Genomic landscape of NDM-1 producing multidrug-resistant Providencia stuartii causing burn wound infections in Bangladesh.

The increasing antimicrobial resistance in Providencia stuartii (P. stuartii) worldwide, particularly concerning for immunocompromised and burn patients, has raised concern in Bangladesh, where the significance of this infectious opportunistic pathogen had been previously overlooked, prompting a need for investigation. The two strains of P. stuartii (P. stuartii SHNIBPS63 and P. stuartii SHNIBPS71) isolated from wound swab of two critically injured burn patients were found to be multidrug-resistant and P. stuartii SHNIBPS63 showed resistance to all the 22 antibiotics tested as well as revealed the co-existence of blaVEB-6 (Class A), blaNDM-1 (Class B), blaOXA-10 (Class D) beta lactamase genes. Complete resistance to carbapenems through the production of NDM-1, is indicative of an alarming situation as carbapenems are considered to be the last line antibiotic to combat this pathogen. Both isolates displayed strong biofilm-forming abilities and exhibited resistance to copper, zinc, and iron, in addition to carrying multiple genes associated with metal resistance and the formation of biofilms. The study also encompassed a pangenome analysis utilizing a dataset of eighty-six publicly available P. stuartii genomes (n = 86), revealing evidence of an open or expanding pangenome for P. stuartii. Also, an extensive genome-wide analysis of all the P. stuartii genomes revealed a concerning global prevalence of diverse antimicrobial resistance genes, with a particular alarm raised over the abundance of carbapenem resistance gene blaNDM-1. Additionally, this study highlighted the notable genetic diversity within P. stuartii, significant informations about phylogenomic relationships and ancestry, as well as potential for cross-species transmission, raising important implications for public health and microbial adaptation across different environments.

Unveiling a high-risk epidemic clone (ST 357) of 'Difficult to Treat Extensively Drug-Resistant' (DT-XDR) Pseudomonas aeruginosa from a burn patient in Bangladesh: A resilient beast revealing coexistence of four classes of beta lactamases.

OBJECTIVES: Pseudomonas aeruginosa (P. aeruginosa) stands out as a key culprit in the colonization of burn wounds, instigating grave infections of heightened severity. In this study, we have performed comparative whole genome analysis of a difficult to treat extensively drug resistant P. aeruginosa isolated from a burn patient in order to elucidate genomic diversity, molecular patterns, mechanisms and genes responsible for conferring antimicrobial resistance and virulence. METHOD: P. aeruginosa SHNIBPS206 was isolated from an infected burn wound of a critically injured burn patient. Whole genome sequencing was carried out and annotated with Prokka. Sequence type, serotype, antimicrobial resistance genes and mechanisms, virulence genes, metal resistance genes and CRISPR/Cas systems were investigated. Later, pangenome analysis was carried out to find out genomic diversity. RESULT: P. aeruginosa SHNIBPS206 (MLST 357, Serotype O11) was resistant to 14 antibiotics including carbapenems and harboured all four classes of beta lactamase producing genes: Class A (blaPME-1, blaVEB-9), Class B (blaNDM-1), Class C (blaPDC-11) and Class D (blaOXA-846). Mutational analysis of Porin D gave valuable insights. Several efflux pump, virulence and metal resistance genes were also detected. Pangenome analysis revealed high genomic diversity among different strains of P. aeruginosa. CONCLUSION: To our knowledge, this is the first report of an extensively drug resistant ST 357 P. aeruginosa from Bangladesh, which is an epidemic high-risk P. aeruginosa clone. Further research and in-depth comprehensive studies are required to investigate the prevalence of such high-risk clone of P. aeruginosa in Bangladesh.

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.

Genomic variability correlates with biofilm phenotypes in multidrug resistant clinical isolates of Pseudomonas aeruginosa.

