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 potential impact of sleep-related movement disorders on stroke risk: a population-based longitudinal study.

BACKGROUND: Sleep-related movement disorders (SRMD) have been shown to increase the risk of cardiovascular diseases. However, the relationship between SRMD and stroke remains unclear. AIM: To explore the relationship between SRMD and stroke in the general population. DESIGN: Two cohorts of patients with SRMD and without SRMD were followed up for the occurrence of hemorrhagic and ischemic stroke. METHODS: The study cohort enrolled 604 patients who were initially diagnosed as SRMD between 2000 and 2005. 2,416 age- and sex-matched patients without prior stroke were selected as the comparison cohort. A Cox-proportional hazard regression analysis was performed for multivariate adjustment. RESULTS: Patients with SRMD had a higher risk for developing all-cause stroke [adjusted hazard ratio (HR) = 2.29, 95% confidence interval (CI) = 1.42-3.80]. Patients of below 45 years old had the greatest stroke risk (HR = 4.03, 95% CI = 3.11-5.62), followed by patients aged ≥65 years (HR = 2.64, 95% CI = 1.12-3.44) and 45-64 years (HR = 1.07, 95% CI = 1.02-1.71). The age-stratified analysis suggested that the increased risk of hemorrhagic stroke was more significant than ischemic stroke among all age groups. Furthermore, males with SRMD were at greater risk to develop all-cause stroke (HR = 2.98, 95% CI = 1.74-4.50) than that of females (HR = 1.94, 95% CI = 1.01-3.77). CONCLUSIONS: Patients with SRMD were found to have an increased risk of all-cause stroke along with a higher possibility of hemorrhagic stroke over ischemic stroke.

Amelioration of experimental arthritis by intra-articular injection of an epidermal growth factor receptor tyrosine kinase inhibitor.

OBJECTIVES: Selectively targeting signalling pathways represents a promising pharmacological approach in rheumatoid arthritis (RA). Abundant levels of epidermal growth factor receptor (EGFR) are expressed in the synovial lining layers, and the anti-arthritis effect of erlotinib and lapatinib, small-molecule EGFR tyrosine kinase inhibitors (TKIs), has been demonstrated through the systemic administration on experimental arthritis models. Nevertheless, their therapeutic responses by the intra-articular (i.a.) route remain to be explored in rheumatoid joint. METHODS: The administration of an EGFR TKI (a gefitinib analogue) was explored in two in vivo models of collagen-induced arthritis (CIA) and in vitro experiments by using synovial fibroblasts (SF) from RA patients and CIA rats. RESULTS: There was a significant reduction of arthritis scores in CIA mice receiving the daily intraperitoneal injection. After the onset of arthritis in CIA rats, ankle joints receiving a single i.a. injection had significant lower articular indexes with reduced synovial inflammation, pannus formation and erosion on cartilage and bone as well as total histological scores by histopathological analyses. In CIASF or RASF, upon in vitro human EGF stimulation, there was a dose-dependent increase in cell proliferation and Akt activation with suppressed responses under the EGFR TKI treatment. CONCLUSIONS: These findings demonstrate the effect of i.a. injection of an EGFR TKI on amelioration of rheumatoid joint through the suppression of synovial inflammation, pannus formation and erosion on cartilage and bone in experimental arthritis, implicating targeting the i.a. EGFR signalling transduction as a pharmacological strategy.

Assessment of genetic diversity of bermudagrass germplasm from southwest China and Africa by using AFLP markers.

Cynodon dactylon (L.) Pers. var. dactylon (common bermudagrass) is widely distributed geographically between approximately 45°N and 45°S latitude, penetrating to approximately 53°N latitude in Europe. The extensive variation of morphological and adaptive characteristics of the taxon has been substantially documented, but information is lacking on DNA molecular variation in geographically disparate forms. The genetic diversity of 51 wild accessions of bermudagrass from southwest China (Sichuan, Chongqing, Yunnan, Guizhou, and Tibet) and 8 African bermudagrass was analyzed using amplified fragment length polymorphism molecular markers. A total of 670 polymorphic bands were detected with 11 primer combinations, of which 663 (98.74%) bands were found to be polymorphic. The genetic similarity among the accessions ranged from 0.64-0.96 with an average of 0.78. All 59 wild accessions were clustered into 5 eco-geographic groups, and nearly all accessions from the same area were classified into the same group and were found to be associated with their geographical distributions. Therefore, complex geographical and ecological environments are important factors for the genetic structure and geographical distribution of C. dactylon.

