Genes最新文献

Background: The family Cyprinidae is predominantly restricted to freshwater habitats, making the evolution of diadromy and seawater adaptation exceptionally rare within this group. Pseudaspius hakonensis, a rare anadromous cyprinid, and its strictly freshwater congener P. leptocephalus, provide an ideal comparative model to investigate the molecular mechanisms underlying salinity adaptation. This study aimed to elucidate the tissue-specific transcriptional reprogramming, identify candidate genes and key pathways, and explore their association with seawater acclimation in P. hakonensis.

Methods: We performed comparative transcriptomic analyses of gill, liver, and kidney tissues from both species using RNA-Seq. Sequencing reads were aligned to a high-quality reference genome of P. hakonensis. Differential expression analysis was conducted using DESeq2, followed by functional enrichment analyses (GO and KEGG) to identify significant biological processes and pathways.

Results: A total of 8784, 5965, and 5719 differentially expressed genes (DEGs) were identified in gill, kidney, and liver tissues, respectively, with the gill showing the highest differences. Functional enrichment revealed tissue-specific roles: gill DEGs were associated with protein synthesis and energy metabolism; kidney DEGs with transport and detoxification; and liver DEGs with metabolic regulation and stress signaling. Cross-tissue analysis highlighted three core pathways consistently enriched: MAPK signaling, ABC transporters, and glutathione metabolism. Key candidate genes, including DUSP10, SLC38A2, ATP8B1, GSTA4, and MGST1, were significantly upregulated in P. hakonensis.

Conclusions: This first multi-tissue transcriptomic comparison of an anadromous and a freshwater cyprinid reveals pervasive, tissue-specific molecular reprogramming underlying seawater adaptation in P. hakonensis. The coordinated activation of MAPK signaling, glutathione metabolism, and transporter pathways suggests an integrated regulatory network for osmoregulation and stress resistance. These findings provide novel insights into the genetic basis of salinity adaptation in cyprinids and identify candidate genes for future functional validation.

Background/objectives: Southeastern Europe and Croatia have served as a genetic crossroads between the Near East and Europe since prehistoric times, shaped by numerous and repeated migrations. By integrating 19 newly generated ancient genomes with 285 previously published ancient genomes from Croatia, we investigated patterns of maternal and paternal landscapes from the Neolithic, Bronze, and Iron Ages through to the Antiquity and medieval periods, as well as the modern Croatian population.

Methods: Ancient DNA extraction from human remains and library preparation were conducted in dedicated clean-room facilities, followed by high-throughput sequencing on the Illumina platform. Sequencing data were analyzed with established pipelines to determine mitochondrial and Y-chromosomal haplogroups and the genetic sex of individuals.

Results: New ancient data reveal a predominantly European maternal profile, dominated by haplogroups H, U, and HV0, whereas Y-chromosomal lineages are characterized by J subclades and R1a, with limited representation of R1b and the absence of I2a. When combined with published ancient Croatian genomes, the results reveal similar haplogroup diversity and patterns, as well as the expansion of mtDNA haplogroup H over time and a substantial increase in Y-chromosome R1a and I2a haplogroup frequency from the prehistoric to the modern period.

Conclusions: Although the analyzed samples are heterogeneous and originate from different historical periods, their genetic signatures conform to the broader patterns expected for the region. In a wider context, the ancient Croatian mitochondrial data reveal stronger genetic persistence from prehistory to modern times, unlike paternal lineages, which show significantly higher divergence.

Background: Alternative pre-mRNA splicing is a combinatorial process involving serine/arginine-rich (SR) and heterogeneous nuclear ribonucleoprotein (hnRNP) splicing factors. These proteins can silence or enhance splicing based on their expression levels and binding positions.

Objectives: To better understand the combinatorial and interdependent regulation between SR and hnRNP splicing factors during alternative splicing.

Methods: Computational analyses were performed using cell knockdown and binding datasets from available databases.

Results: Analyses of differential splicing data for 9 SR proteins and 21 hnRNP knockdowns revealed statistically significant interdependent regulation among several RNA-binding protein (RBP) combinations, albeit at different levels. Neither SR proteins nor hnRNPs showed strong preferences for collaborating with specific RBP classes in mediating exon inclusion. While SRSF3, hnRNPK, hnRNPC, and hnRNPL stand out as major influencers of alternative splicing, they do so predominantly independent of other RBPs. Minor influencers of alternative splicing, such as hnRNPDL and hnRNPR, predominantly regulate exon inclusion in concert with other RBPs, indicating that exon inclusion can be mediated by both single and multiple RBPs. Interestingly, the higher the number of RBPs that regulate the inclusion of an exon, the more variable exon inclusion preferences become. Interdependently regulated exons are more modular and can be characterized by weaker splice sites compared to their independently regulated counterparts. A comparison of RBP interdependence between HeLa and other cell lines provides a framework that explains cell-type-specific alternative splicing.

