Search Results (59)

Copy number variants (CNVs) are large-scale genomic alterations that contribute substantially to genetic diversity and may influence phenotypic variation in livestock. This study investigated the genome-wide CNV landscape of three Vietnamese indigenous chicken breeds. Whole-genome sequencing on the Illumina platform (3–5× coverage) was performed on 24 individuals from Dong Tao (DT), Cay Cum (CC), and Ri (RI) breeds. A total of 1743 CNVs were detected, clustering into 315 copy number variation regions (CNVRs). Most CNVRs were rare, with 31.7% present in only one animal among breeds. Across the genome, 122 unique CNVRs were distributed over 28 chromosomes, predominantly the first five. Losses were the most frequent type (45.9%), followed by gains (39.3%), and mixed events (14.8%). Within these CNVRs, 3633 genes were identified. In DT and RI, CNVR-embedded genes included several candidates, potentially related to adaptability, development, and phenotypic diversification. Notably, DT harbored genes such as EGLN1, OASL, GPX1, DUOX1/DUOXA2 (adaptation, stress/immune response) and LRP4, ZIC1, ZIC4, JARID2, KMT2C, OGN, OMD, and PLOD2 (developmental and skeletal traits), whereas in RI they included genes such as CACNA1S, CALCR, CAPN3, and MAPK13/MAPK14, which may contribute to muscle, bone, and physiological regulation. Functional enrichment analysis revealed numerous genes and Quantitative Trait Loci (QTLs) associated with metabolic, developmental, and immune-related pathways. This study provides the first comprehensive genome-wide CNV profile of Vietnamese indigenous chickens and offers a valuable genomic resource for investigating the genetic basis of breed-specific and adaptive phenotypes. Full article

Ferroptosis is an iron-dependent programmed cell death (PCD) implicated in cancer therapy response, yet its transcriptional control remains unevenly characterized and often centered on a limited subset of transcription factors (TFs) rather than systematically addressing TF families. The Activating enhancer-binding Protein-2 (AP-2) family of TFs is a plausible but understudied regulatory node linking oncogenic programs to ferroptosis, with prior research limited to AP-2α and AP-2γ, suggesting anti-ferroptotic and pro-tumorigenic roles. Thus, the present study aimed to provide a family-wide analysis of the relationships between AP-2 and ferroptosis across tumors in which this PCD type is considered biologically and clinically relevant. The research integrates ferroptosis gene modules with AP-2 targetomes, tumor–normal expression comparisons, survival stratification, ferroptosis scoring, cross-cohort functional analyses, and signaling pathway projection extending canonical ferroptosis circuits with AP-2–associated non-canonical elements. Consistent associations between AP-2 expression, prognosis, and ferroptosis score were observed in five tumor cohorts: cervical squamous cell carcinoma, glioblastoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, and thyroid carcinoma. In addition, cross-cohort clustering highlighted genes enriched in redox- and lipid-metabolism programs linked to apoptosis and autophagy-dependent death. Among the candidates emerging from these analyses, ferroptotic markers (LOX, PTGS2, and NQO1) and AP-2–linked nodes such as CD36, DUOX1, EPHA2, MUC1, PTPRC, SNAI2, and TP63 warrant targeted functional and binding validation to infer whether these associations reflect direct AP-2 regulatory mechanisms. Most importantly, AP-2–centered research appears to be a valuable area for guiding studies of tumor-specific ferroptosis vulnerability or resistance. Full article

Crohn’s disease (CD) is characterized by chronic intestinal inflammation accompanied by gut dysbiosis and redox imbalance. We investigated the role of dual oxidase-2 (DUOX2), a major epithelial source of reactive oxygen species (ROS), in linking oxidative stress to microbe–host crosstalk. DUOX2 expression was upregulated in human intestinal samples and was positively associated with inflammatory readouts, oxidative stress indices, and dysbiosis. Intestinal epithelial cell-specific Duox2 knockout (KO) mice exhibited reduced mucosal ROS, preserved barrier integrity, and attenuated dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Cohousing and fecal microbiota transplantation demonstrated that this protective phenotype was microbiota-dependent. Multi-omics profiling identified enrichment of Parabacteroides, particularly P. distasonis, in Duox2 KO mice, and oral supplementation with P. distasonis enhanced resistance to colitis. Mechanistically, DUOX2-derived oxidative stress constrained Parabacteroides growth, as P. distasonis displayed marked susceptibility to hydrogen peroxide, with excessive intracellular ROS accumulation and an absence of key antioxidant defenses—including peroxide reductase C (AhpC) and superoxide dismutase B (SodB)—indicating that epithelial DUOX2 shapes a hostile luminal redox niche unfavorable to these beneficial microbes. Pharmacological inhibition of DUOX2 with Compound 521 reduced oxidative stress, ameliorated colitis, and partially restored microbial balance. These findings establish a DUOX2–ROS–microbiota axis in which epithelial DUOX2 amplifies oxidative stress, remodels the gut ecosystem, and promotes inflammation, and highlights DUOX2 suppression or ROS-sensitive Parabacteroides as potential redox-centric therapeutic strategies for CD. Full article

