Frontiers in bioscience (Scholar edition)最新文献

Leigh syndrome (LS), first reported in 1951, is the most common primary mitochondrial disease. The overarching term, Leigh Syndrome Spectrum (LSS) was proposed by a ClinGen Expert Panel to encompass the wide continuum of neurodegenerative and non-neurologic manifestations which were associated with classic LS and Leigh-Like Syndrome (LLS). Notably, LSS typically presents developmental regression or delay by two years of age, with about 20% of cases presenting as late-/adult-onset forms after 2 years. Historically defined by clinical, biochemical, and neuropathological findings, the genetic basis of LSS has been elucidated through the use of Sanger and next-generation sequencing (NGS), resulting in the discovery of over 120 causative genes. Moreover, LSS can be caused by mutations in both nuclear-encoded genes and mitochondrial DNA (mtDNA), with overlapping clinical characteristics that occur at similar frequencies. This review aims to summarize the clinical and onset characteristics of LSS, genetic testing-aided diagnosis criteria, and the development of treatments. Furthermore, this review organizes the years since the first reports of gene and mutation discoveries into four consecutive eras: Clinical-Biochemical Era (1990-1999), Early Genomics Era (2000-2009), NGS Revolution Era (2010-2019), and Modern Era (2020-Present). Thus, using this framework, this review chronicles the evolution of LSS molecular genetics and treatment development, highlighting the shift from supportive care to targeted therapies driven by modern technologies. Cornerstone experimental models, such as the Ndufs4 ^-/-knockout mouse and patient-derived induced pluripotent stem cells (iPSCs), have facilitated mechanistic studies and drug repurposing screens, including the identification of sildenafil as a potential therapeutic agent, which has led to medical improvements in patients. Current advances in gene editing, including mitochondrial single-base editors such as eTd-mtABE and mitoBEs, are enabling gene therapy with precise introduction and correction of LS-causing variants in rat and mouse models. On the preventative front, Mitochondrial Replacement Therapy (MRT), guided by precise maternal mtDNA genotyping, has been successfully applied in clinical practice, allowing mothers carrying LSS-causing mtDNA variants to have healthy babies free of the LS manifestation. Collectively, these advances in gene discovery, genetic diagnosis, sophisticated disease modeling, rapid screening of small molecule drugs, precise gene editing for gene therapy, and innovative treatment strategies, such as MRT, are ushering in an era of precision medicine for LSS.

DNA double-strand breaks (DSB) represent one of the most severe forms of genomic damage. Thus, cells have evolved a complex network of DSB repair pathways, including homologous recombination, classical and alternative end joining, and single-strand annealing, which are tightly regulated by genetic and epigenetic factors. The selection and efficiency of these pathways influence genome integrity, oncogenesis, and therapeutic response. This comprehensive review synthesizes recent findings on the genetic regulation of DSB repair, with emphasis on pathway-specific regulators, chromatin context, and post-translational modifications. Moreover, this review integrates primary research from mammalian systems, including CRISPR-based studies, proteomics, and imaging, with a focus on publications from 2020 to 2025. We discuss the role of key players, such as MRE11-RAD50-NBS1 (MRN), ataxia telangiectasia mutated (ATM), mediator tumor suppressor p53-binding protein 1 (53BP1), breast cancer type 1 susceptibility protein (BRCA1), anti-silencing function 1 (ASF1), ring finger protein (RNF)8/168, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and RAD51 recombinase (RAD51), in orchestrating the associated pathway choice. Epigenetic modifications, RNA-mediated mechanisms, and chromatin remodeling dynamically influence the efficiency and fidelity of repair. Particular attention is provided to emerging regulators, including thyroid hormone receptor interactor 13 (TRIP13), ubiquitin-like with plant homeodomain (PHD) and RING finger domains 1 (UHRF1), Shieldin, and polymerase theta. This review highlights novel insights into transcription-associated DSB repair, the interplay of replication stress with repair pathway engagement, and context-dependent synthetic lethality. We also examine implications for cancer biology, including therapy resistance and biomarker development. Ultimately, understanding the genetic regulation of DSB repair pathways can provide critical insights into genome stability maintenance and reveal new therapeutic opportunities in cancer. Future work should focus on pathway crosstalk, phase-specific regulation, and integrating repair modulation into personalized medicine.

Background: Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age and are frequently associated with impaired fertility, reproductive dysfunction, and pregnancy complications. Arterial hypertension (AH) is another prevalent chronic condition in women, while increasing epidemiological evidence demonstrates the existence of a bidirectional relationship between UFs and AH. However, the genetic mechanisms underlying this association remain unclear. We hypothesized that UF-associated loci identified in genome-wide association studies (GWAS) may contribute to AH susceptibility.

