary Inclusion in WGS Intro Classes” Katherine E. Ayers, Virginia Polytechnic Institute and State University “#TheStandardsAren\u27tEnough: Feminist Pedagogy and Teaching Intersectional Feminist Texts in the High School Classroom Justine D. Chew, University of North Carolina at Wilmington “The US Community College as Stepping Stone to Opportunity for Asian/Asian American Women” Suchitra Samanta, Virginia Polytechnic Institute and State University “Intersectional Action-Learning: A Framework for Queer Capacity Building” Jayke A. Hamill, University of North Carolina at Greensbor

A non-precious metal hydrogen catalyst in a commercial polymer electrolyte membrane electrolyser.

We demonstrate the translation of a low-cost, non-precious metal cobalt phosphide (CoP) catalyst from 1 cm2 lab-scale experiments to a commercial-scale 86 cm2 polymer electrolyte membrane (PEM) electrolyser. A two-step bulk synthesis was adopted to produce CoP on a high-surface-area carbon support that was readily integrated into an industrial PEM electrolyser fabrication process. The performance of the CoP was compared head to head with a platinum-based PEM under the same operating conditions (400 psi, 50 °C). CoP was found to be active and stable, operating at 1.86 A cm-2 for >1,700 h of continuous hydrogen production while providing substantial material cost savings relative to platinum. This work illustrates a potential pathway for non-precious hydrogen evolution catalysts developed in past decades to translate to commercial applications

Risk Factors Early in the 2010 Cholera Epidemic, Haiti

During the early weeks of the cholera outbreak that began in Haiti in October 2010, we conducted a case–control study to identify risk factors. Drinking treated water was strongly protective against illness. Our results highlight the effectiveness of safe water in cholera control