Genes最新文献

Background: Interindividual radiosensitivity is largely driven by genetic regulation of DNA damage recognition, repair, and cell-cycle control. TP53 and CDKN1A (p21) are key genomic markers associated with differential responses to ionizing radiation. Methods: This study investigated eight functional SNP markers across several key genes involved in DNA damage responses and cellular stress regulation, including TP53, CDKN1A/p21, APC, VEGF, XPD, and RAD51, in occupational groups exposed to chronic low-dose ionizing radiation at the Stepnogorsk Mining Chemical Combine and the Balkashinskoye uranium deposit. Genotyping was performed using PCR-based assays followed by restriction fragment length polymorphism (RFLP) analysis. Allele and genotype frequencies were compared between radiation-exposed workers and matched controls within Kazakh and Russian ethnic subgroups. Statistical differences were assessed using χ² tests, and associations with radioresistance were interpreted based on established functional characteristics of each polymorphism. Results: Four SNPs showed significant allele and genotype frequency shifts in radiation-exposed populations. The TP53 intron 3 insertion allele, TP53 intron 6 A allele, TP53 Pro72 (C) allele, and p21 codon 31 A allele were consistently enriched among exposed individuals. The strongest deviations were observed in Russian workers from Stepnogorsk (p < 0.01). These alleles are functionally associated with enhanced DNA repair efficiency, modified apoptotic responses, and strengthened cell-cycle checkpoint regulation. Conclusions: Significant enrichment of radioresistance-associated TP53 and CDKN1A (p21) variants was observed in uranium industry workers chronically exposed to low-to-moderate ionizing radiation. The observed patterns support a polygenic model of adaptive responses and emphasize the importance of genetic background in determining individual radiosensitivity under occupational exposure conditions.

Background: Obsessive-compulsive disorder (OCD) is a heterogeneous psychiatric condition with substantial heritability. Early genetic studies were often underpowered and produced limited reproducibility, but recent large-scale genomic and multi-omic approaches are beginning to elucidate the genetic architecture of OCD. Objectives: This review aims to synthesise current evidence from recent genomic and epigenomic studies on OCD and their implications for molecular pathways of pathogenesis, including endophenotypes. Methods: We reviewed peer-reviewed literature and preprints published in recent years, focusing on multiple genetic approaches, including genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), and methylome-wide association studies (MWAS). We then integrated the results with endophenotypic evidence at the biochemical, physiological, structural, functional, and executive/cognitive levels. Results: Recent large-scale genomic studies provide strong evidence of a highly polygenic contribution from common variants, while rare coding and structural variants also contribute measurably, with enriched signals in pathways relevant to neurodevelopment and, in some cohorts, early-onset presentations. Epigenomic studies have moved from scattered findings to more replicable methylation patterns, including loci influenced by nearby genetic variation and indications of sex-dependent effects. Although convergence at the single-gene level remains limited, cross-study and cross-omics signals increasingly point to biological domains involving synaptic organisation and plasticity, neurological development and chromatin regulation, immune/stress pathways, and cellular homeostasis. Conclusions: The biology of OCD risk is best represented by an integrative model combining polygenic load, contributions from rare variants, and regulatory (epigenetic) mechanisms that influence intermediate phenotypes at the circuit and cognitive levels. The current findings are not yet clinically applicable for individual diagnosis; however, they may inform future multidisciplinary research frameworks and, in the longer term, contribute to the development of more personalised approaches in OCD.

Background: The monocarboxylate transporter 1 (MCT1) plays a central role in myocardial lactate handling and metabolic adaptation. The functional rs1049434 polymorphism (T1470A; Asp490Glu) affects MCT1-mediated lactate transport and substrate utilization, but its clinical relevance in sarcomere-related hypertrophic cardiomyopathy (HCM) remains poorly defined.

