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.

Survey and Risk Assessment of Apis mellifera (Hymenoptera: Apidae) Exposure to Neonicotinoid Pesticides in Urban, Rural, and Agricultural Settings.

A comparative assessment of apiaries in urban, rural, and agricultural areas was undertaken in 2013 and 2014 to examine potential honey bee colony exposure to neonicotinoid insecticides from pollen foraging. Apiaries ranged in size from one to hundreds of honey bee colonies, and included those operated by commercial, sideline (semicommercial), and hobbyist beekeepers. Residues in and on wax and beebread (stored pollen in the hive) were evaluated for the nitro-substituted neonicotinoid insecticides imidacloprid and its olefin metabolite and the active ingredients clothianidin, thiamethoxam, and dinotefuran. Beebread and comb wax collected from hives in agricultural landscapes were more likely to have detectable residues of thiamethoxam and clothianidin than that collected from hives in rural or urban areas (∼50% of samples vs. <10%). The maximum neonicotinoid residue detected in either wax or beebread was 3.9 ppb imidacloprid. A probabilistic risk assessment was conducted on the residues recovered from beebread in apiaries located in commercial, urban, and rural landscapes. The calculated risk quotient based on a dietary no observable adverse effect concentration (NOAEC) suggested low potential for negative effects on bee behavior or colony health.

A novel 3D volumetric method for directly quantifying porosity and pore space morphology in flocculated suspended sediments.

Flocculated suspended sediments (flocs) are found in a variety of environments globally, and their transport and behavior bear substantial importance to several industries including fisheries, aquaculture, and shipping. Additionally, the modelling of their behavior is important for estuarine and coastal flood prediction and defence, and the process of flocculation occurs in other unrelated industries such as paper and chemical production. Floc porosity is conventionally assessed using inferential indirect or proxy data approaches. These methods underestimate floc porosity % by c. 30% and cannot measure the micro-scale complexity of these pore spaces and networks, rendering inputs to models sub-optimal. This study introduces a novel 3D porosity and pore space quantification protocol, that produces directly quantified porosity % and pore space data.•3D floc data from micro-CT scanning is segmented volumetrically•This segmented volume is quantified to extract porosity and several pore space parameters from the floc structure.

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. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder.

Neuroimaging and postmortem studies of subjects with major depressive disorder (MDD) reveal smaller hippocampal volume with lengthening duration of illness. Pathology in astrocytes may contribute significantly to this reduced volume and to the involvement of the hippocampus in MDD. Postmortem hippocampal tissues were collected from 17 subjects with MDD and 17 psychiatrically-normal control subjects. Sections from the body of the hippocampus were immunostained for glial fibrillary acidic protein (GFAP), a marker of intermediate filament protein expressed in astrocytes. The density of GFAP-immunoreactive astrocytes was measured in the hippocampus using 3-dimensional cell counting. Hippocampal subfields were also assessed for GFAP-immunoreactive area fraction. In CA1, there was a significant positive correlation between age and either density or area fraction in MDD. The density of astrocytes in the hilus, but not CA1 or CA2/3, was significantly decreased only in depressed subjects not taking an antidepressant drug, but not for depressed subjects taking an antidepressant drug. The area fraction of GFAP-immunoreactivity was significantly decreased in the dentate gyrus in women but not men with depression. In CA2/3, the area fraction of GFAP-immunoreactivity was inversely correlated with the duration of depression in suicide victims. Astrocyte contributions to neuronal function in the hilus may be compromised in depressed subjects not taking antidepressant medication. Due to the cross-sectional nature of the present study of postmortem brain tissue, it remains to be determined whether antidepressant drug treatment prevented a decrease in GFAP-immunoreactive astrocyte density or restored cell density to normal levels.

Detecting Taxus poisoning in horses using liquid chromatography/mass spectrometry.

A method is described for the analysis of taxine alkaloids by liquid chromatography/mass spectrometry. It is applicable to the detection of taxine alkaloids in the stomach contents of horses in which Taxus poisoning is suspected. Analysis of a leaf extract of Taxus baccata revealed unreported alkaloids of the same relative molecular mass as taxine B and isotaxine B.