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 Central Vein: FLAIR Signal Abnormalities Associated with Developmental Venous Anomalies in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Demyelination is a recently recognized cause of FLAIR hyperintensities associated with developmental venous anomalies. Our purpose was to quantify the prevalence of white matter signal abnormalities associated with developmental venous anomalies in patients with multiple sclerosis compared with controls. MATERIALS AND METHODS: A retrospective, blinded, multireader study compared the prevalence of FLAIR hyperintense signal abnormalities adjacent to developmental venous anomalies in patients with MS compared with controls (patients with developmental venous anomalies without MS). Study findings were positive if a central vein was demonstrated using FLAIR and contrast-enhanced fat-saturated T1 sequences. Imaging parameters also included developmental venous anomaly location, developmental venous anomaly drainage, white matter lesion size, and depth of white matter lesions. Clinical parameters included age, sex, and the presence of confounding variables (hypertension, diabetes, migraines, and/or vasculopathy). RESULTS: FLAIR signal abnormality was present around 47.3% (35/74) of developmental venous anomalies in patients with MS, and 13.5% (10/74) of developmental venous anomalies in the control group (P < .001). The multivariate logistic regression model controlling for covariates (including migraines, hypertension, diabetes mellitus, vasculopathy, age, sex, and drainage direction of developmental venous anomalies) showed that the odds of FLAIR hyperintensity around developmental venous anomalies was 6.7-fold higher in patients with MS (relative risk MS = 6.68; 95% CI, 2.79-15.97; P < .001). CONCLUSIONS: The association of developmental venous anomalies and FLAIR hyperintensities was more common in patients with MS, which suggests that the underlying demyelinating pathologic process of MS may be the cause of this propensity in patients with MS. Impaired venous drainage in the territory of developmental venous anomalies may predispose to development of these lesions, and an associated central vein is helpful in understanding an atypical location of MS plaques.

Association of Developmental Venous Anomalies with Demyelinating Lesions in Patients with Multiple Sclerosis.

We present 5 cases of demyelination in patients diagnosed with multiple sclerosis that are closely associated with a developmental venous anomaly. Although the presence of a central vein is a known phenomenon with multiple sclerosis plaques, demyelination occurring around developmental venous anomalies is an underreported phenomenon. Tumefactive demyelination can cause a diagnostic dilemma because of its overlapping imaging findings with central nervous system neoplasm. The relationship of a tumefactive plaque with a central vein can be diagnostically useful, and we suggest that if such a lesion is closely associated with a developmental venous anomaly, an inflammatory or demyelinating etiology should be a leading consideration.

Directly probing spin dynamics in a molecular magnet with femtosecond time-resolution.

We show that a vanadium-chromium Prussian blue analogue, which is a room-temperature molecule-based magnet, displays a fast magnetic response on a femtosecond timescale that is attributed to the super-exchange interaction between the metal ions. These dynamics are obtained from femtosecond Faraday magneto-optical (MO) measurements, performed at 50 and 300 K. Exciting at the ligand-to-metal charge-transfer (LMCT) band results in the formation of the 2E excited state on the Cr ion via intersystem crossing (ISC) from the 4LMCT state in less than 250 fs. Subsequent vibrational relaxation in the 2E state occurs on a 0.78 ± 0.05 ps timescale at 50 K and 1.1 ± 0.1 ps at 300 K. The MO measurements can detect the formation of the 2E state on the Cr ion from the change in the super-exchange interaction taking place as a result of the corresponding spin flip associated with the formation of the 2E state. These results open up a new avenue to study molecular magnets using a powerful method that is capable of directly probing spin dynamics on a sub-picosecond timescale in thin film environments.

Allometric relationship between body size and peak VO2 relative to age at menarche.

The present study examined allometric coefficients relating peak VO2 and body size relative to the time of menarche. Peak oxygen uptake (peak VO2) during exercise on a bicycle ergometer, stature and body mass were measured at annual intervals in a mixed-longitudinal sample of 40 active girls from 11 to 14 years of age. The girls were interviewed about their menarcheal status at each examination. The data were treated relative to the time before and after menarche: 2 years before (n = 18), 1 year before (n = 26), during the year of menarche (+/- 6 months, n = 32), 1 year after (n = 35) and 2 years after menarche (n = 22). Allometric coefficients were calculated for each of the five menarcheal groups based on logarithmic transformations of peak VO2 and body mass and peak VO2 and stature. The major axis of VO2 and body mass or stature (log transformed) was also calculated. This is the most appropriate slope for comparison with theoretical allometry coefficients. Mean peak VO2 increases from 2.1 +/- 0.19 L 2 years before menarche to 2.3 +/- 0.26 L 2 years after menarche. The slope of the major axis for body mass is always higher (0.508-0.926) than that for the allometric coefficient (0.323-0.591) in each of the menarcheal groups. The major axis slope and allometric coefficient are lowest between body mass and peak VO2 during the year of menarche. The slope of the major axis is below the theoretical allometric coefficients assuming geometric or elastic similarity, 2/3 or 3/4, before and at menarche and increases after menarche. Although the differences are not statistically significant, the results suggest that the relationship between body mass and peak VO2 at menarche is lower compared with relationships before and after this maturational landmark. Allometric coefficients for stature relative to peak VO2 show a similar pattern.