Methods: We studied 56 carriers of pathogenic or likely pathogenic sarcomeric variants examined in a familial HCM program. All participants underwent standardized clinical phenotyping, including electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging. Genotyping of MCT1 rs1049434 was performed on genomic DNA. Analyses focused on sex-stratified genotype distribution, phenotypic expression among the 26 individuals who fulfilled diagnostic criteria for HCM, and the influence of habitual vigorous exercise. Septal wall thickness was the primary structural endpoint.

Results: Among the 26 patients with established HCM (10 women, 16 men), a marked sex-specific effect emerged. Female carriers of the T-allele (TT/TA) exhibited significantly greater interventricular septal thickness compared with AA homozygotes (23.2 vs. 14.2 mm; p = 0.037). In men, septal thickness did not differ by genotype. However, male patients engaged in vigorous physical activity showed a consistently milder structural phenotype, including lower septal thickness (18.3 vs. 19.9 mm; p = 0.585) and directionally favorable markers of mechanical severity. Phenotypic distribution was predominantly asymmetric septal hypertrophy in both sexes, without genotype-dependent differences.

Conclusions: The phenotypic impact of MCT1 rs1049434 in sarcomere-positive HCM is context-dependent. In women, impaired monocarboxylate handling is associated with greater hypertrophic remodeling, whereas in men, exercise-related metabolic conditioning appears to attenuate disease severity. These findings support a genotype-sex-environment interaction relevant to precision medicine approaches in HCM.

Background: Interpreting short tandem repeat (STR) profiles from low-template DNA (LT-DNA) requires consideration of the stochastic phenomena that can affect the reliability of genotypes. Although several probabilistic genotyping tools have been developed to model such uncertainties, most have only been used for direct comparisons between persons of interest and crime scene samples. Their application to kinship testing involving LT-DNA has received comparatively little attention. Methods: We evaluated the performance of two PGS, EuroForMix (EFM) and EFMrep, which support alternative hypotheses with relatedness, by comparing them with a standard paternity testing software (Familias) in 33 paternity cases involving LT-DNA samples categorised as 'mildly' (MD) or 'highly' (HD) degraded based on the quality of the STR profiles. The samples included formalin-fixed paraffin-embedded tissues, bone specimens, and stains collected from personal items. Pedigrees with ('trio') and without ('duo') maternal information were considered. Results: In MD and HD duos, the likelihood ratios (LRs) obtained with EFMrep were significantly higher compared to other software. In trios, Familias produced significantly higher LRs than PGS for MD samples, whereas the three software performed comparably for HD samples. Notably, in HD trios, EFMrep was the software most likely to maximise LR values, which were above 10,000 in 60% of the cases, compared to 50% of EFM and 40% of Familias. Conclusions: These findings provide preliminary evidence of the potential and limitations of using PGS for kinship assessments involving LT-DNA specimens.

Purpose: Colorectal cancer (CRC) is a highly aggressive malignancy of the digestive system. Somatic variants in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene have a significant influence on CRC progression and serve as key predictors of resistance to anti-epidermal growth factor receptor (EGFR) therapy. This study aimed to determine the prevalence of KRAS variants, with a particular focus on G12D variants, which represent potential for targeted therapy. Methods: A cohort of 73 CRC patients was evaluated between January 2021 and August 2024. Next-generation sequencing (NGS) was performed using the Archer^® VariantPlex^® Solid Tumor Focus v2 (Integrated DNA Technologies, Inc., Boulder, CO, USA) assay on the Illumina NextSeq platform. The gene panel included 20 genes frequently mutated in solid tumors, assessing point variants, insertions/deletions, and microsatellite instability. Results: The cohort of the study comprised 38 female (52%) and 35 males (48%) patients aged 31-83 years (mean, 58.77 ± 12.72). No significant difference in mean age was observed between males and females (60.31 ± 12.32 vs. 57.34 ± 13.08; p > 0.05). KRAS variants were detected in 30 patients (41%). Among these, the variant frequencies for G12D, G12V, and G13D were 7%, 11%, and 11%, respectively. Additionally, one patient (1.4%) harbored an ERBB2 amplification. All KRAS variants were associated with resistance to anti-EGFR therapy. Notably, KRAS G12D variants have potential responsiveness to targeted therapy, while human epidermal growth factor receptor 2 (ERBB2) amplifications are responsive to anti-HER2 treatments and resistant to anti-EGFR therapies. Conclusions: These findings highlight the clinical significance of KRAS variant profiling for prognosis and personalized treatment planning in CRC. Moreover, assessing KRAS variants individually is crucial to better understanding treatment response and exploring the potential targeted therapy in CRC management.

