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.     

Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma

Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients’ peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients’ cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC.     

Intelligent system for visual web content analytics: A new approach and case study

The accuracy of searches for visual data elements, as well as other types of information, depends on the terms used by the user in the input query to retrieve the relevant results and to reduce the irrelevant ones. Most of the results that are returned are relevant to the query terms, but not to their meaning. For example, certain types of web contents hold hidden information that traditional search engines are unable to retrieve. Searching for the mathematical construct of 1/x using Google will not result in the retrieval of the documents that contain the mathematically equivalent expressions (i.e. x^?1). Because conventional search engines fall short of providing math-search capabilities. One of these capabilities is the ability of these search engines to detect the mathematical equivalence between users’ quires and math contents. In addition, users sometimes need to use slang terms, either to retrieve slang-based visual data (e.g. social media content) or because they do not know how to write using classical form. To solve such a problem, this paper proposed an AI-based system for analysing multilingual slang web contents so as to allow a user to retrieve web slang contents that are relevant to the user’s query. The proposed system presents an approach for visual data analytics, and it also enables users to analyse hundreds of potential search results/web pages by starting an informed friendly dialogue and presenting innovative answers.     

Constrained model predictive control for time-varying delay systems: Application to an active car suspension

This study investigates the problem of robust model predictive control (RMPC) for active suspension systems with time-varying delays and input constraints. The uncertainty is of convex polytopic type. Based on the Lyapunov-Krasovskii functional method, sufficient stability conditions of the time-varying delays systems are derived by linear matrix inequalities (LMIs) terms. At each time set, a feasible state feedback is obtained by minimizing an upper bound of the ‘worst-case’ quadratic objective function over an infinite horizon subject to constraints on inputs. Finally, a quarter-vehicle model is exploited to demonstrate the effectiveness of the proposed method.     

Elucidating the Interaction between Pyridoxine 5′-Phosphate Oxidase and Dopa Decarboxylase: Activation of B6-Dependent Enzyme

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, serves as a cofactor for scores of B6-dependent (PLP-dependent) enzymes involved in many cellular processes. One such B6 enzyme is dopa decarboxylase (DDC), which is required for the biosynthesis of key neurotransmitters, e.g., dopamine and serotonin. PLP-dependent enzymes are biosynthesized as apo-B6 enzymes and then converted to the catalytically active holo-B6 enzymes by Schiff base formation between the aldehyde of PLP and an active site lysine of the protein. In eukaryotes, PLP is made available to the B6 enzymes through the activity of the B6-salvage enzymes, pyridoxine 5′-phosphate oxidase (PNPO) and pyridoxal kinase (PLK). To minimize toxicity, the cell keeps the content of free PLP (unbound) very low through dephosphorylation and PLP feedback inhibition of PNPO and PLK. This has led to a proposed mechanism of complex formation between the B6-salvage enzymes and apo-B6 enzymes prior to the transfer of PLP, although such complexes are yet to be characterized at the atomic level, presumably due to their transient nature. A computational study, for the first time, was used to predict a likely PNPO and DDC complex, which suggested contact between the allosteric PLP tight-binding site on PNPO and the active site of DDC. Using isothermal calorimetry and/or surface plasmon resonance, we also show that PNPO binds both apoDDC and holoDDC with dissociation constants of 0.93 ± 0.07 μM and 2.59 ± 0.11 μM, respectively. Finally, in the presence of apoDDC, the tightly bound PLP on PNPO is transferred to apoDDC, resulting in the formation of about 35% holoDDC.     

Antioxidant capacity and total phenolics of <Emphasis Type="Italic">Cyphostemma digitatum</Emphasis> before and after processing: use of different assays

In the framework of standardisation of new healthy food sources, this paper aimed to study the total phenolics and the antioxidant power of Cyphostemma digitatum (Vitaceae) in water and ethanol extracts, using 96-well micro plates with BMG FLUOstar Optima micro plate reader. Total phenolics by Folin–Ciocalteu method in the water extracts were significantly lower after processing, decreasing from 1.41 ± 0.06 g GAE/100 g in the raw leaves to 0.80 ± 0.08 g GAE/100 g in the processed sample; the ethanol extract revealed the same trend with higher values, decreasing from 1.95 ± 0.03 to 1.56 ± 0.12 g GAE/100 g. The antioxidant capacity was elucidated by four methods: TEAC, DPPH, FRAP and ORAC. No or very weak correlations were found between antioxidant assays and total phenolics; this confirms that the antioxidant capacity could be attributed to other molecules. The ORAC assay proved to be more powerful than the other assays; it showed 103.3 ± 2.5 mmol/100 g Trolox equivalents in the raw leaves ethanol extract and 91.9 ± 3.0 mmol/100 g in the processed sample. ORAC assay showed the opposite for the water extract where the antioxidant capacity increased from 16.7 ± 0.2 to 41.7 ± 2.7 mmol/100 g Trolox equivalents after processing, which could be attributed to new water-soluble compounds generated in the consumed form.     

