Search Results (1,306)

Autoinflammatory diseases involve recurrent systemic inflammation caused by dysregulated innate immunity, arising from genetic or multifactorial mechanisms, as seen in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. About 10% of PFAPA patients show autosomal dominant inheritance. We describe a three-generation family with a PFAPA-like recurrent fever syndrome displaying clear autosomal dominant transmission. All affected individuals tested negative on a diagnostic panel of 13 known autoinflammatory genes. Whole-exome sequencing was performed in two distantly related affected members, followed by variant filtering, segregation analysis, and phenotype-based prioritization. A single heterozygous missense variant in RXFP1, c.154G>A p.(Asp52Asn), co-segregated with disease in all affected relatives. This variant is extremely rare in population databases, absent from ClinVar, present in COSMIC, and predicted as damaging by REVEL and CADD. RXFP1, not previously implicated in autoinflammatory or innate immune disorders, encodes the relaxin family peptide receptor 1, a G protein–coupled receptor involved in extracellular matrix regulation, anti-fibrotic pathways, and modulation of inflammatory cytokine production. Protein network analysis showed interactions with RLXN1-3, inflammatory mediators, PTGDR, ADORA2B, and C1QTNF8, supporting an immunomodulatory function. This is the first report linking RXFP1 variation to a hereditary recurrent fever syndrome, identifying relaxin signalling as a potential immune regulatory pathway. Full article

Acrolein, a highly reactive environmental toxicant widely present in urban air and tobacco smoke, has been implicated in the development of multiple malignancies. In oral tissues, chronic acrolein exposure induces oxidative stress, inflammation, and genetic mutations, all of which are closely linked to the development of oral squamous cell carcinoma (OSCC). Although accumulating evidence indicates a strong association between acrolein exposure and OSCC, its prognostic significance remains poorly understood. In this study, we analyzed transcriptome data to identify differentially expressed genes (DEGs) between tumor and adjacent normal tissues, and screened acrolein-related candidates by intersecting DEGs with previously identified acrolein-associated gene sets. Functional alterations of these genes were assessed using Gene Set Variation Analysis (GSVA), and a protein–protein interaction (PPI) network was constructed to identify key regulatory genes. A prognostic model was developed using Support Vector Machine–Recursive Feature Elimination (SVM-RFE) combined with LASSO-Cox regression and validated in an independent external cohort. Among the acrolein-related DEGs, four key genes (PLK1, AURKA, CTLA4, and PPARG) were ultimately selected for model construction. Kaplan–Meier analysis showed significantly worse overall survival in the high-risk group (p < 0.0001). Receiver operating characteristic (ROC) curve analysis further confirmed the strong predictive performance of the model, with area under the curve (AUC) values of 0.72 at 1 year, 0.72 at 3 years, and 0.75 at 5 years. Furthermore, the high risk score was significantly correlated with a ‘cold’ immune microenviroment, suggesting that acrolein-related genes may modulate the tumor immune microenvironment. Collectively, these findings highlight the role of acrolein in OSCC progression, suggesting the importance of reducing acrolein exposure for cancer prevention and public health, and call for increased attention to the relationship between environmental toxicants and disease initiation, providing a scientific basis for public health interventions and cancer prevention strategies. Full article

Cassava (Manihot esculenta) is a staple crop in sub-Saharan Africa threatened by several viral diseases. Here, we describe the genome sequence of a novel bipartite cheravirus (family Secoviridae) infecting cassava in the Democratic Republic of Congo and Tanzania. We designate the new virus “cassava Congo cheravirus”. Each RNA segment encodes a single polyprotein (P1 and P2 for RNA1 and RNA2, respectively), embedded with various putative cleavage sites (six and three in P1 and P2, respectively), consistent with members of the genus Cheravirus. We note two new features in the P1: (i) the presence of two domains, X1 and X2, upstream of the putative helicase region, which we also predict in other cheraviruses and (ii) the presence of a Maf/HAM1-like inosine triphosphatase (ITPase) domain, a rare motif among viruses only previously detected in three potyviruses and a torradovirus, all of which infect plants from the Euphorbia family. Phylogenetic analyses placed the virus firmly within the genus Cheravirus, with amino acid identities in the Pro-Pol and coat protein regions well below existing ICTV species thresholds, supporting its classification as a virus belonging to a new species in the Cheravirus genus. Spatially distinct isolates from Bas-Congo, South-Kivu, and Tanzania form three genetic clusters, with evidence of recombination in both RNA segments. These results expand the known diversity of cassava viruses and suggest possible adaptation to the cassava host via ITPase acquisition. Full article