Background: Experimental autoimmune thyroiditis is an important animal model for studying Hashimoto's thyroiditis. Our aim was to develop the model using CBA/J-DR3 mice expressing human HLA-DR3, which is associated with autoimmune thyroiditis in humans, to better simulate human autoimmune thyroiditis. Such a humanized model can be used to test specific antigen therapies for autoimmune thyroiditis.

Methods: CBA/J-DR3 mice were produced by back-crossing B6-DR3 mice to the CBA/J background. Female CBA/J-DR3 mice were immunized with human thyroglobulin (Tg) in complete Freund's adjuvant on days 0 and 7. On day 21, mice were sacrificed, blood collected, spleen and thyroid harvested for analysis. Splenocytes were analyzed for T cell responses to Tg and its major T-cell epitope in human autoimmune thyroiditis, Tg.2098. Serum anti-thyroglobulin antibodies were measured by ELISA, and thyroid-stimulating hormone was measured using the Luminex assay. Thyroid histology and immunohistochemistry were examined.

Results: Immunized CBA/J-DR3 mice showed significant T cell proliferation in response to Tg (stimulation index 3.4 ± 4.5) and Tg.2098 (1.5 ± 0.7). Anti-thyroglobulin antibody levels were elevated in immunized mice when compared to control mice (2.05 ± 0.75 vs. 0.15 ± 0.06, p < 0.0001). T cells demonstrated higher reactivity to thyroid antigens by enhanced production of pro-inflammatory cytokines. Thyroid immunohistochemistry revealed mild CD3-positive T-cell infiltration.

Conclusions: This novel humanized CBA/J-DR3 mouse model of Hashimoto's thyroiditis demonstrates key features of human autoimmune thyroiditis. The HLA-DR3 background and the immune response to Tg and Tg.2098 enhance translational relevance, making this a valuable model for studying thyroid disease pathogenesis and testing targeted immune-modifying therapies.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial-mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy-Tetralogy-Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype-phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology.

Objective: Accumulating evidence demonstrates that melatonin is involved in modulating granulosa cell function and follicular development. lncRNAs (long non-coding RNAs) and circRNAs (circular RNAs) have been reported to participate in multiple biological processes. This study aimed to explore the candidate circRNAs and lncRNAs related to molecular mechanisms when exploring the role of melatonin in regulating ovarian function. Methods: Bovine ovary granulosa cells were collected 48 h after treatment with melatonin at 10^-7 M. The lncRNA and circRNA profiles of bovine granulosa cells were further explored using high-throughput sequencing in the absence/presence of melatonin. The differentially expressed lncRNAs and circRNAs were analyzed through the annotation information of source transcripts for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: We identified 99 differentially expressed lncRNAs and 28 differentially expressed circRNAs. Enrichment analysis of differentially expressed lncRNAs and circRNAs showed they were enriched in multiple pathways involved in development, apoptosis, and reproductive function, such as the mTOR (mammalian Target of Rapamycin) signaling pathway, FoxO (Forkhead box O) signaling pathway, MAPK (Mitogen-Activated Protein Kinase) signaling pathway, Hippo signaling pathway, TGF-beta (Transforming Growth Factor-β) signaling pathway, PI3K-Akt (Phosphatidylinositol 3-Kinase-Akt) signaling pathway, apoptosis, and Rap1 (Ras-related protein 1), most of which were mainly related to granulosa cell function and the crosstalk between granulosa cells and oocytes. The present analysis indicated the potential role of melatonin in granulosa cell function by regulating lncRNA and circRNA expression and, thus, mediating follicular development. An lncRNA/circRNA and miRNA regulatory network was also constructed to take their interactions into account. Conclusions: Our study offers details of lncRNA and circRNA expression in bovine granulosa cells and further provides insight into the potential role of melatonin in regulating reproduction by modulating lncRNA and circRNA expression.

