Design of multi-epitope chimeric vaccine against Monkeypox virus and SARS-CoV-2: A vaccinomics perspective.

The current era we experience is full with pandemic infectious agents that no longer threatens the major local source but the whole globe. Almost the most emerging infectious agents are severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), followed by monkeypox virus (MPXV). Since no approved antiviral drugs nor licensed active vaccines are yet available, we aimed to utilize immunoinformatics approach to design chimeric vaccine against the two mentioned viruses. This is the first study to deal with design divalent vaccine against SARS-CoV-2 and MPXV. ORF8, E and M proteins from Omicron SARS-CoV-2 and gp182 from MPXV were used as the protein precursor from which multi-epitopes (inducing B-cell, helper T cells, cytotoxic T cells and interferon-É£) chimeric vaccine was contrived. The structure of the vaccine construct was predicted, validated, and docked to toll-like receptor-2 (TLR-2). Moreover, its sequence was also used to examine the immune simulation profile and was then inserted into the pET-28a plasmid for in silico cloning. The vaccine construct was probable antigen (0.543) and safe (non-allergen) with strong binding energy to TLR-2 (-1169.8 kcal/mol) and found to have significant immune simulation profile. In conclusion, the designed chimeric vaccine was potent and safe against SARS-CoV-2 and MPXV, which deserves further consideration.

The Landscape of Exosomes Biogenesis to Clinical Applications.

Exosomes are extracellular vesicles that originate from various cells and mediate intercellular communication, altering the behavior or fate of recipient cells. They carry diverse macromolecules, such as lipids, proteins, carbohydrates, and nucleic acids. Environmental stressors can change the exosomal contents of many cells, making them useful for diagnosing many chronic disorders, especially neurodegenerative, cardiovascular, cancerous, and diabetic diseases. Moreover, exosomes can be engineered as therapeutic agents to modulate disease processes. State-of-art techniques are employed to separate exosomes including ultracentrifugation, size-exclusion chromatography and immunoaffinity. However, modern technologies such as aqueous two-phase system as well as microfluidics are gaining attention in the recent years. The article highlighted the composition, biogenesis, and implications of exosomes, as well as the standard and novel methods for isolating them and applying them as biomarkers and therapeutic cargo carriers.

Clinical trials of probiotics: Current outlook.

The current investigation provides a summary of the available clinical trials using probiotics as therapeutic worldwide and their fate.

Unveiling the Global Surge: Unraveling the Factors Fueling the Spread of Karoshi Syndrome.

Karoshi syndrome, also known as "death by overwork", has been a topic of study and concern in Japan since the 1980s. World Health Organization (WHO) and International Labour Organization (ILO) joint unveiled that in 2021, approximately 750.000 deaths due to Karoshi syndrome globally. The joint defined long working as having > 55 h work/week. Karoshi nowadays is no longer limited to Japan and has become a global issue. Karoshi is primarily attributed to factors such as long working hours, job-related stress, and poor work-life balance. This perspective was sought to provide a short overview of Karoshi syndrome, the underlying mechanisms and the state-of-art preventive measures.

Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.

Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.

Structure based virtual screening and molecular simulation study of FDA-approved drugs to inhibit human HDAC6 and VISTA as dual cancer immunotherapy.

Cancer immunotherapy has significantly contributed to the treatment of various types of cancers mainly by targeting immune checkpoint inhibitors (ICI). Among them, V-domain immunoglobulin suppressor of T cell activation (VISTA) has been explored as a promising therapeutic target. Besides, histone deacetylase 6 (HDAC6) has been demonstrated to be efficacious target for several cancers. The current theoretical work was performed to explore the virtual repurposing of the FDA-approved drugs as inhibitors against these two (VISTA and HDAC6) cancers therapeutic targets. The crystal structure of the two proteins were downloaded from PDB and subjected to virtual screening by DrugRep webserver while using FDA-approved drugs library as ligands database. Our study revealed that Oxymorphone and Bexarotene are the top-ranked inhibitors of VISTA and HDAC6, respectively. The docking score of Bexarotene was predicted as - 10 kcal/mol while the docking score of Oxymorphone was predicted as - 6.2 kcal/mol. Furthermore, a total of 100 ns MD simulation revealed that the two drugs Oxymorphone and Bexarotene formed stable complexes with VISTA and HDAC6 drug targets. As compared to the standard drug the two drugs Oxymorphone and Bexarotene revealed great stability during the whole 100 ns MD simulation. The binding free energy calculation further supported the Root Mean Square Deviation (RMSD) result which stated that as compared to the ref/HDAC6 (- 18.0253 ± 2.6218) the binding free energy score of the Bexarotene/HDAC6 was good (- 51.9698 ± 3.1572 kcal/mol). The binding free energy score of Oxymorphone/VISTA and Ref/VISTA were calculated as - 36.8323 ± 3.4565, and - 21.5611 ± 4.8581 respectively. In conclusion, the two drugs deserve further consideration as cancer treatment option.

Computational Identification of Most Deleterious Missense Mutations in Human PD-1 Gene.

Traditional cancer treatment approaches are often hindered by the presence of toxic side effects and the high rate of relapse observed in treated organs. In contrast, novel immunotherapeutic strategies targeting immune checkpoint inhibitors, particularly PD-1, have demonstrated promising results with minimal adverse effects. However, the emergence of immunotherapeutic-resistant tumors, predominantly caused by intrinsic mutations, poses a significant obstacle to successful treatment outcomes. Consequently, the primary objective of this study was to screen for the most detrimental missense mutations in the PD-1 gene associated with immunotherapeutic resistance. To achieve this aim, a comprehensive screening process utilizing 20 web servers, incorporating both sequence- and structure-based methodologies, was undertaken. Through meticulous analysis and mutual disease association sorting, four specific missense mutations were successfully identified. These mutations, namely, R38C, D61V, R94C, and D117V, emerged as the leading contributors to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The findings presented in this study are supported by multiple lines of evidence. A thorough examination of protein topology, structural alignment, docking interactions with PD-L1, and protein flexibility collectively confirmed the pathogenic nature of these sorted mutations. By considering these various aspects, we have gained a comprehensive understanding of the underlying mechanisms driving immunotherapeutic resistance. In conclusion, the comprehensive screening process undertaken in this study has successfully identified R38C, D61V, R94C, and D117V as the primary mutations contributing to genetic cancer progression and immunotherapeutic resistance against PD-1 blockers. The integration of protein topology analysis, structural alignment, docking studies with PD-L1, and assessment of protein flexibility have collectively provided robust evidence to support the pathogenic significance of these mutations.

Mini Review of Biochemical Basis, Diagnosis and Management of Crush Syndrome.

Crush syndrome (CS) is a metabolic disorder whose victims are individuals suffered from natural disasters such as earthquake or man-made conflicts. CS complications include acute kidney injury and cardiac arrhythmia that collectively end with death if untreated immediately. These complications are accounted for the liberation of damaged muscle tissues contents, primarily myoglobin and potassium. The present mini review discusses the biochemical basis of the development of CS. In addition, diagnosis and management and the application of novel experimental therapeutics of CS are also highlighted.