Prospective and retrospective longitudinal studies of the growth, maturation, and fitness of Polish youth active in sport.

Results of three longitudinal studies of the growth, maturation and fitness of youth active in sport are summarized. Data include size attained and growth rates for height and body mass, secondary sex characteristics, skeletal age, age at peak height velocity, and two indicators of fitness, peak O2 uptake and power output at a heart rate of 170 bpm (PWC 170). The data for active youth are compared to local reference data and where appropriate to data from other European longitudinal studies. Allowing for variation in methodology and sampling, regular training in sport during puberty and the adolescent spurt does not influence size attained, growth rate, and the timing and progression of somatic, sexual and skeletal maturation in boys and girls. Active and nonactive boys and girls, respectively, do not differ significantly in the mean age at maximum growth in power output at a heart rate of 170 bpm. Boys active in sport, however, have a greater maximal gain in submaximal power output than nonactive boys. Analysis of ontogenetic allometry of peak oxygen uptake and stature and body mass indicate variation between individuals, and between boys of contrasting maturity status.

Comparison of alcohol consumption patterns and social problems between women and men drink-drivers.

OBJECTIVE: To compare the sociodemographic characteristics, patterns of alcohol consumption and driving histories of women and men drink-drivers. DESIGN: Cross-sectional descriptive study. SETTING AND SUBJECTS: All 156 women who attended the Drink-Drive Program at St Vincent's Hospital, Melbourne, between January 1990 and December 1993, and an age-matched sample of 298 men attending in the same period. All had been disqualified from driving after a conviction for driving under the influence of alcohol. OUTCOME MEASURES: Self-reported weekly alcohol consumption and expenditure on alcohol at apprehension and during the program; blood alcohol level (BAL) at apprehension; demographic characteristics; number of previous drink-drive and other traffic convictions; and score on the Michigan Alcoholism Screening Test (MAST). RESULTS: Women had a higher educational level than men, and were more likely to be managers or professionals and to live in areas of high socioeconomic status. Women reported lower levels of weekly alcohol consumption at both apprehension (women: 15.2 standard drinks; men: 31.6 standard drinks) and during the program (women: 7.1 standard drinks; men: 12.0 standard drinks) but had similar BALs to men at apprehension (mean, 0.12% [26 mmol/L]). Sixty percent of women drank wine, or wine, beer and spirits, while 75% of men drank beer. Women had lower MAST scores than men (mean [standard deviation]: women, 5.8 [5.2]; men, 8.9 [8.2]). Women were less likely than men to have prior convictions for drink-driving or other traffic offences. CONCLUSION: Although women presented with similar blood alcohol levels to men, their drinking patterns and sociodemographic characteristics differ greatly. Health education for women drink-drivers needs to have a different strategy to that for men.

Longitudinal study of ontogenetic allometry of oxygen uptake in boys and girls grouped by maturity status.

The utility of removing the confounding effect of body mass on oxygen uptake by simply dividing the measured values by mass has been questioned: Allometric transformation or calculation of covariance analysis have been proposed as more appropriate alternatives. This study hypothesized that scaling factors for individual youths differ with maturity status. Peak oxygen uptake (peak VO2) during exercise on a bicycle ergometer, stature and body mass were measured at annual intervals in 47 active boys and 31 active girls from 11 to 14 years of age. All subjects attended sport schools during the study. The children were classified into two maturity categories, early and average (for the sake of sample size and consistency between sexes), and late on the basis of individual stature velocities in boys and age at menarche in girls. Individual data for peak VO2 were normalized for differences in body mass by double logarithmic transformation and regression analysis (ontogenetic allometry). Individual allometric coefficients (mean +/- SD) for boys showing a good fit were, respectively, 0.799 +/- 0.239 and 0.536 +/- 0.141 in early and average maturing boys combined and in late maturing boys. Logarithmic transforms of VO2 and mass were highly related (r > 0.90) in 10 of 16 early and average maturers, and in 18 of 31 late maturers. Corresponding individual allometric coefficients in girls were more variable, and the logarithmic transforms of VO2 and mass were not highly related (r < 0.70). Similar results were obtained for the relationships between the logarithmic transforms of VO2 and stature. The evidence thus suggests that in boys scaling VO2 for body mass varies with maturity status of the individual, and that there is considerable inter-individual variation in scaling coefficients during early and mid-adolescence. The increase in peak VO2 in active girls 11-14 years is not related to the increase in body mass or stature in the majority.