Background: Multiple Sclerosis (MS) is a chronic, autoimmune, multifactorial, and complex disorder of the central nervous system (CNS), affecting more than 2 million individuals globally. Genome-wide association studies (GWAS) have explained only a small fraction of its high heritability, highlighting the need for alternative approaches to identify rare genetic variants that contribute to its etiology. To address this, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: WES was performed in a MS multigenerational family comprising two affected sisters, their two healthy brothers, and one affected son. Results: Bioinformatics analysis identified 47 co-segregating rare variants. Three missense variants in genes involved in inflammation, autoimmunity, and demyelinization were identified as the most promising candidates: c.443 C>T, p.Pro148Leu in the RTN4 gene, c.1678 T>G, p.Phe560Val in the JAK2 gene, and c.3449 A>G, p.Tyr1150Cys in the DUOX2 gene. Protein modeling and in silico tools suggest that the three selected variants may have a significant impact on protein function. Conclusions: We identified novel candidate genes for MS in a multiplex family, providing evidence for an oligogenic model of disease susceptibility. Further replication and functional studies are required to validate these preliminary results. Full article

The gut microbiota of Drosophila melanogaster offers a simplified yet powerful system to study conserved mechanisms of host–microbe interactions. Unlike the highly complex mammalian gut microbiota, which includes hundreds of species, the fly gut harbors a small and defined community dominated by Lactobacillus and Acetobacter. Despite its low diversity, this microbiota exerts profound effects on host physiology. Commensal bacteria modulate nutrient acquisition, regulate insulin/TOR signaling, and buffer dietary imbalances to support metabolic homeostasis and growth. They also influence neural and behavioral traits, including feeding preferences, mating, and aggression, through microbial metabolites and interactions with host signaling pathways. At the immune level, microbial molecules such as peptidoglycan, acetate, uracil, and cyclic dinucleotides activate conserved pathways including Imd, Toll, DUOX, and STING, balancing antimicrobial defense with tolerance to commensals. Dysbiosis disrupts this equilibrium, accelerating aging, impairing tissue repair, and contributing to tumorigenesis. Research in Drosophila demonstrates how a low-diversity microbiota can shape systemic host biology, offering mechanistic insights relevant to human health and disease. Full article

This long-term observational study aimed to define the spectrum of genetic variation in a congenital hypothyroidism (CH) cohort and investigate the correlations between specific genotypes and clinical phenotypes, including treatment requirements and outcomes. We analyzed the maintenance dose of L-thyroxine (L-T4) at 6, 12, 18, and 24 months, alongside clinical outcomes after 3 years. Data were collected from the Neonatal Disease Screening Center at our hospital between January 2011 and March 2024. Of 247 patients with confirmed CH, 119 had available genetic testing and complete clinical information. The genetic positivity rate was 56.3% (67/119). DUOX2 was the most frequently mutated gene (28.57%), followed by TPO, TG, and TSHR. Phenotypic correlation analysis revealed that patients with DUOX2 variants had significantly lower initial screening TSH levels and required lower L-T4 maintenance doses at 12 months compared to those with TPO or TSHR variants. Patients with TPO and TSHR variants exhibited more severe clinical phenotypes and a higher prevalence of thyroid enlargement on ultrasound. Notably, no significant differences in biochemical data, L-T4 doses, or clinical outcomes were observed between patients with monoallelic and biallelic DUOX2 variations, or among the negative, monogenic, and oligogenic variation groups. This study establishes a high genetic diagnostic yield for CH in the studied cohort, with DUOX2 as the predominant genetic etiology. The findings demonstrate significant genotype–phenotype correlations, where variations in different genes are associated with distinct biochemical severities and treatment demands. Crucially, the lack of correlation between the number of affected DUOX2 alleles and disease severity highlights the complex genetic and phenotypic heterogeneity of CH. These results provide valuable insights for the precise management and prognostic counseling of patients with CH. Full article

