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.     

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.     

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.     

Corrosion inhibition by naturally occurringsubstances—I. The effect of Hibiscus subdariffa (karkade) extract on the dissolution of Al and Zn

The thermometric, the weight-loss and the galvanostatic polarization techniques wereused to establish the inhibition of the dissolution of Al and Zn in HCl and NaOH by different concentrations of aqueous extract of Hibiscus subdariffa (Karkade). The extent of corrosion inhibition as measured by the three techniques is comparable. The results indicated that the additive acts by way of adsorption on both cathodic and anodic corrosion areas. Curves representing the variation of the reaction number (R.N.), in thermometric experiments, and the decrease in weight as a function of the concentration of the additive, are invariably sigmoid in nature. When present in enough amounts, the additive decreases the dissolution rate by as much as 85 per cent of the value recorded in its absence.     

Vitamin C Enhances Vitamin E Status and Reduces Oxidative Stress Indicators in Sea Bass Larvae Fed High DHA Microdiets

Docosahexaenoic acid (DHA) is an essential fatty acid necessary for many biochemical, cellular and physiological functions in fish. However, high dietary levels of DHA increase free radical injury in sea bass (Dicentrarchus labrax) larvae muscle, even when vitamin E (α-tocopherol, α-TOH) is increased. Therefore, the inclusion of other nutrients with complementary antioxidant functions, such as vitamin C (ascorbic acid, vitC), could further contribute to prevent these lesions. The objective of the present study was to determine the effect of vitC inclusion (3,600?mg/kg) in high DHA (5?% DW) and α-TOH (3,000?mg/kg) microdiets (diets 5/3,000 and 5/3,000?+?vitC) in comparison to a control diet (1?% DHA DW and 1,500?mg/kg of α-TOH; diet 1/1,500) on sea bass larvae growth, survival, whole body biochemical composition and thiobarbituric acid reactive substances (TBARS) content, muscle morphology, skeletal deformities and antioxidant enzymes, insulin-like growth factors (IGFs) and myosin expression (MyHC). Larvae fed diet 1/1,500 showed the best performance in terms of total length, incidence of muscular lesions and ossification degree. IGFs gene expression was elevated in 5/3,000 diet larvae, suggesting an increased muscle mitogenesis that was confirmed by the increase in the mRNA copies of MyHC. vitC effectively controlled oxidative damages in muscle, increased α-TOH larval contents and reduced TBARS content and the occurrence of skull deformities. The results of the present study showed the antioxidant synergism between vitamins E and C when high contents of DHA are included in sea bass larvae diets.     

Sugeno Integral with Possibilistic Inputs with Application to Multi‐Criteria Decision Making

We introduce the Sugeno integral and describe how it can be used to provide a weighted mean‐like aggregation of a collection of values drawn from the unit interval. We explain that the underlying measure provides information about the weights associated with the arguments. We provide an alternative view of the Sugeno integral that enables us to extend its use to situations in which the arguments in the aggregation are possibility distributions. We look at the application of the Sugeno integral to the formulation of decision functions in the case of multi‐criteria decision making. We focus on the situation where there exists some possibilistic uncertainty in our knowledge of criteria satisfactions by an alternative. We provide operational formulations for the calculation of some notable decision functions in the case of possibilistically uncertain criteria satisfactions.