On Water Pictet-Spengler Reaction of Tryptophan followed by Buchwald Coupling for the Synthesis of Natural Products Stellarines A, B and β-Carboline Derivatives: Their Molecular Docking against SARS-CoV-2 MPro

Natural products are versatile moiety in the drug discovery and development, however, their synthesis being one of the major challenges in this field. In this regard, an environment friendly synthesis of 1-benzoyl-9H-pyrido[3,4-b] indole-3-carboxamide β-carboline derivatives has been reported via Pictet-Spengler reaction of tryptophan methyl ester with 2-oxoaldehydes in water as solvent. Natural products Stellarines A and Stellarines B having anti-inflammatory activity against iNOS inhibition (IC50 value of 19.3 and 18.6 μM) isolated from the root of Stellaria dichotoma L. var. lanceolata Bunge were also synthesized from β-carboline derivatives using amidation followed by Buchwald coupling. The synthetic strategy has advantage of using non toxic and inexpensive materials for producing excellent yields. These functionalized β-carboline carboxamide derivatives have been evaluated against SARS-CoV-2 Mpro(7BQY) using molecular docking studies. © 2023 Wiley-VCH GmbH.

Reliability of Machine Learning in Eliminating Data Redundancy of Radiomics and Reflecting Pathophysiology in COVID-19 Pneumonia: Impact of CT Reconstruction Kernels on Accuracy

Background: Radiomical data are redundant but they might serve as a tool for lung quantitative assessment reflecting disease severity and actual physiological status of COVID-19 patients. Objective: Test the effectiveness of machine learning in eliminating data redundancy of radiomics and reflecting pathophysiologic changes in patients with COVID-19 pneumonia. Methods: We analyzed 605 cases admitted to Al Ain Hospital from 24 February to 1 July, 2020. They met the following inclusion criteria: age $\geq 18$ years;inpatient admission;PCR positive for SARS-CoV-2;lung CT available at PACS. We categorized cases into 4 classes: mild < 5% of pulmonary parenchymal involvement, moderate - 5-24%, severe - 25-49%, and critical $\geq50$ %. We used CT scans to build regression models predicting the oxygenation level, respiratory and cardiovascular functioning. Results: Radiomical findings are a reliable source of information to assess the functional status of patients with COVID-19. Machine learning models can predict the oxygenation level, respiratory and cardiovascular functioning from a set of demographics and radiomics data regardless of the settings of reconstructionkernels. The regression models can be used for scoring lung impairment and comparing disease severity in followup studies. The most accurate prediction we achieved was 6.454 +/- 3.715% of mean absolute error/range for all thefeatures and 7.069 +/- 4.17% for radiomics.Conclusion:The models may contribute to the proper risk evaluation anddisease management especially when the oxygen therapy impacts the actual values of the functional findings. Still,the structural assessment of an acute lung injury reflects the severity of the disease.

Deep Learning-Based Automatic Assessment of Lung Impairment in COVID-19 Pneumonia: Predicting Markers of Hypoxia With Computer Vision.

Background: Hypoxia is a potentially life-threatening condition that can be seen in pneumonia patients. Objective: We aimed to develop and test an automatic assessment of lung impairment in COVID-19 associated pneumonia with machine learning regression models that predict markers of respiratory and cardiovascular functioning from radiograms and lung CT. Materials and Methods: We enrolled a total of 605 COVID-19 cases admitted to Al Ain Hospital from 24 February to 1 July 2020 into the study. The inclusion criteria were as follows: age ≥ 18 years; inpatient admission; PCR positive for SARS-CoV-2; lung CT available at PACS. We designed a CNN-based regression model to predict systemic oxygenation markers from lung CT and 2D diagnostic images of the chest. The 2D images generated by averaging CT scans were analogous to the frontal and lateral view radiograms. The functional (heart and breath rate, blood pressure) and biochemical findings (SpO2, H C O 3 - , K +, Na +, anion gap, C-reactive protein) served as ground truth. Results: Radiologic findings in the lungs of COVID-19 patients provide reliable assessments of functional status with clinical utility. If fed to ML models, the sagittal view radiograms reflect dyspnea more accurately than the coronal view radiograms due to the smaller size and the lower model complexity. Mean absolute error of the models trained on single-projection radiograms was approximately 11÷12% and it dropped by 0.5÷1% if both projections were used (11.97 ± 9.23 vs. 11.43 ± 7.51%; p = 0.70). Thus, the ML regression models based on 2D images acquired in multiple planes had slightly better performance. The data blending approach was as efficient as the voting regression technique: 10.90 ± 6.72 vs. 11.96 ± 8.30%, p = 0.94. The models trained on 3D images were more accurate than those on 2D: 8.27 ± 4.13 and 11.75 ± 8.26%, p = 0.14 before lung extraction; 10.66 ± 5.83 and 7.94 ± 4.13%, p = 0.18 after the extraction. The lung extraction boosts 3D model performance unsubstantially (from 8.27 ± 4.13 to 7.94 ± 4.13%; p = 0.82). However, none of the differences between 3D and 2D were statistically significant. Conclusion: The constructed ML algorithms can serve as models of structure-function association and pathophysiologic changes in COVID-19. The algorithms can improve risk evaluation and disease management especially after oxygen therapy that changes functional findings. Thus, the structural assessment of acute lung injury speaks of disease severity.