Analysis of genetic diversity among wild bermudagrass germplasm from southwest China using SSR markers.

Fifty-five wild accessions of bermudagrass (Cynodon dactylon) were collected from southwest China (Sichuan, Chongqing, Yunnan, Guizhou, and Tibet), and their genetic diversity was analyzed using simple sequence repeat markers. A total of 267 polymorphic bands were detected with 18 primer combinations. The genetic similarity among the accessions ranged from 0.688 to 0.894 with an average of 0.797. All 55 wild accessions were clustered into 7 eco-geographic groups. Our data showed that the dendrogram was almost in accordance with geographic distribution, and accessions from the same collection sites tended to be clustered into the same group. A genetic differentiation analysis revealed that the percentage of genetic variance was 70.07 and 29.93% within and among groups, respectively. Finally, we discuss the implications of these results for C. dactylon in southwest China.

Hyperbaric oxygen ameliorates delayed neuropsychiatric syndrome of carbon monoxide poisoning.

OBJECTIVES: Delayed neuropsychiatric syndrome (DNS) is characterized by mental impairment, motor dysfunction, dementia, or psychosis that develops between a few days and weeks after acute carbon monoxide (CO) poisoning. One possible mechanism responsible for CO-mediated encephalopathy involves oxidative stress, such as lipid peroxidation, caused by the cellular uptake of CO and which leads to an inflammatory cascade. There is no current effective treatment for DNS. We applied 8-40 sessions of hyperbaric oxygen therapy (HBO2) to patients with DNS and evaluated its effectiveness. METHODS: After admission, all patients were administered piracetam or bromocriptine, or both, and received HBO2. Neuropsychiatric tests included EEG, mini-mental status examination (MMSE), brain MRI, event-related potential (ERP), and brain perfusion scan (brain SPECT). Results of these tests were compared before and after HBO2, and the clinical features were monitored during this period. RESULTS: The symptoms of DNS for all patients improved significantly after HBOT. Although white matter changes remained evident in the brain MRI scans, other examinations such as EEG, MMSE, ERP, and 99mTc-ECD brain SPECT were nearly normal after HBOT. CONCLUSION: Our results suggest that HBO2 decreases the severity of impairment in patients with DNS. Although a large randomized trial is required to address the efficacy of this therapy, therapeutic application of HBO2 may be recommended in patients with DNS after CO poisoning.

Diffusion-tensor MR imaging for evaluation of the efficacy of hyperbaric oxygen therapy in patients with delayed neuropsychiatric syndrome caused by carbon monoxide inhalation.

The purpose of this study is to assess the efficacy of hyperbaric oxygen therapy (HBOT) in patients with delayed neuropsychiatric syndrome (DNS) caused by carbon monoxide (CO) inhalation using diffusion tensor magnetic resonance (MR) imaging and neuropsychological test. Conventional and diffusion tensor brain MR imaging exams were performed in six patients with DNS immediately before and 3 months after the HBOT to obtain fractional anisotropy (FA) values. Six age- and sex-matched normal control subjects also received MR exams for comparison. Mini-Mental State Examination (MMSE) was also performed in patients immediately before and 3 months after the HBOT. A significantly higher mean FA value was found in control subjects as compared with the patients both before and 3 months after the HBOT (P < 0.001). The mean FA value 3 months after the HBOT was also significantly higher than that before the HBOT in the patient group (P < 0.001). All of the patients regained full scores in the MMSE 3 months after the HBOT. Diffusion tensor MR imaging can be a quantitative method for the assessment of the white matter change and monitor the treatment response in patients of CO-induced DNS with a good clinical correlation. HBO may be an effective therapy for DNS.

Composition and antimicrobial activity of the essential oil of Actinidia macrosperma from China.

