Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro,Molecular Docking,Molecular Dynamics,DFT, and SAR Studies

In this article, 34 anticoagulant drugs were screened in silico against the main protease (M^pro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 M^pro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC₅₀). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC₅₀ value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC₅₀ values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 M^pro enzyme was investigated by utilizing the SARS-CoV-2 M^pro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 M^pro inhibitory potential was attained for fondaparinux sodium with an IC₅₀ value of 2.36 µM, surpassing the reference tipranavir (IC₅₀ = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 M^pro inhibitory potential was attained for dabigatran with an IC₅₀ value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.     

MicroRNA Changes Up to 24 h following Induced Hypoglycemia in Type 2 Diabetes

Hypoglycemia, as a complication of type 2 diabetes (T2D), causes increased morbidity and mortality but the physiological response underlying hypoglycemia has not been fully elucidated. Small noncoding microRNA (miRNA) have multiple downstream biological effects. This pilot exploratory study was undertaken to determine if induced miRNA changes would persist and contribute to effects seen 24 h post-hypoglycemia. A parallel, prospective study design was employed, involving T2D (n = 23) and control (n = 23) subjects. The subjects underwent insulin-induced hypoglycemia (2 mmol/L; 36 mg/dL); blood samples were drawn at baseline, upon the induction of hypoglycemia, and 4 h and 24 h post-hypoglycemia, with a quantitative polymerase chain reaction analysis of miRNA undertaken. The baseline miRNAs did not differ. In the controls, 15 miRNAs were downregulated and one was upregulated (FDR < 0.05) from the induction of hypoglycemia to 4 h later while, in T2D, only four miRNAs were altered (downregulated), and these were common to both cohorts (miR-191-5p; miR-143-3p; let-7b-5p; let-7g-5p), correlated with elevated glucagon levels, and all were associated with energy balance. From the induction of hypoglycemia to 24 h, 14 miRNAs were downregulated and 5 were upregulated (FDR < 0.05) in the controls; 7 miRNAs were downregulated and 7 upregulated (FDR < 0.05) in T2D; a total of 6 miRNAs were common between cohorts, 5 were downregulated (miR-93-5p, let-7b-5p, miR-191-5p, miR-185-5p, and miR-652-3p), and 1 was upregulated (miR-369-3p). An ingenuity pathway analysis indicated that many of the altered miRNAs were associated with metabolic and coagulation pathways; however, of the inflammatory proteins expressed, only miR-143-3p at 24 h correlated positively with tumor necrosis factor-α (TNFa; p < 0.05 and r = 0.46) and negatively with toll-like receptor-4 (TLR4; p < 0.05 and r = 0.43). The MiRNA levels altered by hypoglycemia reflected changes in counter-regulatory glucagon and differed between cohorts, and their expression at 24 h suggests miRNAs may potentiate and prolong the physiological response. Trial registration: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03102801","term_id":"NCT03102801"}}NCT03102801.     

Detection by a solid phase independent enzyme immunoassay of monoclonal anti-idiotypic antibodies against monoclonal antibodies neutralizing Semliki Forest virus and encephalomyocarditis virus

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (EC 1.1.1.34) is the rate limiting step in the mevalonate pathway that produces isoprenoids and cholesterol. Inhibitors of HMG-CoA reductase are teratogenic in vivo and induce neural tube defects in rat embryo culture, effects which appear unrelated to cholesterol deficiency. This study is the first to localize HMG-CoA reductase mRNA by in situ hybridization (ISH). Expression of reductase mRNA was examined in post-implantation rat embryos, and for control purposes in rat liver and UT-1 cells, using a digoxigenin-11 (dig-11) labelled cRNA probe. Eighteen-day fetal liver showed heavy but patchy hybridization, and adult rat liver showed strong hybridization only on some periportal hepatocytes, which was absent in livers of fasted animals. UT-1 cells stimulated to overexpress HMG-CoA reductase mRNA were strongly positive with the same probe. Control hybridizations with sense strand RNA probe, or with cRNA probe on pre-RNased tissue were negative. Strong hybridization signal for HMG-CoA reductase mRNA was observed in all tissues of the post-implantation rat embryo, from egg cylinder to 30 somite stages (7 to 12 days). Heavy signal was noted in primitive ectoderm and neural tube. The wide embryonic and extraembryonic distribution and abundance of HMG-CoA reductase mRNA may reflect developmental requirements for products of the mevalonate pathway, e.g., isoprenoids for post-translational farnesylation of p21ras.     