Correlation of Radiological Findings (High Resolution Computed Tomography Chest) with Anti-SARS-COV-2 Antibodies in Patients Visiting Tertiary Care Hospitals

Background: Coronavirus (COVID 19) pandemic has taken so many lives and has contributed to an increase in morbidity due to its complications. The research is still in infancy and much has yet to be investigated. Objective: To correlate the HRCT findings on chest with antibody testing in patients visiting tertiary care hospitals in Lahore. Methodology: Three hundred and thirty-two patients with mild, moderate and severe symptoms of COVID 19 were recruited. Those with raised CRP levels were sent for HRCT chest and PCR testing as protocol of the hospitals. All patients were tested with Rapid antibody kits for reactivity. Results: Showed that males were affected more than females. Similarly, non-health care workers were more affected. All patients with bilateral involvement of lungs on HRCT chest and positive PCR findings also tested reactive on antibody testing. However, a few people with bilateral lung involvement and negative on PCR testing got reactive results on Rapid antibody testing. Linear regression model shows significant correlation of HRCT chest findings with Ant-SARC-COV 2 antibodies. Conclusion: HRCT findings (Unilateral and bilateral lung infiltrates) correlated significantly with Anti SARC-COV 2 Antibodies.

THE ROLE OF WORLD THE FIGHT AGAINST COVID-19

In under two decades, the world has encountered three flare-ups of fatal Coronaviruses, including the ongoing pandemic of Coronavirus Disease 2019 (COVID-19) in China. COVID-19 represented a crisis of worldwide concerns, and cases have been accounted for more than 200 nations/districts that came about in wellbeing, lives, and monetary misfortunes. China's financial development is anticipated to tumble to 5.6% this year, the International Monetary Fund (IMF) anticipated that arrangement venture and expense strategies to execute $3.3 trillion and contributes further $4.5 trillion. IMF conjectures develop from 3.7% of worldwide total national output (GDP) in 2019 to 9.9% in 2020. Gross domestic product proportion anticipated from 3.0% in 2019 to become 10.7% in 2020, the US proportion expected to increment from 5.8-15.7%. There is a desperate requirement for local and universal co-activity to stretch out hands to forestall further spreading of COVID-19. The IMF has reacted to the COVID emergency with exceptional speed and greatness of financial aid. This paper shows the response of the world against COVID-19. How the countries are helping each other to control the spread and discovering the cure of this virus. Asia has survived usefully and also defending the second wave of virus, but on the other hand, the Europe is the most infected region with the highest rate of death. Why Asia is near to win this fight with a stable economy, but the Europe is not, instead of this the economy is going to be crashed. These questions raises to the Economy, Behavior and Policies, of respective Countries.

Effects of surgical masks on aerosol dispersion in professional singing.

BACKGROUND: In the CoVID-19 pandemic, singing came into focus as a high-risk activity for the infection with airborne viruses and was therefore forbidden by many governmental administrations. OBJECTIVE: The aim of this study is to investigate the effectiveness of surgical masks regarding the spatial and temporal dispersion of aerosol and droplets during professional singing. METHODS: Ten professional singers performed a passage of the Ludwig van Beethoven's "Ode of Joy" in two experimental setups-each with and without surgical masks. First, they sang with previously inhaled vapor of e-cigarettes. The emitted cloud was recorded by three cameras to measure its dispersion dynamics. Secondly, the naturally expelled larger droplets were illuminated by a laser light sheet and recorded by a high-speed camera. RESULTS: The exhaled vapor aerosols were decelerated and deflected by the mask and stayed in the singer's near-field around and above their heads. In contrast, without mask, the aerosols spread widely reaching distances up to 1.3 m. The larger droplets were reduced by up to 86% with a surgical mask worn. SIGNIFICANCE: The study shows that surgical masks display an effective tool to reduce the range of aerosol dispersion during singing. In combination with an appropriate aeration strategy for aerosol removal, choir singers could be positioned in a more compact assembly without contaminating neighboring singers all singers.

A New Crystal Form of the SARS-CoV-2 Receptor Binding Domain: CR3022 Complex-An Ideal Target for In-Crystal Fragment Screening of the ACE2 Binding Site Surface.

In-crystal fragment screening is a powerful tool to chemically probe the surfaces used by proteins to interact, and identify the chemical space worth exploring to design protein-protein inhibitors. A crucial prerequisite is the identification of a crystal form where the target area is exposed and accessible to be probed by fragments. Here we report a crystal form of the SARS-CoV-2 Receptor Binding Domain in complex with the CR3022 antibody where the ACE2 binding site on the Receptor Binding Domain is exposed and accessible. This crystal form of the complex is a valuable tool to develop antiviral molecules that could act by blocking the virus entry in cells.