Cholangiocarcinoma (CCA) is a highly aggressive cancer of the biliary tract, distinguished by significant intratumoral heterogeneity (ITH), which contributes to therapy resistance and unfavorable clinical outcomes. Traditional genome profiling has revealed recurring driver changes in CCA; yet, genomic data alone fails to elucidate functional pathway activation, adaptive signaling, and the diverse treatment responses reported among tumor locations and disease subtypes. This review analyses the use of integrated sequencing technologies, proteogenomics, and phosphoproteomics to systematically characterize intratumoral heterogeneity in cholangiocarcinoma and convert molecular diversity into therapeutically applicable discoveries. We present evidence that the combination of genomic sequencing and mass spectrometry–based proteomics facilitates the direct correlation of genetic mutations with protein expression, post-translational modifications, and signaling system activity. Phosphoproteomic profiling specifically offers functional insights into kinase-driven networks that dictate tumor aggressiveness, therapeutic susceptibility, and adaptive resistance mechanisms, which cannot be anticipated only from DNA-level analysis. We propose that integrating proteogenomic and phosphoproteomic analyses into diagnostic and therapeutic assessments can enhance molecular classification, reveal subtype- and region-specific therapeutic dependencies, and guide rational combination treatment strategies, based on recent extensive proteogenomic studies and functional proteomic investigations in CCA. Pathway-level analysis of intratumoral heterogeneity provides a framework for selecting targeted medicines, predicting resistance, and informing personalized treatment strategies in CCA. The combination of sequencing, proteogenomics, and phosphoproteomics is essential for advancing precision oncology in cholangiocarcinoma. The implementation of this multi-layered analytical approach may better patient classification, refine therapy choices, and eventually improve clinical outcomes for individuals with this particular heterogeneous cancer. Full article

The corolla of Rehmannia glutinosa typically exhibits a stable reddish-purple color, but a naturally occurring yellow-flowered variant has recently been identified. To clarify the molecular basis of flower color variant, metabolomics, transcriptomics, and variant analyses were integrated. Metabolomic profiling revealed that the yellow phenotype was associated with lower anthocyanin levels and higher carotenoid levels. Specifically, the decreased cyanidin-3-O-glucoside led to a loss of red, while increased lutein provided the basis for the yellow color. Transcriptomic analysis revealed a downregulation of anthocyanin biosynthetic genes, including CHS, CHI, F3H, DFR, and ANS, in the yellow-flowered variant, and three S6-subgroup R2R3-MYB genes, including the known anthocyanin activator RgMYB41 (gene-DH2020_015992), were downregulated. Variant analysis showed that A12S and G255E in the gene-DH2020_015992 transcription factor were predicted to markedly alter protein conformation and potentially impair regulatory function. Subcellular localization and transcriptional activation assays further supported the functional characterization of gene-DH2020_015992 as a transcription factor. Collectively, these findings suggest that flower color variation in R. glutinosa is driven by MYB-mediated repression of anthocyanin biosynthesis and by carotenoid accumulation. This study provides a comprehensive genetic explanation for flower color variation in R. glutinosa and offers a theoretical foundation for floral pigmentation in plants. Full article