Scaling for the VO2-to-body size relationship among children and adults.

The purpose of this study was to examine the relationship between oxygen consumption (VO2) and both body surface area (BSA) and body size among 30 prepubertal children, 30 circumpubertal children, and 30 adults to determine which scaling model is most appropriate for making comparisons between these populations. All subjects participated in maximal treadmill testing and submaximal treadmill testing at two absolute work rates. Resting metabolic rate was measured on a subset of 48 subjects. It was determined that the submaximal VO2 (VO2 sm)-to-body size relationship provided the most appropriate model for comparisons. Analyses revealed a stronger linear relationship between VO2 sm and BSA than VO2 sm and body mass. Logarithmic transformation of the data revealed an allometric exponential relationship between VO2 sm and body mass. The exponent relating body mass to VO2 sm at 3 mph (1.34 m/s) was 0.60, whereas the exponent at 5 mph (2.24 m/s) was 0.75. VO2 values at 5 mph were significantly less variable (P < or = 0.05) than those at 3 mph. Therefore the exponent of body mass to the 0.75 power was considered a more appropriate basis for analysis. It was determined that, overall, a scaling factor of BSA or body mass to the 0.75 power both provide a more appropriate method of comparison than a simple ratio standard of body weight.

The value and limitations of L-arginine infusion on glomerular and tubular function in the ischemic/reperfused kidney.

PURPOSE: The nitric oxide precursor, L-arginine, has been shown to have a salutary effect on ischemia and reperfusion injury in skeletal muscle, skin, and intestines. Because L-arginine also increases renal blood flow, glomerular filtration, and urine flow in experimental animals with normal renal function, we postulated that L-arginine may also improve renal function after renal ischemic injury. METHODS: Eighteen adult New Zealand white rabbits weighing 3 to 3.5 kg were subjected to bilateral normothermic renal ischemia by clamping both renal pedicles for 1 hour followed by 2 hours of reperfusion. The animals were randomized into three groups: group I (control, n = 6) received no additional treatment; group II (pretreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes before induction of ischemia; group III (posttreatment, n = 6) received systemic intravenous L-arginine at 150 mg/kg over 20 minutes from the onset of reperfusion. Urine flow, creatinine clearance (CCR), fractional excretion of sodium (FENa), and renal failure index (RFI) were calculated before ischemia and 2 hours after reperfusion, by use of standard formulas. The changes of the various renal parameters were compared among the three groups. RESULTS: Bilateral normothermic renal ischemia for 1 hour produced a significant deterioration of glomerular filtration as evidenced by a CCR decrease from 11.1 +/- 1.8 to 2.49 +/- 0.9 ml/min (p < 0.01), FENa increase from 2.9% +/- 1.0% to 20.8% +/- 1.5% (p < 0.01) and RFI increase from 4.0 +/- 1.3 to 28.8 +/- 2.6 (p < 0.01). Pretreatment with L-arginine (group II) minimized the deleterious effects caused by ischemia on glomerular filtration (CCR of 2.49 +/- 0.9 ml/min in group I vs 4.95 +/- 2.5 ml/min in group II, p < 0.05) and tubular function (FENa of 20.8% +/- 1.5% in group I vs 13.0% +/- 5.6% in group II and RFI of 28.8 +/- 2.6 in group I vs 18.6 +/- 8.0 in group II, p < 0.05). Infusion of L-arginine at the onset of reperfusion (group III) produced a significant diuretic effect (urine flow from 32.6 +/- 13.4 ml/hr in group I to 63.3 +/- 18.8 ml/hr in group III, p < 0.05) and also minimized glomerular damage (CCR from 2.49 +/- 0.9 ml/min in group I to 4.80 +/- 1.2 ml/min in group III, p < 0.05); however, no beneficial effect was observed on tubular function. CONCLUSION: Induction of nitric oxide production by systemic L-arginine infusion can best preserve glomerular and tubular function in the ischemic/reperfused kidney when given before the ischemic insult.