The new criteria for a COVID19 patient for the clinical practice to determine the need for an early therapeutic regimen and to decrease mortality.

A new predictive criterion is being proposed for the determination of cytokine storm (CS) in COVID-19 (COVID-CS). It is comprised of results of laboratory that associate the pro-inflammatory status, systemic cell death, multi-organ tissue damage, and pre-renal electrolyte imbalance. The data identifies the patients' stay in hospitals and their mortality with the relevance of hyper-inflammation and tissue damage during the CS. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyper-immune response and possibly decrease mortality. It helps to understand the nature of the virus by following a specific criterion to predict the disease. The SARS-CoV-2 tells us in few days what nature has decided for the patient i.e., recovery, death or permanent disability.

Molecular dynamics simulation perception study of the binding affinity performance for main protease of SARS-CoV-2.

Like common cold and flu, SARC-CoV-2 virus spreads by droplets of sneezes or coughs which virus affects people of various age groups. Today, this virus is almost distributed all over the world. Since binding process plays a crucial role between host and receptor, therefore, we studied the molecules intended toward inhibition process through molecular docking and molecular dynamics simulation process. From the molecular docking study, it is noteworthy that remdesivir shows better binding affinity toward the main protease of SARS-CoV2 compared to other studied drugs. Within studied phytochemicals, carnosic acid shows better binding poses toward main protease of SARS-CoV2 among studied phytochemicals. The amino acid residues GLN110 and PHE294 were almost found in all the studied interactions of drugs and phytochemicals with main protease of SARS-CoV-2. Furthermore, the results show a larger contribution of the Van der Waals energies as compared to others like electrostatic energies suggesting that ligands at the binding pocket are predominantly stabilized by hydrophobic interactions. The conformational change during ligand binding was predicted from Gibbs free energy landscape analysis through molecular dynamics simulation. We observed that, there were two main free energy basins for both docked carnosic acid complex and for docked remdesivir complex, only one main free energy basin was found in the global free energy minimum region.Communicated by Ramaswamy H. Sarma.

Papain-like cysteine proteinase zone (PCP-zone) and PCP structural catalytic core (PCP-SCC) of enzymes with cysteine proteinase fold.

There are several families of cysteine proteinases with different folds - for example the (chymo)trypsin fold family and papain-like fold family - but in both families the hydrolase activity of cysteine proteinases requires a cysteine residue as the catalytic nucleophile. In this work, we have analyzed the topology of the active site regions in 146 three-dimensional structures of proteins belonging to the Papain-like Cysteine Proteinase (PCP) superfamily, which includes papain as a typical representative of this protein superfamily. All analyzed enzymes contain a unique structurally closed conformation - a "PCP-Zone" - which can be divided into two groups, Class A and Class B. Eight structurally conserved amino acids of the PCP-Zone form a common Structural Core. The Structural Core, catalytic nucleophile, catalytic base and residue Xaa - which stabilizes the side-chain conformation of the catalytic base - make up a PCP Structural Catalytic Core (PCP-SCC). The PCP-SCC of Class A and Class B are divided into 5 and 2 types, respectively. Seven variants of the mutual arrangement of the amino-acid side chains of the catalytic triad - nucleophile, base and residue Xaa - within the same fold clearly demonstrate how enzymes with the papain-like fold adapt to the need to perform diverse functions in spite of their limited structural diversity. The roles of both the PCP-Zone of SARS-CoV-2-PLpro described in this study and the NBCZone of SARS-CoV-2-3CLpro presented in our earlier article (Denesyuk AI, Johnson MS, Salo-Ahen OMH, Uversky VN, Denessiouk K. Int J Biol Macromol. 2020;153:399-411) that are in contacts with inhibitors are discussed.

COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties.

Coronavirus disease of 2019 (COVID-19) has emerged as a global health threat. Unfortunately, there are very limited approved drugs available with established efficacy against the SARs-CoV-2 virus and its inflammatory complications. Vaccine development is actively being researched, but it may take over a year to become available to general public. Certain medications, for example, dexamethasone, antimalarials (chloroquine/hydroxychloroquine), antiviral (remdesivir), and IL-6 receptor blocking monoclonal antibodies (tocilizumab), are used in various combinations as off-label medications to treat COVID-19. Essential oils (EOs) have long been known to have anti-inflammatory, immunomodulatory, bronchodilatory, and antiviral properties and are being proposed to have activity against SARC-CoV-2 virus. Owing to their lipophilic nature, EOs are advocated to penetrate viral membranes easily leading to membrane disruption. Moreover, EOs contain multiple active phytochemicals that can act synergistically on multiple stages of viral replication and also induce positive effects on host respiratory system including bronchodilation and mucus lysis. At present, only computer-aided docking and few in vitro studies are available which show anti-SARC-CoV-2 activities of EOs. In this review, role of EOs in the prevention and treatment of COVID-19 is discussed. A discussion on possible side effects associated with EOs as well as anti-corona virus claims made by EOs manufacturers are also highlighted. Based on the current knowledge a chemo-herbal (EOs) combination of the drugs could be a more feasible and effective approach to combat this viral pandemic.