Background: Tibetan sheep (Ovis aries) have evolved remarkable adaptations to the extreme high-altitude environment of the Qinghai–Tibet Plateau. While previous studies have identified some genetic features underlying these adaptations, a comprehensive understanding of their population genetics and selection signatures remains incomplete. We hypothesized that Tibetan sheep harbor unique genetic diversity and population structure distinct from low-altitude sheep (Hu sheep and Small Tail Han sheep), and that whole-genome resequencing could identify key positively selected genes driving their high-altitude adaptation and economic trait variation. Thus, this study aimed to characterize the population structure and genetic diversity of Tibetan sheep via whole-genome resequencing and identify genomic regions and candidate genes under positive selection related to high-altitude adaptation and important economic traits (growth, meat quality, wool, reproduction). Results: Using whole-genome resequencing of 90 Tibetan sheep (ZY) compared to 90 Hu sheep (HY) and 90 Small Tail Han sheep (XWHY), we identified significantly higher genetic diversity in Tibetan sheep (Pn = 0.6399, PIC = 0.1731). Population structure analyses revealed distinct clustering of Tibetan sheep, with principal components explaining 20.69% (PCA1), 12.26% (PCA2), and 14.18% (PCA3) of genetic variation. Selective sweep analysis identified 713 genomic regions (containing 207 genes) under positive selection, including key hypoxia adaptation genes (HDAC5, BMP2/BMPR1B, DUOX2) and economic trait genes (FGF9 for growth; SLC27A2 for meat quality; KRTAP for wool; IZUMO1R for reproduction). Functional enrichment highlighted pathways in oxygen transport (EPO regulation), energy metabolism (fatty acid β-oxidation), and vascular remodeling (TGF-β signaling). Conclusions: Our study provides the most comprehensive genomic characterization of Tibetan sheep to date, revealing both their unique genetic diversity and molecular mechanisms of high-altitude adaptation. The identified candidate genes offer valuable targets for marker-assisted breeding to improve productivity while maintaining adaptive traits, supporting sustainable development of plateau animal husbandry. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive clinical behavior and intricate microenvironment regulation, leading to dismal prognosis. Elucidating the molecular mechanisms underlying PDAC pathogenesis is crucial for developing improved therapeutic approaches. The functional significance and molecular basis of transcobalamin 1 (TCN1) in PDAC remain largely unexplored. Methods and Results: Through integrated analysis of TCGA and GTEx datasets combined with 80 clinical specimens, we identified significant TCN1 overexpression in PDAC, showing a positive association with tumor stage and negative associations with histological differentiation and overall survival. Functional investigations showed that TCN1 enhanced pancreatic cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in both in vitro and in vivo models. Mechanistically, TCN1 physically interacts with signal transducer and activator of transcription 4 (STAT4) to enhance its transcriptional activity. Chromatin immunoprecipitation (ChIP) assays showed that STAT4-mediated transcriptional activation of dual oxidase 2 (DUOX2) occurs through direct promoter binding. As a pivotal reactive oxygen species (ROS)-generating enzyme, DUOX2 overexpression elevates intracellular ROS levels, thereby promoting EMT progression and activating proliferation-related signaling cascades. Antioxidant treatment effectively abrogated TCN1-driven oncogenic phenotypes, establishing ROS as the critical downstream mediator. Conclusions: Collectively, our findings reveal a novel TCN1/STAT4/DUOX2 regulatory axis that exacerbates PDAC progression by remodeling redox homeostasis. This signaling cascade may serve as a prognostic biomarker and a potential therapeutic target for ROS-directed precision therapy in PDAC. Full article

Background/Objectives: Recently, concerns about age-related conditions, such as sarcopenia and chronic inflammation, have increased owing to the global acceleration of population aging. Notably, these conditions are interrelated and further exacerbate functional decline in older adults. Therefore, this study aimed to evaluate the efficacy of a novel bioactive compound, DuoX (a mixture of the postbiotic beLP1 and Cichorium intybus L.), in alleviating muscle wasting and chronic inflammation. Specifically, the mixture consisted of inulin-rich C. intybus L. root extract, known for its anti-inflammatory effects, and beLP1, a postbiotic previously shown to exert anti-sarcopenic effects. Methods: To assess the multifunctional effects of the DuoX, dexamethasone-induced sarcopenia models (C2C12 myotubes and an in vivo rat model) and a lipopolysaccharide-stimulated RAW 264.7 macrophage inflammation model were established. Results: Pretreatment with DuoX prevented the dexamethasone-induced reduction in myotube diameter and effectively inhibited muscle degradation by downregulating the expression of atrogin-1 caused by dexamethasone treatment. In rats with DEX-induced sarcopenia, DuoX prevented muscle weight loss, grip strength reduction, and the upregulation of atrogin-1 expression in vivo. In lipopolysaccharide-stimulated RAW 264.7 macrophages, DuoX significantly reduced nitric oxide production and cyclooxygenase-2 protein expression and suppressed p38 and ERK phosphorylation in the MAPK signaling pathway, thereby alleviating inflammatory responses. Conclusions: DuoX holds promise as a dual-functional candidate with both anti-sarcopenic and anti-inflammatory properties. Further preclinical and clinical studies are required to validate its therapeutic efficacy and safety in humans, which may contribute to the development of preventive strategies for healthy aging. Full article