The multifactorial nature of Pseudomonas aeruginosa biofilm development and genomic variabilities implicates its resistance to conventional antimicrobials and virulence. Therefore, genetic determinants need to be extensively studied to block the early steps of biofilm or already formed biofilms. In this study, a total of 20 multidrug resistant (MDR) clinical P. aeruginosa isolates were evaluated for their biofilm forming abilities and related genes. Of the isolates tested, all of them showed surface attachment tendencies in nutrient limiting conditions, and classified as strong (SBF = 45%), moderate (MBF = 30%) and weak (WBF = 25%) biofilm formers. Complete genome sequencing of representative strong (DMC-27b), moderate (DMC-20c) and weak biofilm former (DMC-30b) isolates was performed. Analysis of biofilm related genes in the sequenced genomes revealed that, 80 of the 88 biofilm related genes possess 98-100% sequence identity to the reference PAO1 strain. Complete and partial sequence data of LecB proteins from tested isolates indicate that isolates containing PA14-like LecB sequences produced strong biofilms. All of the 7 pel operon protein coding genes in weak biofilm former isolate 30b showed significant nucleotide sequence variation with other tested isolates, and their corresponding proteins are 99% identical with the pel operon proteins of PA7. Bioinformatics analyses identified divergent sequence and structural features that separate PA7 like pel operon proteins from reference PAO1-like pel operon. Congo red and pellicle forming assays revealed that the sequence and structure variations may have interfered with the Pel production pathway and resulted in impaired Pel production in isolate 30b that has a PA7 like pel operon. Expression analysis also showed that both pelB and lecB genes were about 5 to 6 folds upregulated after 24 h in SBF 27b in comparison with WBF 30b. Our findings indicate significant genomic divergence in biofilm related genes of P. aeruginosa strains that affect their biofilm phenotypes.

Natural antioxidants from some fruits, seeds, foods, natural products, and associated health benefits: An update.

Antioxidants are compounds that inhibit the oxidation of other molecules and protect the body from the effects of free radicals, produced either by normal cell metabolism or as an effect of pollution and exposure to other external factors and are responsible for premature aging and play a role in cardiovascular disease. degenerative diseases such as cataracts, Alzheimer's disease, and cancer. While many antioxidants are found in nature, others are obtained in synthetic form and reduce oxidative stress in organisms. This review highlights the pharmacological relevance of antioxidants in fruits, plants, and other natural sources and their beneficial effect on human health through the analysis and in-depth discussion of studies that included phytochemistry and their pharmacological effects. The information obtained for this review was collected from several scientific databases (ScienceDirect, TRIP database, PubMed/Medline, Scopus, Web of Science), professional websites, and traditional medicine books. Current pharmacological studies and evidence have shown that the various natural antioxidants present in some fruits, seeds, foods, and natural products have different health-promoting effects. Adopting functional foods with high antioxidant potential will improve the effective and affordable management of free radical diseases while avoiding the toxicities and unwanted side effects caused by conventional medication.

Neurobiological effects of gallic acid: current perspectives.

Gallic acid (GA) is a phenolic molecule found naturally in a wide range of fruits as well as in medicinal plants. It has many health benefits due to its antioxidant properties. This study focused on finding out the neurobiological effects and mechanisms of GA using published data from reputed databases. For this, data were collected from various sources, such as PubMed/Medline, Science Direct, Scopus, Google Scholar, SpringerLink, and Web of Science. The findings suggest that GA can be used to manage several neurological diseases and disorders, such as Alzheimer's disease, Parkinson's disease, strokes, sedation, depression, psychosis, neuropathic pain, anxiety, and memory loss, as well as neuroinflammation. According to database reports and this current literature-based study, GA may be considered one of the potential lead compounds to treat neurological diseases and disorders. More preclinical and clinical studies are required to establish GA as a neuroprotective drug.

Identification of novel inhibitors of high affinity iron permease (FTR1) through implementing pharmacokinetics index to fight against black fungus: An in silico approach.

