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Once dismissed as transcriptional artifacts, noncoding RNAs (ncRNAs) have gained recognition in recent years for their ability to participate in gene regulation, as well as their ability to encode functional molecules referred to as ncRNA-encoded peptides (ncPEPs). The discovery of ncPEPs has opened new avenues in proteomics and genomics research, revealing biological mechanisms that were previously unexplored. This review presents an extensive overview of the computational tools, databases, and in silico strategies used to identify ncRNA-encoded peptides across all major ncRNA classes, including long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and primary microRNAs (pri-miRNAs). Furthermore, we outline publicly available databases that compile experimentally validated and computationally predicted ncPEPs across multiple species, enabling systematic annotation and cross-referencing of candidate peptides. By highlighting the current challenges and emerging methodologies, we emphasize how computational methods continue to advance our ability to uncover hidden functional peptides within the noncoding transcriptome. These developments provide a framework for validating ncPEPs and elucidating their biological significance across diverse systems.

Bacillus velezensis is a bacterium widely recognized for its biocontrol properties and ability to promote plant growth. This study presents the whole-genome sequence of B. velezensis B26, a newly identified strain isolated from chicken carcass soil in Udupi, India. The bacterium showed strong activity against fungal pathogens and exhibited diverse enzymatic activities. The whole-genome sequencing was executed using Illumina technologies. Assembly revealed that strain B26 possesses a genome of 3,946,698-bp with a G+C content of 46.3%. Genome annotation identified 3776 protein-coding genes, 1 rRNA gene, 50 tRNA genes, 5 ncRNA genes, and 59 pseudogenes. Functional analysis of the B. velezensis B26 genome revealed 216 genes involved in carbohydrate metabolism, 3 genes in potassium metabolism, 148 genes linked for cofactors, vitamins, prosthetic groups and pigments, 10 genes involved in phosphorus metabolism, 24 genes associated with iron acquisition and metabolism, 20 genes for nitrogen metabolism, 6 genes involved in sulfur metabolism, 6 genes in secondary metabolism, 12 genes associated with metabolism of aromatic compounds, 43 genes involved in stress response and 36 genes associated with virulence, disease and defence. The raw sequence data generated in this work have been deposited in the NCBI database and the genome sequence is available under the accession number JAYKOV000000000. These genomic data provide insight into the biocontrol ability and plant-growth promoting capabilities of B. velezensis B26.

Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5-methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high-grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes (ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%–100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer.

Background Constitutively activated neutrophil extracellular traps (NETs) have been implicated in the impeded response to infections in Type 2 Diabetes (T2D). However, immuno-metabolic factors contributing to functional plasticity of neutrophils in T2D associated infections are not known. Methods Using both human and mice model of sepsis with either diabetic or non-diabetic background, we investigated functionally confined neutrophil subpopulations either executing phagocytosis or NETosis. An integrated analysis of cytokines regulating granulopoiesis, RNAseq of NETs forming neutrophils and metabolomics was performed. Mitochondrial function was assessed via measuring mitochondrial membrane potential, cellular oxygen consumption rate and mitophagy. Results We identified neutrophil subpopulations either executing phagocytosis or NETosis. Proportions of these functionally restricted neutrophils are significantly altered in T2D and fail to elicit an immune response upon induction of sepsis. Integrated analysis involving cytokines, transcriptome and metabolome data revealed perturbed immunometabolic axis in T2D models majorly effecting mitochondrial metabolism. Molecular dynamic simulations indicate deformed lipid densities and disrupted inner mitochondrial membrane. T2D neutrophils showed decrease in mitochondrial membrane potential, cellular oxygen consumption rate and mitophagy. Arachidonic acid supplementation activated mitochondrial ROS and restored NETs formation in T2D upon sepsis. Conclusions In mouse models, along with preliminary findings in human subjects, our study provides novel and correlative insights into the relationship between metabolic changes and neutrophil dysfunction in T2D-associated sepsis, exploring immuno-metabolism as a therapeutic target to improve neutrophil function.

