In silico and in vitro assays reveal potential inhibitors against 3CLpro main protease of SARS-CoV-2.

The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not showing any sign of slowing down even after the ongoing efforts of vaccination. The threats of new strains are concerning, as some of them are more infectious than the original one. A therapeutic against the disease is, therefore, of urgent need. Here, we use the DrugBank database to screen for potential inhibitors against the 3CLpro main protease of SARS-CoV-2. Instead of using the traditional approach of computational screening by docking, we developed a kernel ridge regressor (using a part of the docking data) to predict the binding energy of ligands. We used this model to screen the DrugBank database and shortlist two lead candidates (bromocriptine and avoralstat) for in vitro enzymatic study. Our results show that the 3CLpro enzyme activity in presence of 100 µM concentration of bromocriptine and avoralstat is 9.9% and 15.9%, respectively. Remarkably, bromocriptine exhibited submicromolar IC50 of 130 nM (0.13 µM). Avoralstat showed an IC50 of 2.16 µM. Further, the interactions of both drugs with 3CLpro were analyzed using molecular dynamics simulations of 100 ns. Results indicate that both ligands are stable in the binding pocket of the 3CLpro receptor. In addition, the MM-PBSA analysis revealed that bromocriptine (-29.37 kcal/mol) has a lower binding free energy compared to avoralstat (-6.91 kcal/mol). Further, hydrogen bond analysis also showed that bromocriptine interacts with the two catalytic residues, His41 and Cys145, more frequently than avoralstat.Communicated by Ramaswamy H. Sarma.

Assessing salt-stress tolerance in barley / Determinación de la Tolerancia al estrés por salinidad en la cebada / Determinação da tolerância ao estresse por salinidade na cevada

Abstract Identifying naturally existing abiotic-stress tolerant accessions in cereal crops is central to understanding plant responses towards stress. Salinity is an abiotic stressor that limits crop yields. Salt stress triggers major physiological changes in plants, but individual plants may perform differently under salt stress. In the present study, 112 barley accessions were grown under controlled salt stress conditions (1 Sm-1 salinity) until harvest. The accessions were then analyzed for set of agronomic and physiological traits. Under salt stress, less than 5 % of the assessed accessions (CIHO6969, PI63926, PI295960, and PI531867) displayed early flowering. Only two (< 2 %) of the accessions (PI327671 and PI383011) attained higher fresh and dry weight, and a better yield under salt stress. Higher K+ /Na+ ratios were maintained by four accessions PI531999, PI356780, PI452343, and PI532041. These top-performing accessions constitute naturally existing variants within barley's gene pool that will be instrumental to deepen our understanding of abiotic-stress tolerance in crops.

Resumen La identificación de accesiones existentes en condiciones naturales que sean tolerantes al estrés abiótico en cultivos de cereales es fundamental para entender las respuestas al estrés. La salinidad es un factor de estrés abiótico que limita el rendimiento de los cultivos. El estrés por salinidad desencadena importantes cambios fisiológicos en las plantas, pero plantas individuales pueden comportarse diferencialmente bajo este tipo de estrés. En el presente estudio se hicieron crecer 112 accesiones de cebada bajo condiciones controladas de estrés por salinidad (1 Sm-1 salinidad) hasta la cosecha. Posteriormente las accesiones se analizaron para determinar sus caracteres agronómicos y fisiológicos. Bajo condiciones de estrés por salinidad, menos del 5 % de las accesiones estudiadas (CIHO6969, PI63926, PI295960 y PI531867) mostraron floración temprana. Solamente dos (< 2 %) de las accesiones (PI327671 y PI383011) alcanzaron mayores pesos fresco y seco y un mayor rendimiento bajo estrés por salinidad. Se mantuvieron mayores proporciones K+/Na+ en cuatro accesiones PI531999, PI356780, PI452343 y PI532041. Estas accesiones que tuvieron el mejor rendimiento constituyen las variantes existentes en condiciones naturales dentro del acervo genético de la cebada, que pueden ser instrumentos para profundizar en nuestro entendimiento de la tolerancia de los cultivos al estrés abiótico.