Methods: Genomic DNA from 606 hospitalized patients with UFs (n = 178 with comorbid AH; n = 428 AH-free) underwent allele-specific PCR amplification targeting 17 common GWAS-derived polymorphisms.

Results: The rs1812266 (LOC105375949) locus was associated with a reduced risk of AH (odds ratio (OR) = 0.74; p = 0.028). Model-based multivariate dimensionality reduction (MB-MDR) analysis revealed significant gene-gene interactions (p_perm ≤ 0.05) involving UF loci and AH risk, including five key variants (rs66998222, LOC102723323; rs2456181, ZNF346; rs1812266, LOC105375949; rs10929757, GREB1; rs7986407, FOXO1) appearing in multiple models. Notably, rs66998222 was observed in five models, suggesting this residue possesses a central role. For gene-environment interactions, five variants, rs66998222, LOC102723323; rs1812266, LOC105375949; rs10929757, GREB1; rs2456181, ZNF346; rs2553772, LOC105376626, appeared in multiple models, with the smoking × rs66998222 interaction being central to five models. These six risk variants subsequently underwent systematic functional annotation to characterize the potential associated biological roles. Bioinformatics analysis indicated that single nucleotide polymorphisms (SNPs) associated with oxidative stress, renin-angiotensin-aldosterone system (RAAS) function, tissue fibrosis, angiogenesis, and smooth muscle cell remodeling are common mechanisms in both UFs and AH. Cis-eQTL genes and transcription factor (TF)-linked biological processes mediate these mechanisms. Validation using the Cardiovascular Disease Knowledge Portal confirmed the relevance of several SNPs to blood pressure traits.

Conclusions: To our knowledge, this is the first study to explore the genetic overlap between UFs and AH, providing novel molecular evidence for shared pathophysiological pathways. Our findings support the concept of a common genetic predisposition underlying both conditions and may inform new directions for integrated reproductive and cardiovascular health strategies.

Background: The relationship between genetic variations and susceptibility to infection provides insight into the pathogenesis of diseases caused by infections, illustrating host-pathogen interactions, informing preventive measures, and offering a novel therapeutic approach.

Methods: This cross-sectional study was conducted at Baghdad Medical City Hospital from April 2024 to October 2024 and involved 100 subjects referred to the laboratory for confirmatory diagnosis. Bacterial isolates were identified using routine phenotypic and biochemical tests. DNA was extracted from participants and used to genotype the rs231775 single-nucleotide polymorphism (SNP) using TaqMan® SNP Genotyping Assays; the serum levels of interleukin-7 (IL-7) were also determined for the studied groups.

Results: A total of 32 patients were infected with Acinetobacter baumannii, and 68 were controls. No statistically significant difference was noted between the blood group and the infection status (p = 0.109). The results indicated a highly statistically significant association between genotype AA and the occurrence of disease (p = 0.003) and an extremely significant association between genotype GG and the occurrence of disease (p < 0.001), respectively. The results indicated that individuals with the AA genotype had lower odds (odds ratio (OR) = 0.217) of having the disease, as did those with the AG genotype (OR = 0.80). However, the presence of the GG genotype GG exhibited higher odds in patients compared to the controls (OR = 5.439). Serum levels of IL-7 differed significantly between patients and controls (p < 0.001) and between the three genotype groups in patients (p = 0.029).

Conclusion: Individuals with genotypes AA and AG are characterized by protective attributes against infection with Acinetobacter baumannii, while those having the genotype GG are more prone to infection with this bacterium. Furthermore, an association between specific genotypes and serum levels of IL-7 can hint at the possible role of genetic polymorphism in modulating immune response in relation to bacterial infection.

Background: Developmental language disorders (DLDs) are common neurodevelopmental conditions, affecting approximately 7-10% of children, with significant impacts on communication, academic achievement, and social integration. While genetic factors are known contributors, the underlying genomic architecture and biological pathways remain incompletely understood. This analysis explores key genomic biomarkers of DLD and investigates their functional interactions.

Methods: We conducted an integrative genomic analysis combining multiple data-driven approaches. Using the Open Targets platform, we compiled a set of genes associated with DLD-related phenotypes (based on evidence scores ≥0.3) and constructed a gene-phenotype network to visualize these associations. Protein-protein interaction mapping of the identified genes was performed using the STRING database to uncover interaction clusters and shared pathways. We then analyzed sequence and structural relationships among the encoded proteins, including pairwise sequence homology (BLAST alignments), 3D structural modeling, and multimeric interaction prediction using AlphaFold 3.

Results: Our analysis identified 89 genes linked to 14 DLD-related phenotypic terms, with strong clustering around delayed speech. Several genes (e.g., GRN, MAPT, FOXP2, FOXP1, AP4E1) showed particularly high-confidence associations. Structural analysis of encoded proteins revealed unexpected similarity between functionally related but sequence-divergent pairs (e.g., WDR45 and GNB1). AlphaFold 3 modeling predicted a potential interaction between DCDC2 and KIAA0319, suggesting a plausible structural mechanism for their co-involvement in dyslexia.