Annual wild soybean, the ancestor of cultivated soybean, underwent a significant increase in seed oil content during domestication. To elucidate the genetic basis of this change, a chromosome segment substitution line population (177 lines) constructed with cultivated soybean NN1138-2 as recipient and wild soybean N24852 as donor was used in this study. Phenotypic evaluation across three distinct environments led to the identification of two major QTL/segments, qOC14 on chromosome 14 and qOC20 on chromosome 20, which collectively explained 39.46% of the phenotypic variation, with individual contributions of 17.87% and 21.59%, respectively. Both wild alleles exhibited negative additive effects, with values of −0.35% and −0.42%, respectively, consistent with the inherently low oil content of wild soybeans. Leveraging transcriptome and genome data from the two parents, two candidate genes were predicted. Notably, Glyma.14G179800 is a novel candidate gene encoding a PHD-type zinc finger domain-containing protein, and the hap-A haplotype exhibits a positive effect on oil content. In contrast, Glyma.20G085100 is a reported POWR1 gene, known to regulate protein and oil content. Our findings not only validate the role of known gene but, more importantly, unveil a new candidate gene, offering valuable genetic resources and theoretical targets for molecular breeding of high-oil soybean. Full article

Brain tumors, particularly glioblastoma, remain among the most lethal cancers, with limited survival benefits from current genetic and molecular-targeted approaches. Emerging evidence reveals that beyond oncogenes and mutations, neuronal plasticity, long-term potentiation, synaptic remodeling, and neurotransmitter-driven signaling play a pivotal role in shaping tumor progression and therapeutic response. This convergence of neuroscience and oncology has given rise to the field of cancer neuroscience, which explores the bidirectional interactions between neurons and malignant cells. In this review, we summarize fundamental principles of neuronal plasticity, contrasting physiological roles with pathological reprogramming in brain tumors. We highlight how tumor cells exploit synaptic input, particularly glutamatergic signaling, to enhance proliferation, invasion, and integration into neural circuits. We further discuss how neuronal-driven feedback loops contribute to therapy resistance, including chemoresistance, radioresistance, and immune evasion, mediated through pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and calcium influx. The tumor microenvironment, including astrocytes, microglia, and oligodendrocyte-lineage cells, emerges as an active participant in reinforcing this neuron-tumor ecosystem. Finally, this review explores therapeutic opportunities targeting neuronal plasticity, spanning pharmacological interventions, neuromodulation approaches (transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), optogenetics), and computational/artificial intelligence frameworks that model neuron tumor networks to predict personalized therapy. Also, we propose future directions integrating connect omics, neuroinformatics, and brain organoid models to refine translational strategies. Full article

Sex determination and differentiation in teleosts are governed by complex genetic regulatory networks that include evolutionarily conserved mechanisms. In this study, we investigated Boleophthalmus pectinirostris, a Gobiidae species lacking heterogametic sex chromosomes, using comparative gonadal transcriptome analysis to identify sex differentially expressed genes (DEGs). RNA sequencing of ovarian and testicular tissues identified 17,214 DEGs, including 14,302 upregulated in males and 2912 upregulated in females. These DEGs were primarily associated with male (e.g., dmrt1, amh, amhr2) or female (e.g., bmp15, gdf9, rspo1) sex determination and differentiation, steroidogenesis (e.g., hsd17b1, hsd3b1, cyp17a1), and meiosis (e.g., cyp26b1, aldh1a2, piwil2). Functional enrichment analysis revealed that male upregulated DEGs were involved in spermatogenesis pathways such as calcium signaling, while female upregulated DEGs were associated with oogenesis pathways including oocyte meiosis and progesterone-mediated oocyte maturation. Conserved regulators, notably dmrt1 and amh, were predicted to act as key hubs in protein–protein interaction networks, being primarily associated with reproductive processes and sex differentiation in B. pectinirostris. The amh gene produces two alternatively spliced isoforms that differ by a partial deletion in the second exon, both expressed in ovaries and testes. Collectively, this study provides the first comprehensive molecular framework of sex determination and differentiation in Gobiidae species, offering critical insights into the regulatory mechanisms of B. pectinirostris reproductive development. Full article

Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein–protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity. Full article