Conclusions: Our study highlights the importance of the interdependent regulation of alternative exons and identifies characteristics of interdependently regulated exons that differ from independently regulated exons.

Background: Common bean (Phaseolus vulgaris L.) is an important grain legume crop of nutritional and economic value across Africa. Genetic improvements of the crop to enhance productivity and resilience depend on understanding the diversity within the African germplasm. Methods: Following PRISMA guidelines, the genetic diversity and population structure of common bean in Africa were reviewed systematically based on existing research. A protocol for conducting the systematic review was developed registered in OSF. Twenty-nine studies met the inclusion criteria after a comprehensive search in ScienceDirect, PubMed, Google Scholar, PubMed, AGRICOLA, Taylor & Francis, and SpringerLink. Data on molecular markers and diversity metrics, thus PIC, He, and AMOVA, were extracted and synthesized qualitatively. Results: Despite substantial heterogeneity in panel sizes, reporting completeness, and marker systems (SSR, SNP, POX, ISSR), consistent patterns emerged. Studies revealed moderate to high levels of genetic diversity. Population-structure analyses recovered the canonical Andean and Mesoamerican gene pools with extensive admixture and high gene flow. AMOVA results indicated that a substantial proportion of total genetic variation was attributed to within-population components. Conclusions: The results are consistent with previous studies, but the sample size and types of markers make direct comparisons impossible. More future studies should use standardized genotyping approaches to increase data consistency. These insights are useful for yield improvement under both non-stress and stress conditions and for developing Africa's diverse environments.

Background/objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl₄)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females.

Methods: Acute liver injury was induced in male and female mice by CCl₄ administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro.

Results: CCl₄ exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl₄ treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs.

Conclusions: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target.

Background: Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary disorder caused by pathogenic variants in TMPRSS6, characterized by microcytic anemia, low circulating iron levels, and inappropriately high hepcidin levels. Although IRIDA is typically an autosomal recessive disorder, some individuals with a monoallelic pathogenic exonic TMPRSS6 variant exhibit the phenotype, suggesting additional contributing factors. The mechanisms underlying monoallelic IRIDA remain unclear, complicating diagnosis. This study aimed to investigate the potential role of non-coding TMPRSS6 variants and polygenic inheritance in monoallelic IRIDA.

Methods: We performed full-gene sequencing of TMPRSS6 in a cohort of 27 subjects, including 6 families (7 symptomatic monoallelic, 7 asymptomatic monoallelic, and 4 wild-type subjects) and 9 isolated symptomatic monoallelic subjects. Whole-exome sequencing of other iron-regulating genes was conducted to evaluate polygenic inheritance. Non-coding variants were assessed for inheritance patterns using family segregation analysis, when available, and for pathogenic potential using in silico prediction tools.

Results: Sequencing identified 219 non-coding variants, of which 31 (14 trans-inherited and 17 with unknown inheritance) were exclusive to symptomatic subjects. Two trans-inherited variants (rs80140288 (c.229+945C>T) and rs146953827 (c.230-938_230-937del)) were predicted to affect splicing, while two additional variants (rs78987624 (c.-7001G>A) and rs117575523 (c.*503C>G)) were located in regulatory regions (with unknown inheritance). Whole-exome sequencing did not support polygenic involving other iron-regulating genes.

Conclusions: This study highlights four candidate non-coding variants that may contribute to IRIDA expression in monoallelic subjects, offering new insights into its genetic basis. Functional validation is required to confirm their role in disease pathogenesis, refine genotype-phenotype correlations, and improve diagnostic accuracy in monoallelic IRIDA.

Background: The STAT4 gene plays a key role in immune regulation and is associated with susceptibility to autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Objectives: The objective of this study is to analyze variants of uncertain significance (VUSs) in STAT4 using bioinformatics tools to predict their functional and structural impact.

Methods: A total of 48,295 variants of the STAT4 gene (ENSG00000138378) were retrieved from the Ensembl database. A tiered filtering approach was used to assess VUS pathogenicity, integrating in silico prediction tools such as SIFT, PolyPhen, MutPred2, and Align-GVGD, as well as structural modeling platforms including Chimera, ModRefiner, Missense3D, HOPE, and DynaMut2.

Results: Eighty missense VUSs were identified; of these, 13 were prioritized based on concordant signals across multiple computational predictors. These variants showed significant alterations in the physicochemical properties of the protein, including changes in hydrophobicity and disruption of hydrogen bonding. Notably, the rs140675301 (Glu128Val) variant lies within a conserved loop, and in silico analyses suggest that this mutation may alter kinase specificity regarding the phosphorylation of serine 130.