Actinidia macrosperma is a medicinal plant in China and has been well known for its attraction to cats and activities against leprosy and cancers. The compositions and the antimicrobial activity of its leaf oil were reported for the first time. The oil obtained by hydrodistillation and analyzed by GC and GC-MS, was characterized by the high content of monoterpenes. Linalool (48.14%) is the major component identified, followed by 1,2-dimethyl-lindoline (7.94%), linolenic acid methylester (6.57%) and (E)-phytol (5.29%). The antimicrobial activity of the oil was evaluated against four bacterial and three fungal species. The results showed that it exhibited a mild antibacterial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), a significant activity against Gram-negative bacteria (Escherichia coli), and no activity on Pseudomonas aeruginosa. The test fungi were more sensitive to the oil, with a MIC range of 0.78-1.56 microL mL(-1) than bacteria in the range which were significantly higher from 0.78 to 25.50 microL mL(-1).

The cytological mechanism of low fertility in the naked seed rice.

The low fertility of naked seed rice (NSR) was investigated by the following observations: somatic chromosome constitute, behavior of pollen mother cells (PMCs), the germination of mature pollen grains, the development of male and female gametes and the structure of the anther opening. The results indicated that somatic chromosomal number was 2n = 24, behavior of PMCs were normal and most of pollen grains could regularly develop further to mature male gametophytes in NSR. And dehiscence chamber and thickened endothecium cell (TEC) in numerous anthers of the NSR were developed abnormally after dicaryotic phase, result in few anthers complete opening and most partly opening or failure to opening, therefore much fewer of pollen grains attach on the stigma as compared with normal variety. Furthermore most of embryo sacs possessed abnormal structure and were sterile. All of above illustrated that the failure of the anther opening and the abortion of female gametophyte were main factors controlling the low seed-setting rate of the NSR.

A salt-responsive receptor-like kinase gene regulated by the ethylene signaling pathway encodes a plasma membrane serine/threonine kinase.

NTHK1 is a salt-inducible ethylene receptor gene in tobacco. Transgenic tobacco plants for this gene show reduced ethylene sensitivity. Using cDNA microarray analysis, we were able to identify those genes that have different expression levels between NTHK1 transgenic plants and wild-type plants under salt stress conditions. One of these, AtLecRK2, which encodes a receptor-like kinase with an extracellular lectin-like domain, was characterized in detail in the present study. AtLecRK2 contains a signal peptide, an extracellular lectin-like domain, a single transmembrane domain and a cytoplasmic protein kinase domain. AtLecRK2 is transcribed in the root, flower and leaf but not in the stem. In wild-type Arabidopsis, salt stress induced the transcription level of AtLecRK2, whereas in the transgenic NTHK1 Arabidopsis induction of the AtLecRK2 transcript was inhibited and retarded. AtLecRK2 was constitutively overexpressed in the ethylene-overproducer mutant, eto1-1, and could be induced by ethylene. However, in the ethylene-insensitive mutant, ein2-1, the salt-induced expression pattern of AtLecRK2 was the same as that in wild-type plants. The results demonstrate that the induction of AtLecRK2 in response to salt stress is regulated by the ethylene signaling pathway. The induction was inhibited by the ethylene receptor, NTHK1, while it was independent of EIN2. The kinase activity of AtLecRK2 was also studied. We found that that AtLecRK2 can be autophosphorylated and has serine/threonine kinase activities. The subcellular localization of AtLecRK2-GFP in onion epidermal cells indicates that AtLecRK2 is localized on the plasma membrane.

MILDOS uranium milling dose assessment code update.

The MILDOS-AREA code was developed to estimate radiological doses and risks from uranium milling activities. The code has been used for demonstrating radiological compliance regarding the U.S. Nuclear Regulatory Commission's licensing requirements for uranium milling activities. The code was recently updated with an enhanced software package to address the following four areas: regulatory changes, in-situ leaching extraction technologies, software user interfaces, and software distribution technologies via the internet. Users can now specify in-situ leaching processes through a Windows object-based Geographic information System interface with incorporated updated regulation methodologies. The code and documentation are freely distributed through the Internet.

[Differential accumulation of the new high-affinity phosphate transporter candidated gene fragment in rice roots in response to phosphorus deficiency stress].

Phosphate is a major constraint to crop production, and phosphate uptake in plant is mainly by high-affinity phosphate transporter under phosphate deficiency condition. Using RT-PCR, a 1,178 bp phosphate transporter gene fragment OjPT1 was cloned from roots of Jingxi17 (Oryza sativa L. ssp. japanica) supplied with no phosphate. The comparison of this sequence with ones in GenBank indicated that it shared about 70% similarity at amino acid level with other phosphate transporters in higher plants, such as Arabidopsis thaliana, potate, tamato, Medicago truncatula and Catharanthus roseus, and high similarity with phosphate transporters in Saccharomyces cerevisiae and Neurospora crassa. RT-PCR assay showed that the OjPT1 transcripts were induced under phosphate deficiency condition. This gene fragment OjPT1 has been deposited in GenBank (accession No. AF249619).