Mucormycosis is a life-threatening fungal infection, particularly in immunocompromised patients. Mucormycosis has been reported to show resistance to available antifungal drugs and was recently found in COVID-19 as a co-morbidity that demands new classes of drugs. In an attempt to find novel inhibitors against the high-affinity iron permease (FTR1), a novel target having fundamental importance on the pathogenesis of mucormycosis, 11,000 natural compounds were investigated in this study. Virtual screening and molecular docking identified two potent natural compounds [6',7,7,10',10',13'-hexamethylspiro[1,8-dihydropyrano[2,3-g]indole-3,11'-3,13-diazatetracyclo[5.5.2.01,9.03,7]tetradecane]-2,9,14'-trione and 5,7-dihydroxy-3-(2,2,8,8-tetramethylpyrano[2,3-f]chromen-6-yl)chromen-4-one] that effectively bind to the active cavity of FTR1 with a binding affinity of -9.9 kcal/mol. Multiple non-covalent interactions between the compounds and the active residues of this cavity were noticed, which is required for FTR1 inhibition. These compounds were found to have inhibitory nature and meet essential requirements to be drug-like compounds with a considerable absorption, distribution, metabolism, and excretion (ADME) profile with no toxicity probabilities. Molecular dynamics simulation confirms the structural compactness and less conformational variation of the drug-protein complexes maintaining structural stability and rigidity. MM-PBSA and post-simulation analysis predict binding stability of these compounds in the active cavity. This study hypothesizing that these compounds could be a potential inhibitor of FTR1 and will broaden the clinical prospects of mucormycosis.

Anxiolytic-like Effect of Quercetin Possibly through GABA Receptor Interaction Pathway: In Vivo and In Silico Studies.

Scientific evidence suggests that quercetin (QUR) has anxiolytic-like effects in experimental animals. However, the mechanism of action responsible for its anxiolytic-like effects is yet to be discovered. The goal of this research is to assess QUR's anxiolytic effects in mouse models to explicate the possible mechanism of action. After acute intraperitoneal (i.p.) treatment with QUR at a dose of 50 mg/kg (i.p.), behavioral models of open-field, hole board, swing box, and light-dark tests were performed. QUR was combined with a GABAergic agonist (diazepam) and/or antagonist (flumazenil) group. Furthermore, in silico analysis was also conducted to observe the interaction of QUR and GABA (α5), GABA (ß1), and GABA (ß2) receptors. In the experimental animal model, QUR had an anxiolytic-like effect. QUR, when combined with diazepam (2 mg/kg, i.p.), drastically potentiated an anxiolytic effect of diazepam. QUR is a more highly competitive ligand for the benzodiazepine recognition site that can displace flumazenil (2.5 mg/kg, i.p.). In all the test models, QUR acted similar to diazepam, with enhanced effects of the standard anxiolytic drug, which were reversed by pre-treatment with flumazenil. QUR showed the best interaction with the GABA (α5) receptor compared to the GABA (ß1) and GABA (ß2) receptors. In conclusion, QUR may exert an anxiolytic-like effect on mice, probably through the GABA-receptor-interacting pathway.

Cell cycle associated miRNAs as target and therapeutics in lung cancer treatment.

Lung cancer is the primary cause of cancer related deaths worldwide. Limited therapeutic options and resistance to existing drugs are the major hindrances to the clinical success of this cancer. In the past decade, several studies showed the role of microRNA (miRNA) driven cell cycle regulation in lung cancer progression. Therefore, these small nucleotide molecules could be utilized as promising tools in lung cancer therapy. In this review, we highlighted the recent advancements in lung cancer therapy using cell cycle linked miRNAs. By highlighting the roles of the specific cell cycle core regulators affiliated miRNAs in lung cancer, we further outlined how these miRNAs can be explored in early diagnosis and treatment strategies to prevent lung cancer. With the provided information from our review, more medical efforts can ensure a potential breakthrough in miRNA-based lung cancer therapy.

Designing potential siRNA molecules for silencing the gene of the nucleocapsid protein of Nipah virus: A computational investigation.

