Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

The oral-systemic personalized medicine model at Marshfield Clinic.

Periodontal disease and diabetes, two diseases that have achieved epidemic status, share a bidirectional relationship driven by micro-inflammatory processes. The present review frames the current understanding of the pathological processes that appear to link these diseases and advances the hypothesis that reversal of the epidemic is possible through application of interdisciplinary intervention and advancement of oral-systemic personalized medicine. An overview of how Marshfield Clinic's unique clinical, informatics and bio-repository resources and infrastructures are being aligned to advance oral-systemic personalized medicine is presented as an interventional model with the potential to reverse the epidemic trends seen for these two chronic diseases over the past several decades. The overall vision is to engineer a transformational shift in paradigm from 'personalized medicine' to 'personalized health'.

Anaesthesia-related maternal mortality.

Complications of anaesthesia leading to death in young pregnant women might be prevented if more experienced personnel could be entrusted with the job. The contribution of anaesthesia to maternal mortality in the United Kingdom is 1.7 per million pregnancies with almost similar incidence from United States. The commonest single factor responsible for anaesthesia-related death is difficult or failed intubation. A pregnant woman with a potentially difficult airway should receive aspiration prophylaxis (mechanical or pharmacological) as soon as operative delivery is anticipated. Anaesthetists should make a plan that comes into effect as soon as failure to view the larynx or to intubate the trachea becomes evident. Unsuspected difficult airway can be managed if the skill of the anaesthetists is of high standard. Pulmonary aspiration is one cause of death in obstetric anaesthesia. Regurgitation and vomiting prevention can minimise pulmonary aspiration. In regional anaesthesia, local anaesthetics toxicity is another cause of concern. This should be tackled with some safe local anaesthetics. Preventing a high spinal or epidural block involves ways to detect inadvertent injection of local anaesthetic into the cerebrospinal fluid. Postoperative care after anaesthesia in obstetric cases is very important.

Randomised controlled trial of eutectic mixture of local anaesthetics cream for venepuncture in healthy preterm infants.

AIM: To assess the safety and efficacy of EMLA cream (eutectic mixture of local anaesthetics) used to induce surface anaesthesia for venepuncture in healthy preterm infants. METHODS: Nineteen infants, median gestational age 31 weeks (range 26-33 weeks) were assessed in a randomised, double blind, placebo controlled, cross-over trial. Changes in physiological variables (heart rate, blood pressure, oxygen saturation) and behavioural responses (neonatal facial coding system score, crying time) before and after venepuncture with EMLA cream were compared with those obtained with a placebo cream to assess efficacy. Toxicity was assessed by comparing methaemoglobin concentrations at 1 hour and 8 hours after application. RESULTS: There was no significant difference in efficacy between EMLA and placebo creams in physiological and behavioural responses. There was no significant difference in methaemoglobin concentrations one hour after the cream had been applied. At eight hours, however, concentrations were significantly higher after EMLA than placebo (p = 0.016). There was no evidence of clinical toxicity. CONCLUSION: This study does not support the routine use of EMLA for venepuncture in healthy preterm infants.

Permissible discontinuity region of the alpha-chain of hemoglobin: noncovalent interaction of heme and the complementary fragments alpha 1-30 and alpha 31-141.

Generation of a fragment-complementing system of the alpha-chain on limited proteolysis with Staphylococcus aureus V8 protease has been investigated. Digestion of the alpha-chain (0.4 mM) of hemoglobin with V8 protease in phosphate buffer at pH 6.0 and 37 degrees C is limited to the peptide bonds of Glu-23, Glu-27, Glu-30, and Asp-47. Gel filtration of a V8 protease digest of the alpha-chain on a Sephadex G-50 column did not release any heme to the low molecular weight region, though some peptides were released from the protein. The filtration studies revealed the presence of two heme-containing components in the digest, the major one eluting at the alpha-chain position and the minor one eluting slightly ahead of the alpha-chain position. Reversed-phase high-performance liquid chromatography and amino-terminal sequence analysis demonstrated that the component eluting at the alpha-chain position contains species generated by the noncovalent interactions of heme and the complementary fragments alpha 1-30 and alpha 31-141. In dilute solutions (0.04 mM) the V8 protease digestion occurred exclusively on the carboxyl side of Glu-30(alpha). This high selectivity was also observed at pH 4.0 and pH 7.8. The visible spectra and the ultraviolet circular dichroic spectra of the digest reflect the native-like structure of the noncovalent fragment system. The dissociation constant of alpha 1-30 appears to be in the range of 10(-8) M. In tetrameric hemoglobin A the peptide bond of Glu-30-Arg-31 of the alpha-chain is not accessible to V8 protease digestion.(ABSTRACT TRUNCATED AT 250 WORDS)