Langer-Giedion syndrome (LGS), also known as trichorhinophalangeal syndrome type II (TRPS II; OMIM #150230), is a contiguous-gene deletion disorder caused by haploinsufficiency of TRPS1 and EXT1. Cornelia de Lange syndrome (CdLS) is genetically heterogeneous; heterozygous variants in RAD21 cause the milder CdLS type 4 phenotype (OMIM #614701). Because RAD21 lies between TRPS1 and EXT1, overlapping phenotypes may arise when all three genes are deleted. We report a unique case of a 4-year-old female presenting with a blended phenotype of Langer-Giedion Syndrome (LGS) and Cornelia de Lange Syndrome (CdLS) type 4. This case is distinct from previously reported 8q deletions in three key aspects: (1) Complex Genomic Architecture: Chromosomal microarray revealed a novel complex rearrangement consisting of a 13.01 Mb mosaic interstitial deletion at 8q23.1-q24.12, flanked by two large duplications (21.5 Mb at 8q11.23-q23.1 and 25.78 Mb at 8q24.12-q24.3). (2) Rare Mosaicism: This represents only the second reported case of mosaicism affecting this contiguous gene region. Notably, the patient demonstrates a "mosaic rescue" effect, where the mosaicism appears to have mitigated the neurodevelopmental phenotype (the patient is bilingual and ambulatory) while failing to protect the skeleton. (3) First Bone-Specific Therapy: The patient suffered from severe, recurrent fractures due to a synergistic "double hit" of TRPS1-related osteopenia and EXT1-related exostoses. We report the first successful use of bisphosphonate therapy (pamidronate) in this specific mosaic profile, which resulted in a complete cessation of fractures during a 12-month follow-up. This case underscores the utility of detailed microarray analysis in complex phenotypes and suggests bisphosphonates as a viable rescue therapy for refractory syndromic osteoporosis.

Objectives: The aroma profile is a key determinant of fruit quality.

Methods: In this study, mature 'Summer Black' grape berries were collected from 36 major producing areas in southern China to evaluate regional differences in fruit quality, volatile compounds were analyzed by via GC-MS, and a representative volatile profile was established. Furthermore, transcriptome sequencing was employed to identify key genes involved in the phenylpropanoid biosynthesis pathway related to aroma formation.

Results: The results showed the following: (1) Samples from CD-2 exhibited the highest soluble solid content and the largest TSS/TA ratio. (2) A total of 20 volatile compounds were selected as indicators for the aroma fingerprint. MS-1 samples contained the most diverse aroma compounds (19 types), while CS-2 had the fewest (12 types). (3) Eight aroma compounds were consistently detected across all regions: hexanal, trans-2-hexenal, n-hexanol, β-citronellol, geraniol, nerol, benzyl alcohol, and phenethyl alcohol. Among these, hexanal and trans-2-hexenal were the most abundant; phenylethyl alcohol exhibited the most significant variation in percentage content across all samples, and was determined to be the representative and dominant volatile compound in 'Summer Black' grapes. (4) A transcriptome analysis of six representative regions identified 15 differentially expressed genes associated with phenylpropanoid biosynthesis and metabolism. Among them, PAO (Vitvi04g01467) was significantly correlated with phenethyl alcohol content.

Conclusions: These findings provide a basis for evaluating the aroma quality of 'Summer Black' grapes and offer insights for regional cultivation selection.