Heart rate responses and oxygen consumption during Tai Chi Chuan practice.

Tai Chi Chuan (TCC) is a popular Chinese conditioning exercise, however, its exercise intensity remains controversial. The objective of this study was to determine the exercise intensity of Yang TCC by measuring heart rate (HR) responses and oxygen consumption (VO2) during practice. Fifteen men aged 39.9 +/- 9.5 yrs (range 26-56 yrs) participated in this study. Subjects had practiced classical Yang TCC for 5.8 +/- 2.4 years. HR responses and VO2 were measured during practice of TCC by using a K4 telemetry system. Blood lactate was measured before and immediately after TCC practice. Additionally, breath-by-breath measurement of cardiorespiratory function and sequential determination of blood lactate were performed during the incremental exercise of leg cycling. Measurements obtained during the TCC practice and exercise testing were compared to determine the exercise intensity of TCC. While performing TCC, the mean HR of subjects was 140 +/- 10 bpm, and the mean VO2 was 21.4 +/- 1.5 mL x kg(-1) min(-1). Compared with the data of the exercise test, the HR during practice was 58% of the heart rate range. Meanwhile, the VO2 during TCC practice was 55% of the VO2peak. Additionally, the level of blood lactate immediately after TCC practice was 3.8 mM, which reflected the level of lactate during TCC, approximated the onset of blood lactate accumulation (OBLA). The results demonstrate that TCC is an exercise with moderate intensity, and is aerobic in nature.

Tai Chi Chuan to improve muscular strength and endurance in elderly individuals: a pilot study.

OBJECTIVE: To evaluate the training effect of a Tai Chi Chuan (TCC) program on knee extensor muscular strength and endurance in elderly individuals. DESIGN: Before-after trial. SETTING: Community setting. PARTICIPANTS: Forty-one community dwelling subjects aged 61.1 +/- 9.8 years undertook a TCC program. Nine dropped out during the study. Pretraining and posttraining measurements were obtained from 15 men and 17 women. INTERVENTION: Subjects participated in a 6-month TCC program. Each session consisted of 20 minutes of warm-up, 24 minutes of structured TCC training, and 10 minutes of cool-down exercises. MAIN OUTCOME MEASURES: Peak torque of dominant and nondominant knee extensors was tested at speeds of 60 degrees , 180 degrees , and 240 degrees/sec concentrically and eccentrically. Muscular endurance of the knee extensor was tested at the speed of 180 degrees /sec. RESULTS: In the group of men, concentric knee extensor peak torque increased by 15.1% to 20.0% and eccentric peak torque increased by 15.1% to 23.7%. The group of women also showed increases, ranging from 13.5% to 21.8% in concentric peak torque, and 18.3% to 23.8% in eccentric peak torque. In addition, the knee extensor endurance ratio increased by 9.6% to 18.8% in the men and 10.1% to 14.6% in the women. CONCLUSION: TCC training may enhance muscular strength and endurance of knee extensors in elderly individuals.

Honokiol and magnolol increased hippocampal acetylcholine release in freely-moving rats.

Honokiol and magnolol, phenolic compounds isolated from the stem bark of Magnolia officinalis, have been demonstrated to increase choline acetyltransferase activity, inhibit acetylcholinesterase, promote potassium-induced acetylcholine release and exhibit neurotrophic function in in vitro studies. The objective of the present study was to determine the effect of these compounds on hippocampal acetylcholine release in conscious, freely-moving rats. 10(-4) M-10(-6) M of honokiol or magnolol was perfused into rat hippocampus via a dialysis probe. The results showed that at 10(-4) M concentration, honokiol and magnolol markedly increased extracellular acetylcholine release to 165.5+/-5.78% and 237.83+/-9.47% of the basal level, respectively. However, lower concentrations of either compounds failed to elicit significant acetylcholine release. This result suggests that a high dose of honokiol or magnolol may enhance in vivo hippocampal acetylcholine release.