Resumo A identificação de acessões existentes em condições naturais que sejam tolerantes ao estresse abiótico em culturas de cereais é fundamental para entender a resposta ao estresse. A salinidade é um fator de estresse abiótico que limita o rendimento das culturas. O estresse por salinidade desencadeia importantes mudanças fisiológicas nas plantas, no entanto, plantas individuais podem se comportar diferentemente sob este tipo de estresse. No presente estudo 112 acessões de cevada foram cultivadas sob condições controladas de estresse por salinidade (1 Sm-1 salinidade) até a colheita. Porteriormente, as acessões foram analizadas para determinar suas características agronômicas e fisiológicas. Sob condições de estresse por salinidade, menos de 5 % das acessões estudadas (CIHO6969, PI63926, PI295960 e PI531867) mostraram floração prematura. Somente duas (< 2 %) acessões (PI327671 e PI383011) atingiram maiores pesos frescos e secos e um maior redimento sob estresse por salinidade. As maiores proporções K+/Na+ foram mantidas em quatro acessões PI531999, PI356780, PI452343 e PI532041. As acessões com maior rendimento constituem as variantes existentes em condições naturais dentro do fundo genético da cevada, que podem ser instrumentos para aprofundar no nosso entendimento da tolerância dos cultivos ao estresse biológico.

Probabilistic Assessment of Glass Forming Ability Rules for Metallic Glasses Aided by Automated Analysis of Phase Diagrams.

The use of machine learning techniques to expedite the discovery and development of new materials is an essential step towards the acceleration of a new generation of domain-specific highly functional material systems. In this paper, we use the test case of bulk metallic glasses to highlight the key issues in the field of high throughput predictions and propose a new probabilistic analysis of rules for glass forming ability using rough set theory. This approach has been applied to a broad range of binary alloy compositions in order to predict new metallic glass compositions. Our data driven approach takes into account not only a broad variety of thermodynamic, structural and kinetic based criteria, but also incorporates qualitative and descriptive attributes associated with eutectic points in phase diagrams. For the latter, we demonstrate the use of automated machine learning methods that go far beyond text recognition approaches by also being able to interpret phase diagrams. When combined with structural descriptors, this approach provides the foundations to develop a hierarchical probabilistic predication tool that can rank the feasibility of glass formation.

Age associated decline in the conversion of leucine to ß-Hydroxy-ß-Methylbutyrate in rats.

BACKGROUND: The loss of muscle mass is considered to be a major factor contributing to strength decline during aging. ß-Hydroxy-ß-Methylbutyrate (HMB), a metabolite of leucine has been shown to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. However, the production and regulation of endogenous levels of HMB over the lifespan have not been investigated. OBJECTIVE: The objective of the present study was to do a cross-sectional analysis of the basal plasma levels of HMB in male Sprague-Dawley rats of different ages and to compare the efficiency of conversion of leucine to HMB in young versus older rats. METHODS: Plasma levels of HMB and α-ketoisocaproate (KIC) were analyzed in rats of different age groups (3, 9, 12 and 24months old, n=10 per group). Levels of 4-HPPD, the enzyme involved in the conversion of KIC to HMB in the liver were determined by ELISA. The conversion efficiency of leucine to HMB was compared between 3 and 24month rats after an oral bolus dose of leucine. RESULTS: Endogenous circulating levels of HMB were significantly reduced in older age rats compared to young rats (100±3.7 vs 156±10 (mean±SEM), ng/mL, p<0.001). A significant negative correlation was seen between HMB levels and age. The liver levels of 4-HPPD were found to be significantly lower in old versus young rats. Consistent with this, the conversion efficiency of leucine to HMB was significantly lower in the aged versus young cohorts. CONCLUSIONS: In summary, this study depicts for the first time that the basal levels of HMB, a metabolite of amino acid leucine, declines with age, and that this decline is due to perturbations in the key enzyme 4-HPPD which catalyzes the conversion of KIC to HMB. As a consequence, the efficiency of conversion of leucine to HMB is diminished in older rats compared to younger rats.

Elements in the hair of non-mining workers of a lignite open mine in Neyveli.

Trace elements are analyzed in the human scalp hair to assess the extent of body burden of pollution. The levels of seven elements (Cd, Cr, Cu, Mn, Ni, Pb and Zn) were determined in the hair of fishermen from Pondicherry, students and businessmen from Madras and non-mining workers from Neyveli lignite open mine. When compared between them, significantly high concentrations of Cd in the non-mining workers from Neyveli and Pb in both the students and businessmen from Madras were observed, thereby indicating environmental source of Cd and Pb pollution. The low Zn level was observed in the fishermen indicating their low nutritional source. In addition to the different residential areas, age, diet, smoking habit and family income of subjects are other factors influencing the concentrations of elements in the hair.