Nipah virus (NiV), a zoonotic virus, engenders severe infections with noticeable complications and deaths in humans and animals. Since its emergence, it is frightening, this virus has been causing regular outbreaks in various countries, particularly in Bangladesh, India, and Malaysia. Unfortunately, no efficient vaccine or drug is available now to combat this baneful virus. NiV employs its nucleocapsid protein for genetic material packaging, which is crucial for viral replication inside the host cells. The small interfering RNAs (siRNAs) can play a central role in inhibiting the expression of disease-causing viral genes by hybridization and subsequent inactivation of the complementary target viral mRNAs through the RNA interference (RNAi) pathway. Therefore, potential siRNAs as molecular therapeutics against the nucleocapsid protein gene of NiV were designed in this study. First, ten prospective siRNAs were identified using the conserved nucleocapsid gene sequences among all available NiV strains collected from various countries. After that, off-target binding, GC (guanine-cytosine) content, secondary structure, binding affinity with the target, melting temperature, efficacy analysis, and binding capacity with the human argonaute protein 2 (AGO2) of these siRNAs were evaluated to predict their suitability. These designed siRNA molecules bear promise in silencing the NiV gene encoding the nucleocapsid protein and thus can alleviate the severity of this dangerous virus. Further in vivo experiments are recommended before using these designed siRNAs as alternative and effective molecular therapeutic agents against NiV.

Activities and Molecular Mechanisms of Diterpenes, Diterpenoids, and Their Derivatives in Rheumatoid Arthritis.

Diterpenes and their derivatives have many biological activities, including anti-inflammatory and immunomodulatory effects. To date, several diterpenes, diterpenoids, and their laboratory-derived products have been demonstrated for antiarthritic activities. This study summarizes the literature about diterpenes and their derivatives acting against rheumatoid arthritis (RA) depending on the database reports until 31 August 2021. For this, we have conducted an extensive search in databases such as PubMed, Science Direct, Google Scholar, and Clinicaltrials.gov using specific relevant keywords. The search yielded 2708 published records, among which 48 have been included in this study. The findings offer several potential diterpenes and their derivatives as anti-RA in various test models. Among the diterpenes and their derivatives, andrographolide, triptolide, and tanshinone IIA have been found to exhibit anti-RA activity through diverse pathways. In addition, some important derivatives of triptolide and tanshinone IIA have also been shown to have anti-RA effects. Overall, findings suggest that these substances could reduce arthritis score, downregulate oxidative, proinflammatory, and inflammatory biomarkers, modulate various arthritis pathways, and improve joint destruction and clinical arthritic conditions, signs, symptoms, and physical functions in humans and numerous experimental animals, mainly through cytokine and chemokine as well as several physiological protein interaction pathways. Taken all together, diterpenes, diterpenoids, and their derivatives may be promising tools for RA management.

In Silico Identification and Characterization of a Hypothetical Protein From Rhodobacter capsulatus Revealing S-Adenosylmethionine-Dependent Methyltransferase Activity.

Rhodobacter capsulatus is a purple non-sulfur bacteria widely used as a model organism to study bacterial photosynthesis. It exhibits extensive metabolic activities and demonstrates other distinctive characteristics such as pleomorphism and nitrogen-fixing capability. It can act as a gene transfer agent (GTA). The commercial importance relies on producing polyester polyhydroxyalkanoate (PHA), extracellular nucleic acids, and commercially critical single-cell proteins. These diverse features make the organism an exciting and environmentally and industrially important one to study. This study was aimed to characterize, model, and annotate the function of a hypothetical protein (Accession no. CAA71016.1) of R capsulatus through computational analysis. The urf7 gene encodes the protein. The tertiary structure was predicted through MODELLER and energy minimization and refinement by YASARA Energy Minimization Server and GalaxyRefine tools. Analysis of sequence similarity, evolutionary relationship, and exploration of domain, family, and superfamily inferred that the protein has S-adenosylmethionine (SAM)-dependent methyltransferase activity. This was further verified by active site prediction by CASTp server and molecular docking analysis through Autodock Vina tool and PatchDock server of the predicted tertiary structure of the protein with its ligands (SAM and SAH). Normally, as a part of the gene product of photosynthetic gene cluster (PGC), the established roles of SAM-dependent methyltransferases are bacteriochlorophyll and carotenoid biosynthesis. But the STRING database unveiled its association with NADH-ubiquinone oxidoreductase (Complex I). The assembly and regulation of this Complex I is mediated by the gene products of the nuo operon. As a part of this operon, the urf7 gene encodes SAM-dependent methyltransferase. As a consequence of these findings, it is reasonable to propose that the hypothetical protein of interest in this study is a SAM-dependent methyltransferase associated with bacterial NADH-ubiquinone oxidoreductase assembly. Due to conservation of Complex I from prokaryotes to eukaryotes, R capsulatus can be a model organism of study to understand the common disorders which are linked to the dysfunctions of complex I.