Cells are assaulted daily by stresses that jeopardize genome integrity. Primary human cells adapt their response to the intensity of replication stress (RS) in a diphasic manner: below a stress threshold, the canonical DNA damage response (cDDR) is not activated, but a noncanonical cellular response, low-level stress-DDR (LoL-DDR), has recently been described. LoL-DDR prevents the accumulation of premutagenic oxidized bases (8-oxoguanine) through the production of ROS in an adaptive way. The production of RS-induced ROS (RIR) is tightly controlled: RIR are excluded from the nucleus and are produced by the NADPH oxidases DUOX1/DUOX2, which are controlled by NF-κB and PARP1; then, RIR activate the FOXO1-detoxifying pathway. Increasing the intensity of RS suppresses RIR via p53 and ATM. Notably, LoL-DDR is dysregulated in cancer cell lines, in which RIR are not produced by NADPH oxidases, are not detoxified under high-level stress, and favor the accumulation of 8-oxoguanine. LoL-DDR dysregulation occurred at an early stage of cancer progression in an in vitro model. Since, conversely, ROS trigger RS, this establishes a vicious cycle that continuously jeopardizes genome integrity, fueling tumorigenesis. These data reveal a novel type of ROS-controlled DNA damage response and demonstrate the fine-tuning of the cellular response to stress. The effects on genomic stability and carcinogenesis are discussed here. Full article

Congenital hypothyroidism (CH) is among the most common endocrine disorders in neonates. Genetic testing is essential for elucidating the underlying etiology, especially in cases of permanent CH. We enrolled 32 patients diagnosed with permanent CH from the Pediatric Endocrinology Clinics at Jeju National University Hospital and Soonchunhyang University Cheonan Hospital. Whole-exome sequencing (WES) was performed on genomic DNA extracted from buccal swabs. Variants were classified according to guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). WES identified 21 distinct genetic variants in 20 of the 32 patients (62.5%), spanning 6 CH-related genes: DUOX2, DUOXA2, TPO, PAX8, TG, and TSHR. Of these, 12 variants classified as pathogenic or likely pathogenic were detected in 15 patients (50%). When classified by inheritance patterns, nine patients had either homozygous (n = 1) or compound heterozygous (n = 8) variants, four patients exhibited oligogenic variants, and two patients carried a single heterozygous variant with pathogenicity. The most frequently affected gene was DUOX2, with pathogenic or likely pathogenic variants found in six patients. Notably, none of the six patients with thyroid agenesis or ectopic thyroid glands harbored detectable pathogenic variants. Our findings underscore the critical role of genetic analysis in determining the etiology of permanent CH. Whole-exome sequencing demonstrated a high prevalence of pathogenic variants, particularly in DUOX2, in Korean patients with CH. These data enhance our understanding of the genetic architecture of CH and have important implications for personalized treatment and genetic counseling. Full article

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, defined by intestinal epithelial cell death. While ferroptosis and disulfidptosis have been linked to IBD pathogenesis, the functional significance of disulfidptosis-related ferroptosis genes (DRFGs) in this disease remains poorly characterized. This investigation sought to pinpoint DRFGs as diagnostic indicators and clarify their mechanistic contributions to IBD progression. Methods: Four IBD datasets (GSE65114, GSE87473, GSE102133, and GSE186582) from the GEO database were integrated to identify differentially expressed genes (DEGs) (|log2FC| > 0.585, adj. p < 0.05). A Pearson correlation analysis was used to link disulfidptosis and ferroptosis genes, followed by machine learning (LASSO and RF) to screen core DRFGs. The immune subtypes and single-cell sequencing (GSE217695) results were analyzed. A DSS-induced colitis Mus musculus (C57BL/6) model was used for validation. Results: Transcriptomic profiling identified 521 DEGs, with 16 defined as DRFGs. Nine hub genes showed diagnostic potential (AUC: 0.71–0.91). Functional annotation demonstrated that IBD-associated genes regulate diverse pathways, with a network analysis revealing their functional synergy. The PPI networks prioritized DUOX2, NCF2, ACSL4, GPX2, CBS, and LPCAT3 as central hubs. Two immune subtypes exhibited divergent DRFG expression. Single-cell mapping revealed epithelial/immune compartment specificity. The DSS-induced murine colitis model confirmed differential expression patterns of DRFGs, with concordant results between qRT-PCR and RNA-seq, emphasizing their pivotal regulatory roles in disease progression and potential for translational application. Conclusions: DRFGs mediate IBD progression via multi-signal pathway regulation across intestinal cell types, demonstrating diagnostic and prognostic potential. Full article