Background and Objectives: Non-coding RNAs (ncRNAs) are genetic transcripts that do not produce proteins but are increasingly recognised for their roles in cellular processes and disease. Specifically, ncRNAs are implicated in the landscape activation of molecular triggers for different diseases, including cancer and viral infections. The function of Sense non-coding mitochondrial RNA-2 (SncmtRNA-2) is currently unknown. This study aims to investigate the roles of SncmtRNA-2 and hsa-miR-620 in Ras-induced cellular transformation. Materials and Methods: The study utilized isoforms V, K, and H of the Ras oncogene and analysed the expression of SncmtRNA-2 and hsa-miR-620 in response to Ras activity. Additionally, both in silico and in vitro analyses were performed to assess whether PML mRNA is a putative target of hsa-miR-620 although direct binding to the PML 3′UTR was not experimentally tested. Results: The research demonstrated that transformation induced by Ras isoforms V, K, and H resulted in decreased expression of both SncmtRNA-2 and hsa-miR-620. Further investigation revealed that hsa-miR-620 is produced by the processing of SncmtRNA-2. It was also shown that Ras increases the expression of Promyelocytic Leukemia Protein (PML). In silico prediction combined with miR-620 gain and loss of function experiments supports PML as a putative hsa-miR-620 target. Conclusions: Ras promotes cellular transformation by decreasing the expression of SncmtRNA-2 and hsa-miR-620, which may contribute to increased PML expression, suggesting but not demonstrating a possible regulatory relationship among these molecules in HPV-immortalised cells. These results highlight a potential SncmtRNA-2/miR-620/PML axis that requires further validation through direct interaction assays and functional necessity/sufficiency experiments. Full article

In the review, the collection of population genetics papers from 1973 to 2025 comprises 400 publications, 81 of which were significant and consulted with representatives from water and sewage companies. Reviewed Proteobacteria (mean H_S = 0.42), Firmicutes (mean H_S = 0.43), Actinobacteria (mean H_S = 0.33), and Spirochaetes (mean H_S = 0.54) represent the 60 species under investigation through the lens of “h” coefficients related to gene diversity and expected heterozygosity. The research also included ESKAPE, emerging pathogens, bacterial indicators of wastewater treatment efficiency, environmental sanitary surveillance and public health. The restoration of the expected heterozygosity for haploids “h” was proposed in wastewater-based epidemiology as an innovative tool for public health. The unique “h” coefficient allows for the comparison of genetic variability in various organisms, regardless of their ploidy, using multiple markers and traits. The parameter represents a noble character for both the variability of phenotypes (proteins) and genotypes (nucleic acids). Leveraging the genetic diversity highlighted by the “h” coefficient can support wastewater-based epidemiology, offering the ability to predict the stages and trajectories of disease outbreaks. Full article

The auxin/indole-3-acetic acid (Aux/IAA) gene family encodes central regulators of plant development and stress adaptation. Eggplant (Solanum melongena), an economically important vegetable crop, is highly susceptible to abiotic stresses, yet its Aux/IAA family remains uncharacterized. This study aimed to systematically characterize the Aux/IAA gene family in eggplant and to explore its potential roles in development and abiotic stress responses using a genome-wide approach. Here, 35 SmIAA genes were identified through comprehensive bioinformatic analyses, including phylogenetic classification, synteny analysis, protein–protein interaction prediction, and qRT-PCR validation. Phylogenetic analysis classified these genes into Clades A and B, encompassing nine subgroups, with subgroup B4 showing lineage-specific expansion and encoding non-canonical Aux/IAA proteins. Expression profiling revealed that SmIAA18 and SmIAA33 were strongly responsive to salt stress, whereas SmIAA1/2/8 were preferentially induced by drought stress. Furthermore, SmIAA8 and SmIAA33 exhibited contrasting responses to IAA treatment, characterized by delayed induction and rapid repression, respectively. This study presents the first genome-wide analysis of the Aux/IAA family in eggplant, elucidating its roles in development and stress adaptation, and provides valuable genetic resources for the molecular breeding of stress-tolerant varieties. Full article

