Modified oxymatrine as novel therapeutic inhibitors against Monkeypox and Marburg virus through computational drug design approaches.

Global impact of viral diseases specially Monkeypox (mpox) and Marburg virus, emphasizing the urgent need for effective drug interventions. Oxymatrine is an alkaloid which has been selected and modified using various functional groups to enhance its efficacy. The modifications were evaluated using various computatioanal analysis such as pass prediction, molecular docking, ADMET, and molecular dynamic simulation. Mpox and Marburg virus were chosen as target diseases based on their maximum pass prediction spectrum against viral disease. After that, molecular docking, dynamic simulation, DFT, calculation and ADMET prediction were determined. The main objective of this study was to enhance the efficacy of oxymatrine derivatives through functional group modifications and computational analyses to develop effective drug candidates against mpox and Marburg viruses. The calculated binding affinities indicated strong interactions against both mpox virus and Marburg virus. After that, the molecular dynamic simulation was conducted at 100 ns, which confirmed the stability of the binding interactions between the modified oxymatrine derivatives and target proteins. Then, the modified oxymatrine derivatives conducted theoretical ADMET profiling, which demonstrated their potential for effective drug development. Moreover, HOMO-LUMO calculation was performed to understand the chemical reactivity and physicochemical properties of compounds. This computational analysis indicated that modified oxymatrine derivatives for the treatment of mpox and Marburg virus suggested effective drug candidates based on their binding affinity, drug-like properties, stability and chemical reactivity. However, further experimental validation is necessary to confirm their clinical value and efficacy as therapeutic candidates.

XRCC1 and XPD polymorphisms: clinical outcomes and risk of prostate cancer in Bangladeshi population.

BACKGROUND: In Bangladesh, only a fraction of prostate cancer patients are diagnosed annually due to lack of symptom awareness and screening challenges, resulting in high mortality. Aiming to improve screening methods, we evaluated X-ray cross-complementing gene 1 (XRCC1) Arg194Gln and Xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms to determine their relevance as potential markers for predicting prostate cancer risk, severity and clinical parameters in Bangladeshi population. METHODS AND RESULTS: This study included 132 prostate cancer patients and 135 healthy controls. Genotype analysis was done from blood samples by the PCR-RFLP method. The XRCC1 Trp/Trp genotype was associated with prostate cancer (ORadj = 5.51; 95% CI = 1.13-26.78; p-value = 0.03) compared to Arg/Arg genotype. No significant association was found between the XPD variants and prostate cancer risk. The XRCC1 Trp/Trp genotype increased prostate cancer risk in smokers and non-smokers but was statistically non-significant. In individuals without a family history of cancer, the XRCC1 Trp/Trp genotype had a non-significant 4.64-fold higher risk (ORadj=4.64; 95% CI = 0.88-24.36; p-value = 0.07), while the XPD Gln/Gln had a 2.66-fold non-significant higher risk (ORadj=2.66; 95% CI = 0.88-8.10; p-value = 0.09). The XRCC1 Trp/Trp variant was associated with hematuria risk, higher mean serum creatinine, and mean prostate-specific antigen (PSA) levels in prostate cancer patients. The XPD Gln/Gln variant was only associated with higher mean serum creatinine levels. CONCLUSION: Our findings suggest that XRCC1 screening may be used as a biomarker for prostate cancer to improve early diagnosis in Bangladesh.

Acceptability, cost-effectiveness, and capacity of a facility-based seasonal influenza vaccination among high-risk groups: a study protocol in selected tertiary care hospitals of Bangladesh.