Unlocking SGK1 inhibitor potential of bis-[1-N,7-N, pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compounds: a computational study.

SGK1 (Serum and Glucocorticoid Regulated Kinase 1), a serine/threonine kinase that is activated by various stimuli, including serum and glucocorticoids. It controls inflammation, apoptosis, hormone release, neuro-excitability and cell proliferation, all of which play an important role in cancer progression and metastasis. SGK1 was recently proposed as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In this study, molecular docking, physiochemical, toxicological properties and molecular dynamic simulation of the Bis-[1-N,7-N, Pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compoundsand reference EMD638683 against new SGK1 target protein. Compared to the reference inhibitor EMD638683, we choose the best compounds (series 2-6) based on the binding energy (in the range from -11.0 to -10.6 kcal/mol). With the exception of compounds 2 and 6, none of the compounds posed a risk for AMES toxicity or carcinogenicity due to their toxicological properties. 100 ns MD simulation accompanied by MM/PBSA energy calculations and PCA. According to MD simulation results, the binding of compounds 3, 4 and 5 stabilizes the SGK1 structure and causes febrile conformational changes compared to EMD638683. As a result of this research, the final selected compounds 3, 4 and 5 can be used as scaffolds to develop promising SGK1 inhibitors for the treatment of related diseases such as cancer.Communicated by Ramaswamy H. Sarma.

Molecular docking and simulation studies of flavonoid compounds against PBP-2a of methicillin-resistant Staphylococcus aureus.

Methicillin-Resistant Staphylococcus aureus (MRSA), a pathogenic bacterium that causes life-threatening outbreaks such as community-onset and nosocomial infections as emerging 'superbug'. Time and motion study of its virulent property developed resistance against most of the antibiotics such as Vancomycin. Thereby, to curb this problem entails the development of new therapeutic agents. Plant-derived antimicrobial agents have recently piqued people's interest, so in this research, 186 flavonoids compound selected to unmask the best candidates that can act as potent inhibitors against the Penicillin Binding Protein-2a (PBP-2a) of MRSA. Molecular docking performed using PyRx and GOLD suite to determine the binding affinities and interactions between the phytochemicals and the PBP-2a. The selected candidates strongly interact with the different amino acid residues. The 30 ns molecular dynamics (MD) simulations with five top-ranked compounds such as Naringin, Hesperidin, Neohesperidin, Didymin and Icariin validated the docking interactions. These findings are also strongly supported by root-mean-square deviation, root-mean-square fluctuation and the radius of gyration. ADME/T analysis demonstrates that these candidates appear to be safer inhibitors. Our findings point to natural flavonoids as a promising and readily available source of adjuvant antimicrobial therapy against resistant strains in the future.Communicated by Ramaswamy H. Sarma.

Genomic characterization of the dominating Beta, V2 variant carrying vaccinated (Oxford-AstraZeneca) and nonvaccinated COVID-19 patient samples in Bangladesh: A metagenomics and whole-genome approach.

