Association between DPP6 gene rs10260404 polymorphism and increased risk of sporadic amyotrophic lateral sclerosis (sALS): a meta-analysis.

BACKGROUND: Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease characterized by continuous diminution of motor neurons in the brain and spinal cord. Earlier studies indicated that the DPP6 gene variant has a role in the development of sALS. This meta-analysis was designed to uncover the role of rs10260404 polymorphism of the DPP6 gene and its association with sALS. METHODS: All case-control articles published prior to October 2022 on the association between DPP6 (rs10260404) polymorphism and sALS risk were systematically extracted from different databases which include PubMed, PubMed Central, and Google Scholar. Overall odds ratios (ORs) and "95% confidence intervals (CIs)" were summarized for various genetic models. Subgroup and heterogeneity assessments were performed. Egger's and "Begg's tests were applied to evaluate publication bias. Trial sequential analysis (TSA) and false-positive report probability (FPRP) were performed. RESULTS: Nine case-control studies containing 4202 sALS cases and 4444 healthy controls were included in the meta-analysis. A significant association of the DPP6 (rs10260404) variant with an increased sALS risk in overall pooled subjects under allelic model [C allele vs. T allele, OR = 1.149, 95% CI (1.010-1.307), p-value = 0.035], dominant model [CC + CT vs. TT, OR = 1.165, 95% CI (1.067-1.273), p-value = 0.001], and homozygote comparison [CC vs. TT, OR = 1.421, 95% CI (1.003-2.011), p-value = 0.048] were observed. Moreover, in subgroup analysis by nationality, remarkable associations were detected in Dutch, Irish, American, and Swedish under allelic, dominant, and homozygote models. Additionally, stratification analysis by ethnicity exhibited an association with sALS risk among Caucasians and Americans under different genetic models. Interestingly, none of the models found any significant association with Asians. CONCLUSION: The present meta-analysis indicates that DPP6 (rs10260404) polymorphism could be a candidate risk factor for sALS predisposition.

Modeling mRNA-based vaccine YFV.E1988 against yellow fever virus E-protein using immuno-informatics and reverse vaccinology approach.

To surmount constraints of live-attenuated vaccines we have in silico designed mRNA vaccine using envelope protein as a target antigen. From the alignment of 216 envelope proteins, a consensus sequence was obtained which was used for codon optimization. The secondary structure was predicted using Mfold and RNAfold tool. IEDB server was used to predict T-cell and B-cell epitopes, epitope conservancy, immunogenicity, and population coverage. Antigenicity, allergenicity, and toxicity were predicted using Vaxijen, AllerTOP, and ToxinPred tools, respectively. Interactions between MHC and identified epitopes were confirmed by docking and molecular dynamics simulation. In silico immune simulation was done using the C-ImmSim server. Vaccine peptide 3D structure was predicted and validated based on the Ramachandran plot. Finally, we designed the vaccine construct for simulating restriction cloning using the SnapGene tool. Our optimization of consensus E protein is highly immunogenic, conserved, has immune-dominance characteristics, and suggests high translational efficiency in the host cell. We validated the presence of T and B cell epitopes and interestingly we found one CD4+ and four CD8+ T-cell epitopes that satisfied all the criteria of an effective vaccine candidate. We found high-affinity interactions between epitope and HLA alleles that can stimulate the T-cell response. The immune simulation verified the immune cell response to eliminate the antigen. To ensure effective expression of the vaccine, a circular plasmid has been designed using in silico cloning approach for the in vitro transcription process. Obtained results suggest that the vaccine YFV.E1988 will elicit specific immune responses against YFV and it is a potential model ready for laboratory testing. HighlightsThe envelope (E) protein was found to be highly conserved and it has the potential to protect individuals against YFV infection.YFV.E1988 vaccine has been capable to stimulate both the CD8+ and CD4+ T cell, solving the major limitations of the current live-attenuated vaccines against YFV.Presence of T- and B-cell epitopes across the antigen have been validated using several computational tools.Molecular docking ensured the epitope-allele binding and protein-TLR/MR interaction. The vaccine was found to be immune-stimulatory, safe, and stable.The codons were optimized for efficient translation and increased stability into the human host. The UTR regions and poly (A) tail used for the development of YFV.E1988 showed immune stimulatory potential in several experiments.Communicated by Ramaswamy H. Sarma.

Deciphering the role of predicted miRNAs of polyomaviruses in carcinogenesis.

Human polyomaviruses are relatively common in the general population. Polyomaviruses maintain a persistent infection after initial infection in childhood, acting as an opportunistic pathogen in immunocompromised populations and their association has been linked to carcinogenesis. A comprehensive understanding of the underlying molecular mechanisms of carcinogenesis in consequence of polyomavirus infection remains elusive. However, the critical role of viral miRNAs and their potential targets in modifying the transcriptome profile of the host remains largely unknown. Polyomavirus-derived miRNAs have the potential to play a substantial role in carcinogenesis. Employing computational approaches, putative viral miRNAs along with their target genes have been predicted and possible roles of the targeted genes in many significant biological processes have been obtained. Polyomaviruses have been observed to target intracellular signal transduction pathways through miRNA-mediated epigenetic regulation, which may contribute to cancer development. In addition, BKPyV-infected human renal cell microarray data was coupled with predicted target genes and analysis of the downregulated genes indicated that viruses target multiple signaling pathways (e.g. MAPK signaling pathway, PI3K-Akt signaling pathway, PPAR signaling pathway) in the host as well as turning off several tumor suppression genes (e.g. FGGY, EPHX2, CACNA2D3, CDH16) through miRNA-induced mechanisms, assuring cell transformation. This study provides a conceptual framework for the underlying molecular mechanisms involved in the course of carcinogenesis upon polyomavirus infection.

