An mRNA vaccine for pancreatic cancer designed by applying in silico immunoinformatics and reverse vaccinology approaches.

Pancreatic ductal adenocarcinoma is the most prevalent pancreatic cancer, which is considered a significant global health concern. Chemotherapy and surgery are the mainstays of current pancreatic cancer treatments; however, a few cases are suitable for surgery, and most of the cases will experience recurrent episodes. Compared to DNA or peptide vaccines, mRNA vaccines for pancreatic cancer have more promise because of their delivery, enhanced immune responses, and lower proneness to mutation. We constructed an mRNA vaccine by analyzing S100 family proteins, which are all major activators of receptors for advanced glycation end products. We applied immunoinformatic approaches, including physicochemical properties analysis, structural prediction and validation, molecular docking study, in silico cloning, and immune simulations. The designed mRNA vaccine was estimated to have a molecular weight of 165023.50 Da and was highly soluble (grand average of hydropathicity of -0.440). In the structural assessment, the vaccine seemed to be a well-stable and functioning protein (Z score of -8.94). Also, the docking analysis suggested that the vaccine had a high affinity for TLR-2 and TLR-4 receptors. Additionally, the molecular mechanics with generalized Born and surface area solvation analysis of the "Vaccine-TLR-2" (-141.07 kcal/mol) and "Vaccine-TLR-4" (-271.72 kcal/mol) complexes also suggests a strong binding affinity for the receptors. Codon optimization also provided a high expression level with a GC content of 47.04% and a codon adaptation index score 1.0. The appearance of memory B-cells and T-cells was also observed over a while, with an increased level of helper T-cells and immunoglobulins (IgM and IgG). Moreover, the minimum free energy of the mRNA vaccine was predicted at -1760.00 kcal/mol, indicating the stability of the vaccine following its entry, transcription, and expression. This hypothetical vaccine offers a groundbreaking tool for future research and therapeutic development of pancreatic cancer.

Genome-wide study of globally distributed respiratory syncytial virus (RSV) strains implicates diversification utilizing phylodynamics and mutational analysis.

Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes mild cold-like symptoms and severe lower respiratory tract infections, causing hospitalizations in children, the elderly and immunocompromised individuals. Due to genetic variability, this virus causes life-threatening pneumonia and bronchiolitis in young infants. Thus, we examined 3600 whole genome sequences submitted to GISAID by 31 December 2022 to examine the genetic variability of RSV. While RSVA and RSVB coexist throughout RSV seasons, RSVA is more prevalent, fatal, and epidemic-prone in several countries, including the United States, the United Kingdom, Australia, and China. Additionally, the virus's attachment glycoprotein and fusion protein were highly mutated, with RSVA having higher Shannon entropy than RSVB. The genetic makeup of these viruses contributes significantly to their prevalence and epidemic potential. Several strain-specific SNPs co-occurred with specific haplotypes of RSVA and RSVB, followed by different haplotypes of the viruses. RSVA and RSVB have the highest linkage probability at loci T12844A/T3483C and G13959T/C2198T, respectively. The results indicate that specific haplotypes and SNPs may significantly affect their spread. Overall, this analysis presents a promising strategy for tracking the evolving epidemic situation and genetic variants of RSV, which could aid in developing effective control, prophylactic, and treatment strategies.

In Silico Functional Characterization of a Hypothetical Protein From Pasteurella Multocida Reveals a Novel S-Adenosylmethionine-Dependent Methyltransferase Activity.

Genomes may now be sequenced in a matter of weeks, leading to an influx of "hypothetical" proteins (HP) whose activities remain a mystery in GenBank. The information included inside these genes has quickly grown in prominence. Thus, we selected to look closely at the structure and function of an HP (AFF25514.1; 246 residues) from Pasteurella multocida (PM) subsp. multocida str. HN06. Possible insights into bacterial adaptation to new environments and metabolic changes might be gained by studying the functions of this protein. The PM HN06 2293 gene encodes an alkaline cytoplasmic protein with a molecular weight of 28352.60 Da, an isoelectric point (pI) of 9.18, and an overall average hydropathicity of around -0.565. One of its functional domains, tRNA (adenine (37)-N6)-methyltransferase TrmO, is a S-adenosylmethionine (SAM)-dependent methyltransferase (MTase), suggesting that it belongs to the Class VIII SAM-dependent MTase family. The tertiary structures represented by HHpred and I-TASSER models were found to be flawless. We predicted the model's active site using the Computed Atlas of Surface Topography of Proteins (CASTp) and FTSite servers, and then displayed it in 3 dimensional (3D) using PyMOL and BIOVIA Discovery Studio. Based on molecular docking (MD) results, we know that HP interacts with SAM and S-adenosylhomocysteine (SAH), 2 crucial metabolites in the tRNA methylation process, with binding affinities of 7.4 and 7.5 kcal/mol, respectively. Molecular dynamic simulations (MDS) of the docked complex, which included only modest structural adjustments, corroborated the strong binding affinity of SAM and SAH to the HP. Evidence for HP's possible role as an SAM-dependent MTase was therefore given by the findings of Multiple sequence alignment (MSA), MD, and molecular dynamic modeling. These in silico data suggest that the investigated HP might be used as a useful adjunct in the investigation of Pasteurella infections and the development of drugs to treat zoonotic pasteurellosis.