Cervical cancer (CC) is a key contributor to cancer‐related mortality in several countries. The identification of molecular markers and the underlying mechanism may help improve CC management. We studied the regulation and biological function of the chromosome 14 microRNA cluster (C14MC; miR‐379/miR‐656) in CC. Most C14MC members exhibited considerably lower expression in CC tissues and cell lines in The Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma patient cohorts. Bisulfite Sanger sequencing revealed hypermethylation of the C14MC promoter in CC tissues and cell lines. 5‐aza‐2 deoxy cytidine treatment reactivated expression of the C14MC members. We demonstrated that C14MC is a methylation‐regulated miRNA cluster via artificial methylation and luciferase reporter assays. C14MC downregulation correlated with poor overall survival and may promote metastasis. C14MC activation via the lentiviral‐based CRISPRa approach inhibited growth, proliferation, migration, and invasion; enhanced G2/M arrest; and induced senescence. Post‐transcriptional regulatory network analysis of C14MC transcriptomic data revealed enrichment of key cancer‐related pathways, such as metabolism, the cell cycle, and phosphatidylinositol 3‐kinase (PI3K)–AKT signaling. Reduced cell proliferation, growth, migration, invasion, and senescence correlated with the downregulation of active AKT, MYC, and cyclin E1 (CCNE1) and the overexpression of p16, p21, and p27. We showed that C14MC miRNA activation increases reactive oxygen species (ROS) levels, intracellular Ca2+ levels, and lipid peroxidation rates, and inhibits epithelial–mesenchymal transition (EMT). C14MC targets pyruvate dehydrogenase kinase‐3 (PDK3) according to the luciferase reporter assay. PDK3 is overexpressed in CC and is inversely correlated with C14MC. Both miR‐494‐mimic transfection and C14MC activation inhibited PDK3 expression. Reduced glucose uptake and lactate production, and upregulation of PDK3 upon C14MC activation suggest the potential role of these proteins in metabolic reprogramming. Finally, we showed that C14MC activation may inhibit EMT signaling. Thus, C14MC is a tumor‐suppressive and methylation‐regulated miRNA cluster in CC. Reactivation of C14MC can be useful in the management of CC. miR‐379/miR‐656 (C14MC) is the second largest microRNA cluster in the human genome. C14MC is a methylation‐driven tumor‐suppressive miRNA cluster in cervical cancer. C14MC activation inhibited cell growth, proliferation, migration, invasion, G2/M arrest, and senescence induction. C14MC activation increased ROS, intracellular Ca2+ and lipid peroxidation, and inhibited epithelial–mesenchymal transition. C14MC activation targets pyruvate dehydrogenase kinase 3.

BackgroundMitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation.MethodsThe clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations.ResultsAnalysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation.ConclusionIndividuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.

Objective miR-497/195, located at 17p13.1, is a highly conserved miRNA cluster whose abnormal expression is a key regulator of carcinogenesis. We performed a comprehensive analysis of the miR-497/195 cluster to determine its prognostic utility and role in cervical cancer (CC) using publicly available datasets. Results In silico analysis and validation revealed that this cluster is downregulated in CC. A total of 60 target genes of miR-497/195 cluster were identified as differentially expressed between normal and CC samples. ShinyGO, STRING, CytoHubba, Timer 2.0, HPA, and HCMBD were used for functional enrichment, PPIN network construction, hub gene identification, immune infiltration correlation, histopathological expression, and determination of the metastatic potential of miR-497/195 cluster and their target genes. PPIN analysis identified CCNE1, CCNE2, ANLN, RACGAP1, KIF23, CHEK1, CDC25A, E2F7, CDK1, and CEP55 as the top 10 hub genes (HGs). Furthermore, the upregulation of RECK, ATD5, and BCL2, downregulation of OSBPL3, RCAN3, and HIST1H3H effected overall survival of CC patients. We identified 6 targets (TFAP2A, CLSPN, RASEF, HIST1H3H, AKT3, and ITPR1) of miR-497/195 cluster to influence metastasis. In addition, 8 druggable genes and 38 potential drugs were also identified. Our study identified miR-497/195 cluster target genes and pathways that could be used for prognostic and therapeutic applications in CC.