Synthesis and Anti-Cancer Activity of New Pyrazolinyl-Indole Derivatives: Pharmacophoric Interactions and Docking Studies for Identifying New EGFR Inhibitors

Newly designed series of indole-containing pyrazole analogs, pyrazolinylindoles, were synthesized, and their structures were confirmed based on the spectral data of the ¹H NMR, ¹³C NMR, and HR-MS analyses. Preliminary anti-cancer activity testings were carried out by the National Cancer Institute, United States of America (NCI, USA). Compounds HD02, HD05, and HD12 demonstrated remarkable cytotoxic activities against nine categories of cancer types based cell line panels which included leukemia, colon, breast, melanoma, lungs, renal, prostate, CNS, and ovarian cancer cell lines. The highest cytotoxic effects were exhibited by the compounds HD02 [1-(5-(1-H-indol-3-yl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenylethanone], HD05 [1-(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-2-phenoxyethanone], and HD12 [(3-(4-chlorophenyl)-5-(1H-indol-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(pyridin-4-yl)methanone] against some of the 56 types of NCI-based cell lines in different panels. Compound HD05 showed the maximum range of cancer cell growth inhibitions against all categories of the cell lines in all nine panels. On average, in comparison to the referral standard, imatinib, at a dose level of 10 µM, the HD05 showed significant activity against leukemia in the range of 78.76%, as compared to the imatinib at 9% of cancer cells’ growth inhibitions. Molecular docking simulation studies were performed in silico on the epidermal growth factor receptor (EGFR) tyrosine kinase, in order to validate the activity.     

Three-level designs: Evaluation and comparison for screening purposes

Since their introduction by Box and Hunter, resolution criteria have been widely used when comparing regular fractional factorials designs. In this article, we investigate how a generalized resolution criterion can be used to assess some recently developed three-level screening designs, such as definitive screening designs (DSDs) and screening designs from weighing matrices. The aim of this paper is to capture the projection properties of those three-level screening designs, complementing the work of Deng and Tang, who used generalized resolution and minimum aberration criteria for ranking different two-level designs, particularly Plackett-Burman and other nonregular factorial designs. An advantage of generalized resolution, extended here to work on three-level designs, is that it offers a useful criterion for ranking three-level screening designs, whereas the Deng and Tang resolution is used mainly for the assessment of two-level designs. In addition, we applied a projection estimation capacity (PEC) criterion to select three-level screening designs with desirable properties. Practical examples and the best projections of the designs are presented in tables.     

Perception,navigation, and manipulation in the team KAUST approach to the MBZIRC ground robotics challenge

The ground robotics challenge in the Mohammed Bin Zayed International Robotics Challenge required a ground vehicle equipped with a robotic arm to autonomously locate a panel, select a proper size wrench among several options mounted on the panel, and use the wrench to rotate a valve. Autonomy was the critical factor in this challenge, which required the teams to devise algorithms that can operate successfully in a semistructured environment without human supervision. This paper presents the approaches taken by team KAUST to meet this challenge, ranging from in‐house hardware designs to algorithm integration and customization. We separated the whole objective into three interconnected tasks: Navigation, perception, and manipulation. For the navigation task, we developed a basic robotic exploration scheme to find the panel front side where the wrenches were present. For the perception task, we integrated common object detection algorithms with neural networks to identify the proper size wrench precisely. For successful manipulation, we designed and built a custom gripper, which was inspired by the common grasping behavior of a human hand under tight clearance conditions. The modular structure of the proposed approach allowed the team to progress in several subtasks simultaneously. However, the interconnection between the subtasks necessitated a reliable integration framework between these modules for effective implementation. We tuned our algorithms in extensive experimental studies and eventually obtained 10 consecutive successful navigation runs, 96% true wrench detection rate, and high success rate in wrench grasping. Furthermore, successful complete tests proved the reliability and repeatability of our system.     

Antioxidant and cardioprotective activities of phenolic extracts from fruits of Chilean blackberry Aristotelia chilensis (Elaeocarpaceae), Maqui

The methanol extract from mature fruits of Aristotelia chilensis (Mol) Stuntz (Elaeocarpaceae) showed antioxidant activities and cardioprotective effects on acute ischemia/reperfusion performed in rat heart in vivo. This extract protected animals from heart damage by the incidence of reperfusion dysrythmias, and the no-recovery of sinus rhythm. On the other hand, the MeOH extract of the fruit was able to prevent these harmful events in the animal’s heart by diminishing lipid oxidation and reducing the concentration of thiobarbituric acid reactive substances (TBARS), a lipid peroxidation index. In addition, MeOH extract of A. chilensis was evaluated for DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging, crocin radical scavenging, oxygen radical absorption capacity (ORAC), ferric reducing antioxidant power (FRAP), an estimation of lipid peroxidation in liposomes through the inhibition of formation of TBARS. MeOH extract was found to have IC₅₀ of 1.62 ppm against DPPH and 2.51 ppm against TBARS, compared with the juice, whose IC₅₀ was 12.1 ppm and 9.58 ppm against DPPH and TBARS formation, respectively. Antioxidant activities of MeOH extract were strongly correlated with total polyphenol content. Consistent with this finding, MeOH had the greatest ORAC and FRAP values as percentage of activity. These results show that these fruits could be useful as antioxidant, cardioprotective and nutraceutical sources.