The role of oxidants and antioxidants in inflammatory bowel disease (IBD) has been actively explored since the early 1980s, starting with the role of the respiratory burst of neutrophils and ischemia in bowel pathology. Since that time, the enzymatic components contributing to the pool of reactive oxygen species, including superoxide, H₂O₂, and lipid hydroperoxides, and the counteracting antioxidants—catalase, glutathione peroxidases (Gpx), peroxiredoxins (PRDX), superoxide dismutases, and others—have been fleshed out. My perspective on IBD is from the role of the balance or imbalance of enzymatic oxidant sources and enzymatic antioxidants in the inflammatory process. I will present evidence on the involvement of oxidant and antioxidant processes in IBD based, as much as possible, on my experiences with Gpxs. This evidence will be discussed in terms of both the immune system and local bowel oxidant and antioxidant systems. As Gpxs are generally selenium-dependent, possible deficiencies in selenium uptake in active IBD and the impact on Gpx expression will be explored. The more recently introduced ferroptosis, an iron-dependent lipid peroxidation-based pathological process, will be reviewed for its possible involvement in IBD. Full article

As crucial vectors that transmit pathogens to humans and livestock, ticks pose substantial global health threats and economic burdens. We analyzed 328 tick genomes to explore the population’s genetic structure and the adaptive evolution of H. longicornis and R. microplus, two tick species with distinct life cycle characteristics. We observed distinct genetic structures in H. longicornis and R. microplus. Gene flow estimation revealed a closer genetic connection in R. microplus than H. longicornis, which was facilitated by geographical proximity. Notably, we identified a set of candidate genes associated with possible adaptations. Specifically, the immune-related gene DUOX and the iron transport gene ACO1 showed significant signals of natural selection in R. microplus. Similarly, H. longicornis exhibited selection in pyridoxal-phosphate-dependent enzyme genes associated with heme synthesis. Moreover, we observed significant correlations between the abundance of pathogens, such as Rickettsia and Francisella, and specific tick genotypes, which highlights the role of R. microplus in maintaining these pathogens and its adaptations that influence immune responses and iron metabolism, suggesting potential coevolution between vectors and pathogens. Our study highlights the vital genes involved in tick blood feeding and immunity, and it provides insights into the coevolution of ticks and tick-borne pathogens. Full article

Newborn congenital hypothyroidism (CH) screening has been widely used worldwide. The objective of this study was to evaluate the effectiveness of applying biochemical and gene panel sequencing as screening tests for CH and to analyze the mutation spectrum of CH in China. Newborns were prospectively recruited from eight hospitals in China between February and December 2021. Clinical characteristics were collected. Second-generation sequencing was used to detect four CH-related genes, and the genetic patterns of the pathogenic genes were analyzed. We analyzed the relationship between genotype and biochemical phenotype. A total of 29,601 newborns were screened for CH. Gene panel sequencing identified 18 patients, including 10 patients affected by biochemically and genetically screened disorders and 8 patients affected by solely genetically screened disorders. The predictive positive value of genetic screening was 34.62%, which was much greater than that of biochemical screening alone (17.99%). A total of 94 cases of congenital thyroid dysfunction were confirmed by biochemical and genetic screening, including 30 CHs and 64 isolated hyperthyrotropinemia (HTT), with an incidence of 1/987 for CH and 1/463 for HTT, and a total incidence of 1/315 for hypothyroidism. The incidence rate and number of patients in Jinan were the highest, and the incidence rates in Shijiazhuang and Shanghai were the lowest. The gene mutation rate in this study was 19.1%, mainly DUOX2 mutation. The most common variant of DUOX2 was c.1588A>T(p.Lys530*). There was only a difference in sFT4 between groups with gene mutations and those without mutations. Genetic screening is a supplement to biochemical screening. Combining biochemical screening with genetic screening is useful for improving screening efficiency. The incidence of CH in China according to a multicenter study of nearly 30,000 NBS surveys was 1/315. DUOX2 gene mutations are commonly detected in these patients. Full article