BACKGROUND: In Bangladesh, seasonal influenza imposes considerable disease and economic burden, especially for those at high-risk of severe disease. The most successful approach for influenza prevention is the administration of a vaccine. Many poor and middle-income nations, including Bangladesh, do not have a national strategy or program in place for seasonal influenza vaccines, despite the World Health Organization's (WHO) advice to prioritize high-risk populations. Additionally, there is a scarcity of substantial data on the cost-effectiveness of seasonal influenza vaccination in these countries. The aim of our study is to determine acceptability, health beliefs, barriers, and intention of receiving influenza vaccine among high-risk populations, assess the cost-effectiveness of implementing a facility-based seasonal influenza vaccination programme, and investigate the required capacity for a potential seasonal influenza vaccination programme. METHODS: We will undertake this study following STROBE guidelines. We will conduct the study in inpatient and outpatient departments of three selected tertiary-level hospitals leveraging the ongoing hospital-based influenza surveillance (HBIS) platform. The study population will include the WHO-defined four high-risk groups excluding healthcare workers: children six months to eight years, pregnant women, elderly ≥ 60 years, and adults with chronic diseases. We will collect quantitative data on participants' acceptability, health beliefs, barriers, and vaccination intentions using the health belief model (HBM) from patients meeting the criteria for high-risk populations attending two public tertiary-level hospitals. In one of the two public tertiary-level hospitals, we will arrange an influenza vaccination campaign before the influenza season, where the vaccine will be offered free of cost to high-risk patients, and in the second hospital, vaccination will not be offered. Both the vaccinated and unvaccinated participants will then be followed-up once a month for one year to record any influenza-like illness, hospitalization, and death. Additional data for objective two will be collected from patients with symptoms of influenza-like illness (ILI) and severe acute respiratory infection (SARI) at one public and one private hospital to determine both direct and indirect costs associated with influenza illness. We will estimate the required number of influenza vaccines, safe injections, and total storage volume utilizing secondary data. We will use a deterministic Markov decision-analytic model to estimate the cost-effectiveness of facility-based influenza vaccination in Bangladesh. DISCUSSION: The results of this study will enable the National Immunization Technical Advisory Group and the Ministry of Health & Family Welfare of Bangladesh to decide what steps to take to develop and implement an influenza vaccination strategy targeting high-risk populations. TRIAL REGISTRATION: The Clinicaltrials.gov registration number is NCT05996549. The registration for the protocol version 2.0 took place in August 2023, with the initial participant being enrolled in March 2022.

An in-depth analysis of COVID-19 treatment: Present situation and prospects.

Coronavirus disease 2019 (COVID-19) the most contagious infection caused by the unique type of coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), produced a global pandemic that wreaked havoc on the health-care system, resulting in high morbidity and mortality. Several methods were implemented to tackle the virus, including the repurposing of existing medications and the development of vaccinations. The purpose of this article is to provide a complete summary of the current state and future possibilities for COVID-19 therapies. We describe the many treatment classes, such as antivirals, immunomodulators, and monoclonal antibodies, that have been repurposed or developed to treat COVID-19. We also looked at the clinical evidence for these treatments, including findings from observational studies and randomized-controlled clinical trials, and highlighted the problems and limitations of the available evidence. Furthermore, we reviewed existing clinical trials and prospective COVID-19 therapeutic options, such as novel medication candidates and combination therapies. Finally, we discussed the long-term consequences of COVID-19 and the importance of ongoing research into the development of viable treatments. This review will help physicians, researchers, and policymakers to understand the prevention and mitigation of COVID-19.

Isolation and Characterization of One New Natural Compound with Other Potential Bioactive Secondary Metabolites from Glycosmis cyanocarpa (Blume) Spreng. (Family: Rutaceae).