Biocomputational characterisation of MBO_200107 protein of Mycobacterium tuberculosis variant caprae: a molecular docking and simulation study.

The principal objective of this study was to delineate the potentiality of the MBO_200107 protein from the Mycobacterium tuberculosis variant caprae in cancer research. It is a cytoplasmic protein, comprised of a 354-long amino acid chain, alkaline, had a molecular weight of 39089.37 Da, an isoelectric point of 9.62 and a grand average of hydropathicity of -0.345. One of the functional domains was predicted as Gammaglutamylcyclotransferase (GGCT). Among tertiary structures, the Modeller and Phyre2 model satisfied all the quality parameters, though they are truncated; contrarily, the I-TASSER model is full length and contains the sequence for the GGCT domain, though it did not meet all the quality parameters. It also has significant sequence similarities (47.5% by EMBOSS Water and 72.4% by EMBOSS Matcher) with a human GGCT, and the conserved sequences are confined to the GGCT domain of the MBO_200107. According to molecular docking analyses, the protein has a binding affinity of -4.8 kcal/mol by Autodock Vina and -56.465 kcal/mol by HPEPDOCK to the human glutathione (GSH), an essential metabolite for GGCT metabolism. The Molecular dynamic simulation of the docked complex showed the binding efficiency of the GSH to MBO_200107 with a minimal structural alteration. The in silico findings mentioned above revealed that the protein could be used as a supplementary tool in cancer research, such as designing vaccines or drugs where the role of GGCT has been implicated. Further, we recommend fully characterising the protein and conducting essential in vitro and in vivo experiments to determine its detailed usefulness.Communicated by Ramaswamy H. Sarma.

Coinfection of fungi with SARS-CoV-2 is a detrimental health risk for COVID-19 patients.

Background: Notable fungal coinfections with SARS-CoV-2 in COVID-19 patients have been reported worldwide in an alarming way. Mucor spp. and Rhizopus spp. were commonly known as black fungi, whereas Aspergillus spp. and Candida spp. were designated as white fungi implicated in those infections. In this review, we focused on the global outbreaks of fungal coinfection with SARS-CoV-2, the role of the human immune system, and a detailed understanding of those fungi to delineate the contribution of such coinfections in deteriorating the health conditions of COVID-19 patients based on current knowledge. Main body: Impaired CD4 + T cell response due to SARS-CoV-2 infection creates an opportunity for fungi to take over the host cells and, consequently, cause severe fungal coinfections, including candidiasis and candidemia, mucormycosis, invasive pulmonary aspergillosis (IPA), and COVID-19-associated pulmonary aspergillosis (CAPA). Among them, mucormycosis and CAPA have been reported with a mortality rate of 66% in India and 60% in Colombia. Moreover, IPA has been reported in Belgium, Netherlands, France, and Germany with a morbidity rate of 20.6%, 19.6%, 33.3%, and 26%, respectively. Several antifungal drugs have been applied to combat fungal coinfection in COVID-19 patients, including Voriconazole, Isavuconazole, and Echinocandins. Conclusion: SARS-CoV-2 deteriorates the immune system so that several fungi could take that opportunity and cause life-threatening health situations. To reduce the mortality and morbidity of fungal coinfections, it needs immunity boosting, proper hygiene and sanitation, and appropriate medication based on the diagnosis.

A comprehensive review on COVID-19 vaccines: development, effectiveness, adverse effects, distribution and challenges.

The present SARS-CoV-2 induced COVID-19 pandemic is responsible for millions of deaths, illnesses, and economic loss worldwide. There are 21 COVID-19 vaccines from different platforms approved worldwide for emergency use until 13 August 2021. Later, BNT162b2 obtained full approval from the FDA. The efficacy of the leading vaccines such as BNT162b2, mRNA-1273, Gam-Covid-Vac, Ad26.COV2.S, ChAdOx1 nCoV-19, and BBIBP-CorV, against SARS-CoV-2 documented as 95%, 94.1%, 91.6%, 67%, 70.4%, and 78.1%, respectively. Moreover, against the Delta variant of SARS-CoV-2, BNT162b2, ChAdOx1 nCoV-19, and BBV152 showed 88%, 70%, and 65.2% efficacy, respectively. Apart from the common adverse effects such as fever, fatigue, headache, and pain in the injection site, Bell's palsy with BNT162b2, myocarditis and pericarditis with mRNA-1273, and thrombosis with ChAdOx1 nCoV-19 have been reported though seemed not alarming. Furthermore, global production and distribution of vaccines should be ensured in an equal and justifiable way that the immunity and protection against the virus would be optimum and persistent.