Background: Duchenne muscular dystrophy (DMD) results from pathogenic variants in the DMD gene, one of the most significant and most mutation-prone genes in the human genome. Although global mutation registries are well developed, genetic data from Central Asian populations remain extremely limited, leaving essential gaps in regional epidemiology and in the understanding of genotype–phenotype patterns. Methods: We conducted a retrospective analysis of patients with genetically confirmed dystrophinopathy in Kazakhstan. Variants were identified using multiplex ligation-dependent probe amplification (MLPA) for exon-level copy number alterations and next-generation sequencing (NGS) with Sanger confirmation for sequence-level changes. All variants were classified under ACMG guidelines. Statistical modelling incorporated mutation-class grouping, exon-hotspot mapping, reading-frame status, CPK stratification, chi-squared association testing, Spearman correlations, Kaplan–Meier ambulation survival curves, and multivariable logistic and Cox regression. Results: multi-exon deletions were the predominant mutation class, with a marked concentration within the canonical hotspot spanning exons 44–55. Recurrent deletions affecting exons 46–50 and 45–50 appeared in several unrelated patients. NGS confirmed severe protein-truncating variants, including p. Lys1049* and p. Ser861Ilefs*7. Phenotypic severity followed a consistent hierarchy: hotspot-associated deletions and early truncating variants showed the earliest loss of ambulation, whereas splice-site variants and duplications demonstrated the mildest courses. CPK levels correlated with the extent of genomic involvement, though extreme elevations did not consistently predict early functional decline. Regression models identified hotspot localization and out-of-frame effect as independent predictors of ambulation loss. Conclusions: This study provides the first statistically modelled characterisation of DMD gene mutations in Kazakhstan. While the mutational landscape largely mirrors global patterns, notable variability in clinical severity suggests the presence of population-specific modifiers. Integrating comprehensive molecular diagnostics with statistical-genetics approaches enhances prognostic accuracy and supports the development of mutation-targeted therapeutic strategies in Central Asia. Full article

Sucrose is a key quality trait in peanuts, yet high-sucrose varieties are scarce. Although sucrose transporters (SUT/SUC) play crucial roles in sucrose transport and accumulation during seed development, systematic analyses in peanuts are limited. This study conducted a genome-wide analysis of the SUC gene family in cultivated peanut (Arachis hypogaea L.). Sixteen AhSUC genes were identified and characterized for genomic distribution, phylogeny, and expression across tissues and developmental stages. The genes are unevenly distributed across the genome with clustered chromosomal localization. All AhSUC proteins contain the conserved sucrose/proton co-transporter domain (IPR005989), exhibit the typical 12 transmembrane α-helical structure of the major facilitator superfamily, are hydrophobic, and predicted to localize to the membrane. Promoter analysis revealed cis-regulatory elements associated with growth, development, light, hormone, and stress responses. Expression profiling showed tissue-specific patterns, with eight AhSUC genes being highly expressed in cotyledons and embryos. Comparative analysis between high-sugar and conventional varieties showed higher expression of AhSUC2, AhSUC9, and AhSUC11 in the high-sugar variety, correlating with increased sucrose accumulation. Functional validation using a sucrose transport-deficient yeast mutant confirmed the sucrose transport activity of these genes. These findings provide insight into sucrose accumulation mechanisms and offer genetic targets for breeding high-sugar peanut varieties. Full article

The sodium iodide symporter (NIS) is a key protein in thyroid function responsible for iodine uptake, and it may be involved in the pathogenesis of autoimmune thyroiditis. However, it is also expressed in the salivary glands, the primary target of autoreactive cells in Sjögren’s syndrome (SS). Given the common link between the two diseases, we computationally investigated whether the epitopes of NIS can trigger an immune response leading to SS in Hashimoto’s thyroiditis (HT) patients genetically predisposed to both diseases. The TepiTool 2016, ABCpred 2006, and DiscoTope 2.0 servers were used to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of NIS, thyroid peroxidase (TPO) and Ro60 Y RNA-binding protein (Ro60), which served as reference antigens for HT and SS, respectively. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) alleles associated with both SS and HT. We identified a total of 376 linear T-cell epitopes, 64 linear B-cell epitopes and 68 conformational B-cell epitopes of NIS. Compared to TPO, NIS T-cell epitopes showed significantly lower affinity for HLA alleles (p < 0.0001), while no significant difference was found compared to Ro60. While linear B-cell epitopes of NIS, TPO, and Ro60 showed similar binding affinity, conformational epitopes of NIS were predicted to have higher immunogenicity than Ro60 (p = 0.04), while no significant difference was found compared to TPO. These pivotal findings, discovered by the methods of computer modeling, suggest that NIS can potentially activate T cells and B cells in patients with genetic predisposition to SS and HT and need to be confirmed by further laboratory studies. Full article