Glycosmis cyanocarpa (Blume) Spreng is a plant in the Rutaceae family and a species in the Glycosmis genus that has received little attention. Therefore, this research aimed to report the chemical and biological analysis of Glycosmis cyanocarpa (Blume) Spreng. The chemical analysis involved the isolation and characterization of secondary metabolites through an extensive chromatographic study, and the structures of these metabolites were elucidated on the basis of a detailed analysis of NMR and HRESIMS spectroscopic data and by comparison with those of related compounds reported in the literature. Different partitions of the crude ethyl acetate (EtOAc) extract were evaluated for antioxidant, cytotoxic, and thrombolytic potentials. In chemical analysis, one new phenyl acetate derivative, namely 3,7,11,15-tetramethylhexadec-2-en-1-yl 2-phenylacetate (1), along with four known compounds N-methyl-3-(methylthio)-N-(2-phenylacetyl) acrylamide (2), penangin (3), ß-Caryophyllene oxide (4), and acyclic diterpene-phytol (5) were isolated for the first time from the stem and leaf of the plant. The ethyl acetate fraction showed significant free radical scavenging activity with an IC50 value of 11.536 µg/mL compared to standard ascorbic acid (4.816 µg/mL). In the thrombolytic assay, the dichloromethane fraction showed the maximum thrombolytic activity of 16.42% but was still insignificant compared to the standard streptokinase (65.98%). Finally, in a brine shrimp lethality bioassay, the LC50 values of dichloromethane, ethyl acetate, and aqueous fractions were found to be 0.687 µg/mL, 0.805 µg/mL, and 0.982 µg/mL which are significant compared to the standard vincristine sulfate of 0.272 µg/mL.

Robust Identification of Differential Gene Expression Patterns from Multiple Transcriptomics Datasets for Early Diagnosis, Prognosis, and Therapies for Breast Cancer.

Background and Objectives: Breast cancer (BC) is one of the major causes of cancer-related death in women globally. Proper identification of BC-causing hub genes (HubGs) for prognosis, diagnosis, and therapies at an earlier stage may reduce such death rates. However, most of the previous studies detected HubGs through non-robust statistical approaches that are sensitive to outlying observations. Therefore, the main objectives of this study were to explore BC-causing potential HubGs from robustness viewpoints, highlighting their early prognostic, diagnostic, and therapeutic performance. Materials and Methods: Integrated robust statistics and bioinformatics methods and databases were used to obtain the required results. Results: We robustly identified 46 common differentially expressed genes (cDEGs) between BC and control samples from three microarrays (GSE26910, GSE42568, and GSE65194) and one scRNA-seq (GSE235168) dataset. Then, we identified eight cDEGs (COL11A1, COL10A1, CD36, ACACB, CD24, PLK1, UBE2C, and PDK4) as the BC-causing HubGs by the protein-protein interaction (PPI) network analysis of cDEGs. The performance of BC and survival probability prediction models with the expressions of HubGs from two independent datasets (GSE45827 and GSE54002) and the TCGA (The Cancer Genome Atlas) database showed that our proposed HubGs might be considered as diagnostic and prognostic biomarkers, where two genes, COL11A1 and CD24, exhibit better performance. The expression analysis of HubGs by Box plots with the TCGA database in different stages of BC progression indicated their early diagnosis and prognosis ability. The HubGs set enrichment analysis with GO (Gene ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways disclosed some BC-causing biological processes, molecular functions, and pathways. Finally, we suggested the top-ranked six drug molecules (Suramin, Rifaximin, Telmisartan, Tukysa Tucatinib, Lynparza Olaparib, and TG.02) for the treatment of BC by molecular docking analysis with the proposed HubGs-mediated receptors. Molecular docking analysis results also showed that these drug molecules may inhibit cancer-related post-translational modification (PTM) sites (Succinylation, phosphorylation, and ubiquitination) of hub proteins. Conclusions: This study's findings might be valuable resources for diagnosis, prognosis, and therapies at an earlier stage of BC.

Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice.

Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

Insight rifampicin-resistant (rpoB) mutation in Pseudomonas stutzeri leads to enhance the biosynthesis of secondary metabolites to survive against harsh environments.