Overshoot in the step response of fractional-order control systems

In this paper, a sufficient condition for existence of an overshoot in the step response of fractional-order systems is presented. Based on this condition, it can be shown that the existence of an overshoot in the step responses of some classes of fractional-order systems (for example, the class of fractional-order systems having commensurate orders between 1 and 2) is unavoidable. To show the usefulness of the obtained condition, this condition is applied to prove some results on the time response analysis of fractional-order control systems.     

精炼工艺对椰子油品质的影响

研究了精炼工艺对椰子油品质的影响。分析了毛椰油、碱炼油、脱色油、脱臭油的理化指标、脂肪酸、甘油酯组成和脂肪伴随物(甾醇、生育酚、多酚)的变化情况。结果表明:精炼工艺使椰子油的酸值、过氧化值显著降低,脂肪酸和甘油酯组成无显著变化;总甾醇、总生育酚和多酚含量显著降低,损失率分别为63.77%、68.03%、71.20%。综上表明,精炼能够显著影响油脂品质,需注重油脂适度加工技术的应用。     

全桥拓朴隔离式开关电源主变压器磁设计

全桥拓朴结构的隔离式开关电源能在较小的尺寸下实现较高的功率变换,是高功率密度电源的重要电路结构,其高频主变压器磁心一般选择低损耗功率锰锌软磁铁氧体材料,其设计对电源的尺寸、性能有显著影响.磁设计的目的是用尽可能小的磁心传输尽可能高的功率,但受到两个限制性条件的制约,即磁心的发热和磁饱和.在散热充分的情况下,限制性条件就...     

含有零值和负值的随机准备金模型

在准备金评估中,由于多数随机准备金模型基本假设的限制是不能直接处理含有零值和负值增量赔款三角形,本文利用一个变换和广义线性模型的混合模型去解决这种情况．     

An E-Business Event Stream Mechanism for Improving User Tracing Processes

With the rapid development in business transactions, especially in recent years, it has become necessary to develop different mechanisms to trace business user records in web server log in an efficient way. Online business transactions have increased, especially when the user or customer cannot obtain the required service. For example, with the spread of the epidemic Coronavirus (COVID-19) throughout the world, there is a dire need to rely more on online business processes. In order to improve the efficiency and performance of E-business structure, a web server log must be well utilized to have the ability to trace and record infinite user transactions. This paper proposes an event stream mechanism based on formula patterns to enhance business processes and record all user activities in a structured log file. Each user activity is recorded with a set of tracing parameters that can predict the behavior of the user in business operations. The experimental results are conducted by applying clustering-based classification algorithms on two different datasets; namely, Online Shoppers Purchasing Intention and Instacart Market Basket Analysis. The clustering process is used to group related objects into the same cluster, then the classification process measures the predicted classes of clustered objects. The experimental results record provable accuracy in predicting user preferences on both datasets.     

The use of basalt powder as a natural heterogeneous catalyst in the Fenton and Photo-Fenton oxidation of cationic dyes

The use of naturally present heterogeneous catalysts has recently been an essential issue in the Fenton and photo-Fenton processes. In this study, the uses of basalt as a catalyst for the Fenton and photo-Fenton reactions for methylene Blue (MB) and Basic Red 18 (BR18) degradations were investigated. Basalt was selected because of the presence of the iron (III) oxide in the structure. Basalt was characterized by X-Ray Fluorescence (XRF) and X-Ray Diffraction (XRD) analysis to obtain the chemical composition and the crystalline phase. The surface charge and the surface area were obtained by zeta potential and Brunauer Emmett-Teller (BET) analysis. Fourier Transform Infrared Spectroscopy (FTIR) and scanning electron microscope (SEM) were utilized to explore the functional group and the surface morphology. Fenton and photo-Fenton processes were applied to explore the best degradation method. Adsorption was also tested and the adsorption process had minimum removal efficiency (12% for MB and 17% for BR18). The removal efficiencies for MB and BR18 by the Fenton process were 87% and 28%, respectively. The photo-Fenton process had maximum removal efficiency with 100% for MB and 70% for BR18. The optimum conditions were 70 mg/L dye concentration, 5 mM H₂O₂, 1.0 g/L basalt loading and pH 2. Basalt has shown reuse capability as a catalyst for three consecutive cycles.