Conclusions: The integrative use of the bioinformatic tools employed represents a valuable preliminary step prior to undertaking more complex and resource-intensive functional studies. This complementary strategy strengthens the interpretative framework for VUS, guiding subsequent experimental validation and supporting a structured assessment of variant relevance, particularly in the context of immune-related genes such as STAT4.

Background/Objectives: Ameloblastoma is a benign odontogenic neoplasm characterized by locally aggressive behavior and frequent recurrences despite surgical treatment. It originates from odontogenic epithelium, including the cell rests of the dental lamina, remnants of the enamel organ, epithelial cell rests of Malassez, or the basal cell layer of the oral mucosa. Investigation of the etiopathogenesis of ameloblastoma has gained critical relevance due to the need for extensive surgical procedures, high recurrence rates, and its malignant potential. Accordingly, the aim of the present narrative review is to summarize current evidence regarding key aspects of ameloblastoma etiopathogenesis, with emphasis on signaling pathways, mutations, epigenetics, and epithelial-stromal interactions. Methods: An extensive literature search was conducted using the PubMed, Scopus, and Google Scholar databases, employing the keywords: "etiology", "pathogenesis", "molecular", "biomarkers", "cellular", "epigenetic", "mutation", "pathway", and "ameloblastoma". In vitro studies, clinical studies, case reports, and narrative and systematic reviews published in English were included, without restriction on publication year. Results: Current evidence indicates that ameloblastoma pathogenesis is driven by dysregulation of multiple signaling pathways, particularly the MAPK and Sonic Hedgehog pathways, through recurrent activating BRAF and SMO mutations. In addition, alterations affecting the WNT/β-Catenin and PI3K/AKT signaling cascades, epigenetic modifications, and epithelial-stromal interactions, contribute to tumor behavior. Conclusions: Despite significant advances, genotype-phenotype correlations, mutation frequencies and coexistence, clonality, and other associations remain incompletely understood. Larger tumor cohorts and robust meta-analyses are required to clarify these associations and to leverage the development of personalized therapeutic strategies.

Background: Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in genomics and transcriptomics have begun to elucidate the molecular mechanisms underlying corneal thinning and ectasia.

Objectives: This review synthesizes two decades of evidence on the genetic and epigenetic architecture of keratoconus, highlights key molecular pathways implicated by these findings, and discusses translational implications for early diagnosis, risk prediction, and novel therapeutic strategies.

Methods: A narrative review was conducted of peer-reviewed human, animal, and in vitro studies published from 2000 to 2025, with emphasis on genome-wide association studies (GWAS), sequencing data, methylation profiling, and non-coding RNA analyses. Findings were integrated with functional studies linking genetic variation to molecular and biomechanical phenotypes.

Results: Genetic studies consistently implicate loci such as ZNF469, COL5A1, LOX, HGF, FOXO1, and WNT10A, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers-Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene-environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. Conclusions: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification.

Background/objectives: Active surveillance (AS) has become the standard of care for many men with localised prostate cancer, aiming to avoid the overtreatment of indolent disease while maintaining oncological safety. Despite improvements in diagnostic techniques, misclassification at diagnosis and the limited ability to predict disease progression remain major challenges in AS. Novel molecular and genetic biomarkers, assessed through liquid biopsy approaches, offer the potential to refine patient selection and support risk-adapted monitoring in AS.

Methods: We conducted a narrative review of biomarkers in the context of AS for prostate cancer, framing the discussion in terms of the challenges in AS and how biomarkers may address these. PubMed and Embase were searched for English-language peer-reviewed studies published between 2000 and 2025. International guidelines (AUA, EAU, NCCN, NICE) and reference lists were reviewed manually. Priority was given to large prospective cohorts, meta-analyses, and high-impact publications.

Results: Blood-based assays such as PHI and the 4K score, urinary tests including ExoDx and SelectMDx, and the Prostate Urine Risk (PUR) signatures have all shown associations with disease progression or decisions to undergo earlier treatment. However, studies are often small, use surrogate endpoints, and lack validation in MRI-integrated cohorts. Biomarkers appear most informative in men with Gleason Grade 1 (GG1) disease, while evidence in GG2 cohorts is limited. Cost-effectiveness, heterogeneity of endpoints, and uncertainty in managing discordant biomarker and MRI results remain barriers to clinical adoption.

Conclusions: Molecular and genetic biomarkers show promise for improving AS by reducing diagnostic misclassification and enhancing prediction of progression. Future research should define clinically relevant cut-offs, clarify integration with MRI, and evaluate longitudinal use. Demonstrating utility in contemporary cohorts could enable the development of biomarker-guided, personalised AS that maintains safety while minimising harm.