Biology subjects

Ben Khalaf, N.

Publications and source records attributed to Ben Khalaf, N..

3 recordsLinked to original sources

bioRxiv2022

Concomitant Vascular Calsequestrin 2 overexpression and leukocytes transmigration in a rat model of skeletal muscle traumatic inflammatory injury

The network of molecular mediators involved in the transmigration of leukocytes to inflamed tissues has been expanding with the identification of new molecules involved in the inflammatory response. We have previously shown using a rat model that Protein Disulfide Isomerase PDIA4 (ERP72) is involved in the inflammatory response to skeletal muscle traumatic injury. In this paper, we report observations suggesting that calsequestrin 2 (CASQ2), another member of the thioredoxin/PDI family, might contribute to the inflammatory response that leads to adhesion and transmigration of leukocytes into injured skeletal muscle. Indeed, real time PCR assay showed that the expression level CASQ2 is significantly enhanced [p<0.01] in the mechanically injured muscle. Immunohistological and immunofluorescence analysis showed that CASQ2 but not CASQ1 is expressed in the vessels present in the muscle-injured area. In addition, CASQ2 overexpression and PMN transmigration to the inflamed muscle injury are concomitant. This overexpression occurs most likely in the smooth muscle of the inflamed vessel. These observations together with the known Ca2+ buffering role of CASQ2 suggest that the protein contributes to the inflammatory process by providing the Ca2+ needed to activate the inflammasome and the leukocytes adhesion molecules which enhances transmigration of inflammatory cells into the injured muscle.

molecular biology↗

bioRxiv2022

HOW 1 CONCERNING IS A SARS-COV-2 VARIANT OF2 CONCERN? COMPUTATIONAL PREDICTIONS AND3 THE VARIANTS LABELING SYSTEM.

We herein report a study to evaluate the use of computational prediction of SARS-CoV-2 genetic variations in improving the current variants labeling system. First, we reviewed the basis of the system developed by the World Health Organization (WHO) for the labeling of SARS-CoV-2 genetic variants and the adaptations made to it by the United States Center of Diseases Control (CDC). We observed that the labeling system is based upon the virus major attributes. However, we found that the labeling criteria of the SARS-CoV-2 variants derived from these attributes are not accurately defined and are used differently by the two health management agencies. Consequently, discrepancies exist between the labels given by WHO and CDC to same variants. Our observations suggest that giving the VOC label to a new variant is premature and might not be appropriate. Therefore, we carried out a comparative computational study to predict the effects of the mutations on the virus structure and functions of five VOCs. By linking these data to the criteria used by WHO and the CDC for variant labeling, we ascertained that comparative computational predictions of the impact of genetic variations are a better ground for rapid and more accurate labelling of SARS-CoV-2 variants. We propose to label all emergent variants VUM or VBM and to carry out computational predictive studies and thorough variants comparison, upon which more appropriate and informative labels can be attributed. Furthermore, harmonization of the variants labeling system would be globally beneficial to communicate about and fight COVID-19 pandemic.

molecular biology↗

bioRxiv2020

SARS-CoV-2 RBD mutations, ACE2 genetic polymorphism, and stability of the virus-receptor complex: The COVID-19 host-pathogen nexus.

SARS-CoV-2 infectivity is largely determined by the virus Spike protein binding to the ACE2 receptor. Meanwhile, marked infection rate differences were reported between populations and individuals. To understand the disease dynamic, we developed a computational approach to study the implications of both SARS-CoV-2 RBD mutations and ACE2 polymorphism on the stability of the virus-receptor complex. We used the 6LZG PDB RBD/ACE2 3D model, the mCSM platform, the LigPlot+ and PyMol software to analyze the data on SARS-CoV-2 mutations and ACE variants retrieved from GISAID and Ensembl/GnomAD repository. We observed that out of 351 RBD point mutations, 83% destabilizes the complex according to free energy ({Delta}{Delta}G) differences. We also spotted variations in the patterns of polar and hydrophobic interactions between the mutations occurring in 15 out of 18 contact residues. Similarly, comparison of the effect on the complex stability of different ACE2 variants showed that the pattern of molecular interactions and the complex stability varies also according to ACE2 polymorphism. We infer that it is important to consider both ACE2 variants and circulating SARS-CoV-2 RBD mutations to assess the stability of the virus-receptor association and evaluate infectivity. This approach might offers a good molecular ground to mitigate the virus spreading.

molecular biology↗