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.

Effect of protein supplementation and forage allowance on the growth and reproduction of beef heifers grazing stockpiled tall fescue.

Stockpiled tall fescue can provide adequate winter forage for beef cattle, although unsupplemented replacement heifers may display marginal performance before breeding. The objective of this study was to determine if protein supplementation and/or additional forage improves growth and reproductive performance of replacement heifers grazing stockpiled fescue. Cattle averaging 272 ± 1.59 kg were stratified by BW and then randomly assigned to 1 of 4 plots within a pasture replication. Treatment combinations were assigned in a 2 × 2 factorial arrangement and included 1) a conservative forage allocation ("normal," targeting 85% forage use) and mineral supplement (normal forage allocation with mineral supplement [FM]), 2) normal forage allocation with protein tub (FT), 3) more liberal forage allocation ("extra," targeting 70% forage use) and mineral supplement (extra forage allocation with mineral supplement [EM]), and 4) "extra forage allocation with protein tub (ET). Treatments were administered for 8 wk from early November to early January. Heifers were fed fescue hay for 1 wk before breeding in late January. Heifers were synchronized with the 7-d CO-Synch + controlled internal drug release device protocol and inseminated in late January. Heifers were checked for pregnancy by ultrasonography at 35 and 90 d after AI. Main and interaction effects between the 2 treatments were determined. Total supplement intake was greater for protein tub than mineral supplement (0.36 vs. 0.11 kg·heifer·d, respectively; < 0.0001), and the additional dietary protein in the tub groups resulted in greater serum urea N concentrations ( < 0.0001; 8.15 vs. 10.4 mg/dL for mineral and protein tub, respectively). Forage utilization efficiency was greater for normal than extra forage allocation (74.7 vs. 65.8%, respectively; < 0.0001). Main effects of both treatments on ADG were significant ( < 0.0001; 0.28, 0.43, 0.43, and 0.51 kg·heifer·d for FM, FT, EM, and ET, respectively). There was an interaction effect of the 2 treatments on change in BCS ( < 0.05; 0.12, 0.10, 0.18, and 0.31 for FM, FT, EM, and ET, respectively). Reproductive tract scores, pelvic area, and AI pregnancy rates were not different between treatments ( > 0.05). Overall, feeding a protein supplement or providing extra forage increased gain and interacted to increase BCS but did not have an effect on reproductive performance. Supplementing with protein and providing extra forage are strategies that can increase gain in heifers, which could aid heifers in reaching puberty before estrous synchronization.

Children's eyewitness reports after exposure to misinformation from parents.

This study examined how misleading suggestions from parents influenced children's eyewitness reports. Children (3 to 8 years old) participated in science demonstrations, listened to their parents read a story that described experienced and nonexperienced events, and subsequently discussed the science experience in two follow-up interviews. Many children described fictitious events in response to open-ended prompts, and there were no age differences in suggestibility during this phase of the interview. Accuracy declined markedly in response to direct questions, especially for the younger children. Although the older children retracted many of their false reports after receiving source-monitoring instructions, the younger children did not. Path analyses indicated that acquiescence, free recall, and source monitoring all contribute to mediating patterns of suggestibility across age. Results indicate that judgments about the accuracy of children's testimony must consider the possibility of exposure to misinformation prior to formal interviews.

Accumulation of copper on albumin in bovine plasma in vivo after intravenous trithiomolybdate administration.

The initial disappearance of intravenously administered copper (10 to 20 mg) from bovine plasma in vivo was delayed by the intravenous injection of trithiomolybdate (20 to 75 mg molybdenum per 400 to 445 kg steer); however, the most characteristic effect was the retention of up to about 0.5 mg copper per litre plasma for up to 24 hours after injection. Sephadex G-100 gel filtration of plasma samples showed that this retained copper was associated with the albumin fraction. The effect of trithiomolybdate was very dependent upon the interval between the injections of trithiomolybdate and copper. It is suggested that this variability was due to thiomolybdate metabolism. The infusion of trithiomolybdate (12 to 75 mg molybdenum) over 24 hours also caused the accumulation of albumin-bound copper. The amount bound did not exceed approximately 0.5 mg copper per litre plasma even when the diet of the steers was supplemented with copper sulphate or when copper sulphate (2 X 15 mg copper) was injected directly during the infusion. It is suggested that the longer term effects of trithiomolybdate are not merely a consequence of a simple copper-thiomolybdate reaction but result from three-way interactions between trithiomolybdate, albumin and copper, and that slow infusion of trithiomolybdate provides a model for the study of the systemic effects of dietary molybdenum in cattle.