A Brief Recent History of Women in Computational Chemistry at Vertex Pharmaceuticals.

Countless reports cite the importance of diversity in the academic, industrial, and government workplace. This article shares the different perspective on gender diversity from five women who have recently joined Vertex's computational chemistry group. It is written with the hope that other scientists will take the themes which resonant and adopt them to their own institutions to inspire the fostering of an inclusive environment while in pursuit of scientific discoveries.

Effect of Single-Use Negative Pressure Wound Therapy on Postcesarean Infections and Wound Complications for High-Risk Patients.

OBJECTIVE: To evaluate the effect of a single-use negative pressure wound therapy (NPWT) system on postoperative complications after cesarean delivery. STUDY DESIGN: A historical control cohort of women was collected as part of a quality improvement project over a 6-month period. All women with at least 1 risk factor for postoperative complications were included in this control cohort. An intervention cohort of 110 women with at least 1 risk factor for postoperative complications was eligible to have a single-use NPWT system placed at the time of cesarean delivery. Primary outcomes were wound/infectious morbidity, including any surgical site infection (deep or superficial) as defined by the Centers for Disease Control, or wound separation without infection. RESULTS: Despite significantly higher overall burden of risk factors for postoperative complications, the intervention group showed a significantly lower rate (21.0% vs. 6.4%, p = 0.0007) of overall wound/infectious morbidity. The rate of isolated wound separation betweenthe 2 groups was not statistically significant (3.8% vs. 2.7%, p = 0.754) and was likely due to the low rate of wound separations. CONCLUSION: Application of an NPWT system to a primarily closed cesarean incision at time of surgery significantly decreased both deep and superficial infectious morbidity in our intervention group, which had more risk factors for wound complications and postoperative infection.

Investigation of the conformational dynamics of the apo A2A adenosine receptor.

The activation/deactivation processes for G-protein coupled receptors (GPCRs) have been computationally studied for several different classes, including rhodopsin, the ß2 adrenergic receptor, and the M2 muscarinic receptor. Despite determined cocrystal structures of the adenosine A2A receptor (A2A AR) in complex with antagonists, agonists and an antibody, the deactivation process of this GPCR is not completely understood. In this study, we investigate the convergence of two apo simulations, one starting with an agonist-bound conformation (PDB: 3QAK)(14) and the other starting with an antagonist-bound conformation (PDB: 3EML)(11) . Despite the two simulations not completely converging, we were able to identify distinct intermediate steps of the deactivation process characterized by the movement of Y288(7.53) in the NPxxY motif. We find that Y288(7.53) contributes to the process by forming hydrogen bonds to residues in transmembrane helices 2 and 7 and losing these interactions upon full deactivation. Y197(5.58) also plays a role in the process by forming a hydrogen bond only once the side chain moves from the lipid interface to the middle of the helical bundle.

Assessment of uterus position as a surrogate for high-risk clinical target volume with respect to the applicator position for multiple fractions of brachytherapy in cervical cancer.

AIM: Hybrid magnetic resonance imaging/computerized tomography (MRI/CT) planning for high-dose-rate (HDR) brachytherapy in cervical cancer with MR/CT fusion for the first fraction followed by CT for fraction 2 and 3 is used at our center. The aim of this study is to evaluate the position of applicator intrauterine tube (IU) in relation to uterine serosa with each fraction of intracavitary high-dose-rate brachytherapy. METHODS: Position of the applicator relative to uterus was measured from tip of the applicator (IU) to the top of uterus in the plane of IU and perpendicular to IU in anterior, posterior, left and right directions at the tip of IU, mid-point of the IU and 1 cm from the surface of vaginal ring. The mean absolute difference (±95 % confidence interval) between these positions at fraction 2 and 3 was calculated with fraction one as reference. RESULTS: The mean absolute difference (±95 %) of the applicator relative to uterus was 2.7 ± 0.5 mm at the tip, 1.5 ± 4 mm at mid-point and 1.1 ± 0.3 mm at 1 cm from the surface of the ring. CONCLUSION: This study shows that there is consistency in inter-fraction applicator position relative to uterus apart from at the tip and, therefore, in situations where high-risk clinical target volume (HRCTV) extends towards uterine fundus, MRI should be used for each fraction of brachytherapy planning to accurately define HRCTV.

Discovery of novel inhibitors of HIV-1 reverse transcriptase through virtual screening of experimental and theoretical ensembles.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are potent anti-HIV chemotherapeutics. Although there are FDA-approved NNRTIs, challenges such as the development of resistance have limited their utility. Here, we describe the identification of novel NNRTIs through a combination of computational and experimental approaches. Based on the known plasticity of the NNRTI binding pocket (NNIBP), we adopted an ensemble-based virtual screening strategy: coupling receptor conformations from 10 X-ray crystal structures with 120 snapshots from a total of 480 ns of molecular dynamics (MD) trajectories. A screening library of 2864 National Cancer Institute (NCI) compounds was built and docked against the ensembles in a hierarchical fashion. Sixteen diverse compounds were tested for their ability to block HIV infection in human tissue cultures using a luciferase-based reporter assay. Three promising compounds were further characterized, using a HIV-1 RT-based polymerase assay, to determine the specific mechanism of inhibition. We found that 2 of the three compounds inhibited the polymerase activity of RT (with potency similar to the positive control, the FDA-approved drug nevirapine). Through a computational approach, we were able to discover two compounds which inhibit HIV replication and block the activity of RT, thus offering the potential for optimization into mature inhibitors.