Associations of plasma aflatoxin B1-albumin adduct level with plasma selenium level and genetic polymorphisms of glutathione S-transferase M1 and T1.

Mortality from hepatocellular carcinoma (HCC) is extraordinarily high in Matzu, an island off the coast of Southeastern China. To investigate factors associated with plasma aflatoxin B1 (AFB1)-albumin adduct level, we studied 304 healthy adult residents from Matzu. AFB1-albumin adducts were determined by competitive enzyme-linked immunosorbent assay, hepatitis B surface antigen status by enzyme immunoassay, genotypes of glutathione S-transferase (GST) M1 and T1 by polymerase chain reaction, plasma selenium by atomic absorption spectrometry, and plasma retinol, alpha-tocopherol, alpha-carotene, and beta-carotene levels by high-performance liquid chromatography. Men had higher AFB1-albumin adduct levels than women. GSTM1-nonnull and GSTT1-null genotypes and low plasma selenium level were significantly associated with an increased level of AFB1-albumin adducts among men, whereas age was significantly correlated with adduct level among women. High intake of fermented beans was associated with an increased adduct level among men and women. The inverse associations between plasma selenium level and AFB1-albumin adducts were statistically significant among those with null genotypes of GSTM1 and GSTT1, but not among the nonnull genotypes. This study provides insight into the dietary and genetic factors influencing AFB1-albumin adduct formation in an isolated population with high liver cancer mortality.

Protocols for implementing DOE authorized release of radioactive scrap metals.

A process to implement the U.S. Department of Energy's (DOE) policy for authorized release of radioactive materials from DOE facilities is provided in the Draft Handbook for Controlling Release for Reuse or Recycle of Property Containing Residual Radioactive Material, published by DOE in 1997 and distributed to DOE field offices for interim use and implementation. The authorized release of such property is intended to permit its beneficial use across the entire DOE complex. A computerized management tool--P2Pro(RSM)--has been developed to aid in carrying out the release process for radioactive metals. It contains protocols for the authorized release process and relevant information to facilitate the evaluation of scrap metals for reuse and recycle. The P2Pro(RSM) protocols provide DOE and its contractors with an effective, user-friendly tool for managing authorized release activities P2Pro(RSM) is designed to be used in the Windows environment. The protocols incorporate a relational database coupled with a graphic-user interface to guide the user through the appropriate steps so authorized release limits can be developed. With the information provided in the database, an as-low-as-reasonably-achievable (ALARA) optimization process can be easily set up and run for up to 10 alternatives for disposition of radioactive scrap metals. The results of the ALARA optimization process can be printed in a series of reports and submitted as part of the application for the authorized release of the radioactive scrap metals.

The effect of Tai Chi on cardiorespiratory function in patients with coronary artery bypass surgery.

PURPOSE: This study prospectively evaluated the training effect of a 1-yr Tai Chi Chuan (TCC) program for low-risk patients with coronary artery bypass surgery (CABS) after a postoperative outpatient (phase II) cardiac rehabilitation program. METHODS: Twenty patients with mean age of 56.5+/-7.4 yr completed this study. The TCC group included nine men who practiced classical Yang TCC with an exercise intensity of 48-57% heart rate range (HRR). The control group included 11 men whom were recommended to do a home-based self-adjusted exercise program with similar intensity of phase II cardiac rehabilitation. Graded exercise tests were performed before and after 1 yr of training for all subjects. RESULTS: Mean attendance of the TCC group was 3.8+/-1.5 times weekly in contrast to 1.7+/-1.1 times for the control group. During the follow-up examination, the TCC group increased 10.3% in VO2peak (from 26.2+/-4.4 to 28.9+/-5.0 mL x kg(-1) min(-1), P<0.01) and increased 11.9% in peak work rate (from 135+/-26 W to 151+/-28 W, P<0.01). However, the control group showed slight decrease in VO2peak from 26.0+/-3.9 to 25.6+/-4.6 mL x kg(-1) x min(-1) and in peak work rate from 131+/-23 W to 128+/-32 W. At the ventilatory threshold, the TCC group also showed significant increase in VO2 and work rate (P<0.05). The control group did not significantly change in these variables. CONCLUSIONS: The study demonstrated that a 1-yr TCC program for low-risk patients with CABS could favorably enhance cardiorespiratory function.