Bangladesh is experiencing a second wave of COVID-19 since March 2021, despite the nationwide vaccination drive with ChAdOx1 (Oxford-AstraZeneca) vaccine from early February 2021. Here, we characterized 19 nasopharyngeal swab (NPS) samples from COVID-19 suspect patients using genomic and metagenomic approaches. Screening for SARS-CoV-2 by reverse transcriptase polymerase chain reaction and metagenomic sequencing revealed 17 samples of COVID-19 positive (vaccinated = 10, nonvaccinated = 7) and 2 samples of COVID-19 negative. We did not find any significant correlation between associated factors including vaccination status, age or sex of the patients, diversity or abundance of the coinfected organisms/pathogens, and the abundance of SARS-CoV-2. Though the first wave of the pandemic was dominated by clade 20B, Beta, V2 (South African variant) dominated the second wave (January 2021 to May 2021), while the third wave (May 2021 to September 2021) was responsible for Delta variants of the epidemic in Bangladesh including both vaccinated and unvaccinated infections. Noteworthily, the receptor binding domain (RBD) region of S protein of all the isolates harbored similar substitutions including K417N, E484K, and N501Y that signify the Beta, while D614G, D215G, D80A, A67V, L18F, and A701V substitutions were commonly found in the non-RBD region of Spike proteins. ORF7b and ORF3a genes underwent a positive selection (dN/dS ratio 1.77 and 1.24, respectively), while the overall S protein of the Bangladeshi SARS-CoV-2 isolates underwent negative selection pressure (dN/dS = 0.621). Furthermore, we found different bacterial coinfections like Streptococcus agalactiae, Neisseria meningitidis, Elizabethkingia anophelis, Stenotrophomonas maltophilia, Klebsiella pneumoniae, and Pseudomonas plecoglossicida, expressing a number of antibiotic resistance genes such as tetA and tetM. Overall, this approach provides valuable insights on the SARS-CoV-2 genomes and microbiome composition from both vaccinated and nonvaccinated patients in Bangladesh.

Genome-wide identification and prediction of SARS-CoV-2 mutations show an abundance of variants: Integrated study of bioinformatics and deep neural learning.

Genomic data analysis is a fundamental system for monitoring pathogen evolution and the outbreak of infectious diseases. Based on bioinformatics and deep learning, this study was designed to identify the genomic variability of SARS-CoV-2 worldwide and predict the impending mutation rate. Analysis of 259044 SARS-CoV-2 isolates identified 3334545 mutations with an average of 14.01 mutations per isolate. Globally, single nucleotide polymorphism (SNP) is the most prevalent mutational event. The prevalence of C > T (52.67%) was noticed as a major alteration across the world followed by the G > T (14.59%) and A > G (11.13%). Strains from India showed the highest number of mutations (48) followed by Scotland, USA, Netherlands, Norway, and France having up to 36 mutations. D416G, F106F, P314L, UTR:C241T, L93L, A222V, A199A, V30L, and A220V mutations were found as the most frequent mutations. D1118H, S194L, R262H, M809L, P314L, A8D, S220G, A890D, G1433C, T1456I, R233C, F263S, L111K, A54T, A74V, L183A, A316T, V212F, L46C, V48G, Q57H, W131R, G172V, Q185H, and Y206S missense mutations were found to largely decrease the structural stability of the corresponding proteins. Conversely, D3L, L5F, and S97I were found to largely increase the structural stability of the corresponding proteins. Multi-nucleotide mutations GGG > AAC, CC > TT, TG > CA, and AT > TA have come up in our analysis which are in the top 20 mutational cohort. Future mutation rate analysis predicts a 17%, 7%, and 3% increment of C > T, A > G, and A > T, respectively in the future. Conversely, 7%, 7%, and 6% decrement is estimated for T > C, G > A, and G > T mutations, respectively. T > G\A, C > G\A, and A > T\C are not anticipated in the future. Since SARS-CoV-2 is mutating continuously, our findings will facilitate the tracking of mutations and help to map the progression of the COVID-19 intensity worldwide.

Draft genome sequence of a carbapenem-resistant clinical Acinetobacter baumannii revealing co-existence of four classes of ß-lactamases.