Determinants of the Early Childhood Development Index among children aged < 5 years in Bangladesh, Costa Rica and Ghana: a comparative study.

BACKGROUND: Early child development is a crucial factor for children that controls health and well-being in later life. AIMS: To determine the influence of sociodemographic factors on the Early Child Development Index (ECDI) among children aged < 5 years. METHODS: The analysis was performed using cross-sectional survey data from 2019, 2017-2018 and 2018 Multiple Indicator Cluster Surveys from Bangladesh, Ghana and Costa Rica, respectively. We used the χ2 test for bivariate analysis and binary logistic regression model for multivariate analysis for all 3 countries. All the statistical analyses were performed with IBM SPSS version 25 and R version 4.0.0. RESULTS: Child age and sex, followed by maternal education level, economic status, child nutritional status, reading children's books, and maternal functional difficulties had the greatest effect on ECDI. Children aged 36-47 months had lower odds of development than those aged 48-59 months, and boys had lower odds of development than girls in Bangladesh, Costa Rica and Ghana. Urban children had lower odds of development than rural children in Costa Rica but higher odds in Ghana. CONCLUSION: We recommend that governments should take the necessary steps to enhance children's early development and well-being in all 3 countries by raising education, improving economic conditions and providing balanced nutrition.

Fenugreek steroidal saponins hinder osteoclastogenic bone resorption by targeting CSF-1R which diminishes the RANKL/OPG ratio.

Osteoporosis is skeletal fragility caused by the excessive bone resorption due to osteoclastogenesis. But current drugs are less bioavailable and possess higher toxicity. Our study was conducted to identify safe oral bioavailable drugs from Fenugreek steroidal saponins and to delineate underlying mechanism of them to lower the osteoclastogenic bone resorption. We observed higher molecular docked binding affinities in finally selected eight hit compounds within the range of -11.0 to -10.1 kcal/mol which was greater than currently used drugs. Molecular Dynamics simulation with Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Solvent Accessible Surface Area (SASA) and Gyration trajectory projection reinforced the stability of the protein-ligand complexes. Pharmacokinetics analysis confirmed bioavailability of seven compounds out of eight, and drug likeliness and bioavailability profile evaluation indicated that they all are eligible to be developed as a potent oral inhibitor of CSF-1R. By literature mining knowledge-driven analysis, RNAseq data and Molecular Dynamics Simulation, we proposed that, the hit derivatives block the CSF-1/CSF-1R induced phosphorylation signaling pathway in both osteoclast and osteoblast resulting in hindrance of RANK expression and formation of Reactive oxygen species (ROS) in osteoclast and osteoblast respectively, thus declines the RANKL/OPG ratio, lowering the osteoclast survival, proliferation and differentiation.

Sociodemographic factors and early marriage among women in Bangladesh, Ghana and Iraq: An illustration from Multiple Indicator Cluster Survey.

Early marriage is a form of violation of child rights to grow and develop. The Sustainable Development Goals had included early marriage in target 5.3, aiming to eliminate by 2030. This study examines the socio-demographic factors associated with women's early marriage in Bangladesh, Ghana, and Iraq using information extracted from 2019, 2017-2018, and 2018 Multiple Indicator Cluster Surveys (MICSs) of Bangladesh, Ghana, and Iraq, respectively. The chi-square test examined the association between socio-demographic factors and early marriage separately in all three countries. In logistic regression, key factors were primarily evaluated for determining effects on early marriage separately in all three countries. The mean age of the mother at first marriage was found to be 16.86, 20.23, and 20.05 years in Bangladesh, Ghana, and Iraq successively. According to surveys conducted in Bangladesh, Ghana, and Iraq, education levels of household heads and women, wealth status, mass media, number of household members, and residence were significant factors linked to early marriage. The odds of getting married early were significantly higher among women with no formal education and primary education than women with secondary or higher education in all three countries. In terms of economic status, a negative association was found between wealth status and early marriage in both Bangladesh and Ghana. Based on the findings, the study recommended that government take the necessary steps to reduce child marriage in all three countries by raising women's education and campaigning women by media to harmful effects of early marriage, particularly women from low-income families.

Regional variations of child development index in Bangladesh.

Early development is a vital phase in childhood life. The study aimed to identify factors that were associated with the early development of 36-59 months children in Bangladesh. The findings of this study will formulate the design of appropriate policy and programmed responses. Utilizing Multiple Indicator Cluster Survey data, influencing components of child development status were evaluated for both rural and urban areas of Bangladesh. A total of 23,099 children under the age of five were included in this analysis. Chi-square analysis was conducted to assess the association between outcome variables and selected covariates. At the same time, this study uses two separate multivariate binary logistics regression models (respectively for urban areas and rural areas) to determine the risk factors that are primarily related to child development. Our research estimates that more than 70 percent of children develop early throughout the country. The multivariate analysis on the determinants of child development index among children aged between 36 and 59 months old regarding residence discovered a significant impact on child age and sex, maternal education, child education, wealth status, reading children's books. The adjusted odds of child nutrition status, playthings, and maternal functional difficulties have had a major impact on early child development in rural Bangladesh. Based on the findings, educational status, nutritional status, wealth-status, and some determinants of children care the most noteworthy findings in this study. Hence, policymakers should emphasize on such factors for improving children's development in residence.