In this study, a wild-type and five distinct rifampicin-resistant (Rifr) rpoB mutants of Pseudomonas stutzeri (i.e., Q518R, D521Y, D521V, H531R and I614T) ability were investigated against harsh environments (particularly nutritional complexity). Among these, the robust Rifr phenotype of P. Stutzeri was associated only with base replacements of the amino deposits. The use of carboxylic and amino acids significantly increased in various Rifr mutants than that of wild type of P. stutzeri. The assimilation of carbon and nitrogen (N) sources of Rifr mutants' confirmed that the organism maintains the adaptation in nutritionally complex environments. Acetylene reduction assay at different times also found the variability for N-fixation in all strains. Among them, the highest nitrogenase activity was determined in mutant 'D521V'. The assimilation of carbon and nitrogen sources of P. stutzeri and its Rifr mutants ensures that the organism maintains the adaptability in nutritionally complex environments through fixing more nitrogen.

Seasonal influenza vaccine uptake among healthcare workers in tertiary care hospitals, Bangladesh: Study protocol for influenza vaccine supply and awareness intervention.

BACKGROUND: Healthcare workers (HCWs), such as doctors, nurses, and support staffs involved in direct or indirect patient care, are at increased risk of influenza virus infections due to occupational exposures. Vaccination is the most effective way to prevent influenza. Despite the World Health Organization (WHO) recommendations, Bangladesh lacks a seasonal influenza vaccination policy for HCWs, and thus vaccination rates remain low. The current project aims to investigate the effect of interventions on influenza vaccine awareness and availability of vaccine supply, explore HCWs' knowledge and perceptions about influenza vaccination, understand the barriers and motivators for influenza vaccine uptake, and understand policymakers' views on the practicality of influenza vaccination among HCWs. METHOD: We will conduct the study at four tertiary care teaching hospitals in Bangladesh, using a cluster randomized controlled trial approach, with the hospital as the unit of randomization and intervention. The study population will include all types of HCWs.The four different types of intervention will be randomly allocated and implemented in four study hospitals separately. The four interventions will be: i) ensuring the availability of influenza vaccine supply; ii) developing influenza vaccine awareness; iii) both ensuring influenza vaccine supply and developing influenza vaccine awareness and iv) control arm with no intervention. Both quantitative and qualitative approaches will be applied to assess the intervention effect. We will estimate the Difference in Differences (DID) with 95% CI of the proportion of vaccine uptake between each intervention and control (non-intervention) arm, adjusting for the clustering effect. The qualitative data will be summarised using a framework matrix method. DISCUSSION: The results of this study will inform the development and implementation of a context-specific strategy to enhance influenza vaccination rates among Bangladeshi HCWs. TRIAL REGISTRATION: Clinicaltrials.gov NCT05521763. Version 2.0 was registered in September 2022, and the first participant enrolled in March 2022. Retrospectively registered.

Trappc9 Deficiency Impairs the Plasticity of Stem Cells.

Genetic mutations of trappc9 cause intellectual disability with the atrophy of brain structures and variable obesity by poorly understood mechanisms. Trappc9-deficient mice develop phenotypes resembling pathological changes in humans and appear overweight shortly after weaning, and thus are useful for studying the pathogenesis of obesity. Here, we investigated the effects of trappc9 deficiency on the proliferation and differentiation capacity of adipose-derived stem cells (ASCs). We isolated ASCs from mice before overweight was developed and found that trappc9-null ASCs exhibited signs of premature senescence and cell death. While the lineage commitment was retained, trappc9-null ASCs preferred adipogenic differentiation. We observed a profound accumulation of lipid droplets in adipogenic cells derived from trappc9-deficient ASCs and marked differences in the distribution patterns and levels of calcium deposited in osteoblasts obtained from trappc9-null ASCs. Biochemical studies revealed that trappc9 deficiency resulted in an upregulated expression of rab1, rab11, and rab18, and agitated autophagy in ASCs. Moreover, we found that the content of neural stem cells in both the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus vastly declined in trappc9-null mice. Collectively, our results suggest that obesity, as well as brain structure hypoplasia induced by the deficiency of trappc9, involves an impairment in the plasticity of stem cells.