Bacillus velezensis, is a bacterium widely recognized for its biocontrol properties and ability to promote plant growth. This study presents the whole genome sequence of B. velezensis B26, a newly identified strain isolated from chicken carcass soil, Udupi, India. The bacterium showed strong activity against fungal pathogens and exhibited diverse enzymatic activities. The whole genome sequencing was executed using Illumina technologies. Assembly revealed that strain B26 possesses a genome of 3,946,698-bp with a G+C content of 46.3%. Genome annotation identified 3776 protein-coding genes, 1 rRNA gene, 50 tRNA genes, 5 ncRNA genes, and 59 pseudogenes. Functional analysis of the B. velezensis B26 genome revealed 216 genes involved in carbohydrate metabolism, 3 genes in potassium metabolism, 148 genes linked for cofactors, vitamins, prosthetic groups and pigments, 10 genes involved in phosphorus metabolism, 24 genes associated with iron acquisition and metabolism, 20 genes for nitrogen metabolism, 6 genes involved in sulfur metabolism, 6 genes in secondary metabolism, 12 genes associated with metabolism of aromatic compounds, 43 genes involved in stress response and 36 genes associated with virulence, disease and defense. The raw sequence data generated in this work has been deposited in the NCBI database and the genome sequence is available under the accession number JAYKOV000000000. This genomic data provides insight into the biocontrol ability and plant-growth promoting capabilities of B. velezensis B26.

Background Aberrant miRNA expression has been associated with cervical cancer (CC) progression. The present study aimed to identify the miRNA clusters (MCs) altered in CC, identify their clinical utility, and understand their biological functions via computational analysis. Methods We used small RNA sequencing and qRT‒PCR to identify and validate abnormally expressed MCs in cervical squamous cell carcinoma (CSCC) samples. We compared our data with publicly available CC datasets to identify the differentially expressed MCs in CC. The potential targets, pathways, biological functions, and clinical utility of abnormally expressed MCs were predicted via several computational tools. Results Small RNA sequencing revealed that 229 miRNAs belonging to 48 MCs were significantly differentially expressed in CSCC (p-value ≤ 0.05). Validation by qRT‒PCR confirmed the downregulation of members of the miR-379/656, namely, hsa-miR-376c-3p (2.8-fold; p-value 0.03), hsa-miR-494-3p (3.4-fold; p-value 0.02), hsa-miR-495-3p (eightfold; p-value 0.01), and hsa-miR-409-3p (fivefold; p-value 0.03), in CSCC samples compared with normal samples. The prognostic model generated via miRNA expression and random forest analysis showed robust sensitivity and specificity (0.88 to 0.92) in predicting overall survival. In addition, we report 22 prognostically important miRNAs in CC. Pathway analysis revealed the enrichment of several cancer-related pathways, notably p53, the cell cycle, viral infection and MAPK signalling. CDC25A, CCNE1, E2F1, CCNE2, RBL1, E2F3, CDK2, RBL2, E2F2 and CCND2 were identified as the top ten gene targets of MC. Drug‒gene interaction analysis revealed enrichment of 548 approved drugs and 62 unique genes. Conclusion Our study identified MCs, their target genes, their prognostic utility, and their potential functions in CC and recommended their usefulness in CC management.

Brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) are key regulators of neuronal function and cognitive health. Genetic variations in these genes, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), have been linked to Alzheimer's disease (AD). This study employs a computational approach to predict the potential functional impacts of nsSNPs in BDNF and APOE to explore their contributions to AD pathogenesis. A total of 3590 BDNF and 27,830 APOE SNPs were retrieved from the dbSNP database. Following quality filtering of coding region localization and minor allele frequency (≥ 0.001), 33 BDNF nsSNPs and 95 APOE nsSNPs underwent systematic analysis. Pathogenicity was assessed using SIFT and PolyPhen-2 algorithms, with functional impact evaluated via CADD scoring. Protein stability effects were predicted using MUpro and I-Mutant tools, and posttranslational modifications were analyzed via a GPS prediction system. Secondary structure alterations were assessed using GOR4, and three-dimensional structural models were generated through SWISS-MODEL with Ramachandran plot validation. Three variants demonstrated concordant pathogenic predictions: rs1048218 (BDNF Q75H), rs7412 (APOE R176C), and rs769455 (APOE R163C). Protein stability analysis of these variants revealed consistent destabilization for rs1048218 (ΔΔG: -1.001 to -2.08 kcal/mol) and rs7412 (ΔΔG: -0.859 to -0.07 kcal/mol), whereas rs769455 showed conflicting predictions between algorithms. Posttranslational modification sites remained conserved across all the variants. Secondary structure analysis demonstrated minimal α-helix reduction (0.31%-0.81%) with compensatory random coil increases. Three-dimensional modeling revealed preserved overall protein folds despite localized structural perturbations, with acceptable model quality metrics (MolProbity scores ≤ 1.39, Ramachandran favored regions >91%). In silico analysis suggested that certain nsSNPs in BDNF and APOE may negatively affect protein function and stability, despite preserved structural and posttranslational features. These computational predictions need further experimental validation to better understand their roles in AD pathogenesis.