OBJECTIVES: Nosocomial carbapenem-resistant Acinetobacter baumannii is a challenge in the treatment of intensive care unit (ICU) patients. The presence of antimicrobial resistance genes (ARGs) and mobile genetic elements can further complicate effects to combat antibiotic resistance in this post-antibiotic era. The aim of this study was to analyse the molecular basis of carbapenem resistance in A. baumannii strain DMC-32a. METHODS: Strain DMC-32a, isolated from a wound swab of an ICU patient, was screened phenotypically and genotypically for carbapenem resistance. The isolate was subjected whole-genome sequencing (WGS) to investigate the resistance mechanisms. RESULTS: Strain DMC-32a was resistant to all tested antibiotics belonging to seven classes, except for the polymyxins. MICs determined against imipenem and meropenem were 512 mg/L and >512 mg/L, respectively. Gene-specific PCR confirmed the presence of blaNDM-1 and intI1. WGS confirmed the isolate as sequence type ST1053, the presence of four classes of ß-lactamases [A (blaPER-7, blaTEM-116), B (blaNDM-1), C (blaADC-26) and D (blaOXA-23, blaOXA-51)], and four genes encoding aminoglycoside-modifying enzymes [aph(6)-Id, aph(3'')-Ib, aph(3')-VI and ant(3'')-IIc] conferring resistance to streptomycin, amikacin, kanamycin and spectinomycin. The analysis also confirmed the presence of a class 1 integron gene cassette harbouring ARGs to rifamycin (arr-2) and phenicols (cmlA5). No plasmid replicon was found from the sequence data. CONCLUSION: The co-existence of four ß-lactamase classes in A. baumannii DMC-32a has not been reported previously from Bangladesh and not in this ST elsewhere. The emergence of such a nosocomial pathogen creates the need for effective therapeutics for critically-ill patients and for controlling hospital-acquired infections.

Cytotoxicity of synthetic derivatives against breast cancer and multi-drug resistant breast cancer cell lines: a literature-based perspective study.

Cancer is the second most killer worldwide causing millions of people to lose their lives every year. In the case of women, breast cancer takes away the highest proportion of mortality rate than other cancers. Due to the mutation and resistance-building capacity of different breast cancer cell lines against conventional therapies, this death rate is on the verge of growth. New effective therapeutic compounds and treatment method is the best way to look out for in this critical time. For instance, new synthetic derivatives/ analogues synthesized from different compounds can be a ray of hope. Numerous synthetic compounds have been seen enhancing the apoptosis and autophagic pathway that directly exerts cytotoxicity towards different breast cancer cell lines. To cease the ever-growing resistance of multi-drug resistant cells against anti-breast cancer drugs (Doxorubicin, verapamil, tamoxifen) synthetic compounds may play a vital role by increasing effectivity, showing synergistic action. Many recent and previous studies have reported that synthetic derivatives hold potentials as an effective anti-breast cancer agent as they show great cytotoxicity towards cancer cells, thus can be used even vastly in the future in the field of breast cancer treatment. This review aims to identify the anti-breast cancer properties of several synthetic derivatives against different breast cancer and multi-drug-resistant breast cancer cell lines with their reported mechanism of action and effectivity.

Prediction of the Effects of Variants and Differential Expression of Key Host Genes ACE2, TMPRSS2, and FURIN in SARS-CoV-2 Pathogenesis: An In Silico Approach.

A new strain of the beta coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is solely responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic. Although several studies suggest that the spike protein of this virus interacts with the cell surface receptor, angiotensin-converting enzyme 2 (ACE2), and is subsequently cleaved by TMPRSS2 and FURIN to enter into the host cell, conclusive insight about the interaction pattern of the variants of these proteins is still lacking. Thus, in this study, we analyzed the functional conjugation among the spike protein, ACE2, TMPRSS2, and FURIN in viral pathogenesis as well as the effects of the mutations of the proteins through the implementation of several bioinformatics approaches. Analysis of the intermolecular interactions revealed that T27A (ACE2), G476S (receptor-binding domain [RBD] of the spike protein), C297T (TMPRSS2), and P812S (cleavage site for TMPRSS2) coding variants may render resistance in viral infection, whereas Q493L (RBD), S477I (RBD), P681R (cleavage site for FURIN), and P683W (cleavage site for FURIN) may lead to increase viral infection. Genotype-specific expression analysis predicted several genetic variants of ACE2 (rs2158082, rs2106806, rs4830971, and rs4830972), TMPRSS2 (rs458213, rs468444, rs4290734, and rs6517666), and FURIN (rs78164913 and rs79742014) that significantly alter their normal expression which might affect the viral spread. Furthermore, we also found that ACE2, TMPRSS2, and FURIN proteins are functionally co-related with each other, and several genes are highly co-expressed with them, which might be involved in viral pathogenesis. This study will thus help in future genomics and proteomics studies of SARS-CoV-2 and will provide an opportunity to understand the underlying molecular mechanism during SARS-CoV-2 pathogenesis.