Conclusions: DLDs emerge from diverse genetic contributors but converge on shared neurodevelopmental pathways. Structural modeling enhances genomic insights by uncovering hidden relationships and candidate interactions, paving the way for more precise genetic screening and functional studies in language disorders.

Kidney disease is a growing public health problem globally. Multiple or repeated acute injuries to the kidney due to chronic exposure to toxicants promote the development of chronic kidney disease (CKD), an irreversible disease for which there is no current treatment. Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is a well-known pathological stage during the progression of acute kidney injury (AKI) to CKD. Over the years, tremendous progress has been made in understanding the regulatory molecules involved in kidney fibrosis; however, there are currently no effective therapies for treating renal fibrosis. The mechanism involved in the transition of AKI to fibrosis and its progression to CKD involves various pathological changes, including cellular remodeling. At the molecular level, these pathological features are mediated by changes in the expression of genes and signaling pathways that control cellular dedifferentiation. Meanwhile, the generation of oxidative stress is a common feature of nephrotoxicants. Thus, the kidneys are highly susceptible to oxidative stress-induced injury, and accumulating evidence suggests that oxidative stress plays a causative role in the development of kidney disease. Oxidative stress has been shown to modulate various signaling pathways associated with AKI and fibrogenic changes in the kidney. Accumulating evidence suggests that targeting oxidative stress through antioxidants and/or inhibitors of reactive oxygen species (ROS)-regulated pathways holds promise for the clinical management of this disease, for which there is currently no effective therapy. This review summarizes the research development that provides a mechanistic perspective on the role of oxidative stress in regulating of target genes and signaling pathways associated with AKI and CKD. Additionally, recent reports highlighting the clinical significance of targeting oxidative stress for the treatment of CKD are discussed.

Background: Hydatidosis, caused by Echinococcus granulosus, is a neglected zoonotic disease with significant public health implications in endemic regions, such as in Cusco, Peru. Genetic factors influencing susceptibility to infection and responses to albendazole, the primary treatment, remain unclear. Thus, this study aimed to investigates genetic polymorphisms associated with hydatidosis susceptibility and albendazole metabolism in the Cusco region.

Methods: Hence, a cross-sectional study was conducted using 20 individuals from endemic areas. Peripheral blood samples were collected for genomic DNA extraction, followed by single-nucleotide polymorphism (SNP) genotyping using the Illumina Global Screening Array. Polymorphisms in genes related to immunity (interleukin 10 (IL10), interleukin 17A (IL17A), vitamin D receptor (VDR), interferon gamma (IFNG), forkhead box P3 (FOXP3), interleukin 4 (IL4), tumor necrosis factor (TNF), toll-like receptor 4 (TLR4), cytotoxic T-lymphocyte antigen 4 (CTLA4), mannose-binding lectin 2 (MBL2), interleukin 12B (IL12B), and transforming growth factor-beta 1 (TGFB1)) and drug metabolism genes (cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 2 subfamily B member 6 (CYP2B6), cytochrome P450 family 1 subfamily A member 2 (CYP1A2), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), and cytochrome P450 family 2 subfamily E member 1 (CYP2E1)) were analyzed.

Results: High-frequency alleles were identified in six SNPs associated with susceptibility to Echinococcus granulosus: IL10 rs1800896 (77.5%), IL17A rs2275913 (97.5%), IFNG rs2779249 (92.5%), FOXP3 rs11568821 (97.5%), TGFB1 rs1800469 (80.0%), and VDR rs2228570 (87.5%). Likewise, elevated allele frequencies were observed for two SNPs potentially involved in albendazole metabolism: CYP3A4 rs2740574 (87.5%) and CYP2B6 rs2266780 (97.5%). A comparative analysis with other populations revealed significant differences in SNP frequencies in the Cusco population, both in SNPs related to susceptibility (IL17A rs2275913, VDR rs2228570, and TGFB1 rs1800469; p < 0.001) and pharmacogenetic-related SNPs (CYP2B6 rs2266782, SLCO1B1 rs4149056, and CYP2E1 rs8330; p < 0.05), suggesting the existence of unique local genetic patterns.

Conclusion: These findings underscore the importance of pharmacogenetic screening to optimize albendazole therapy and support precision medical approaches for hydatidosis management in endemic regions. Further studies with larger cohorts are required to confirm these associations.

Background: The enterotype concept allows the differentiation of gut microbiota in relation to individual characteristics and is determined by the genetics and external stressors of the host. It was previously shown that not all clustering methods can accurately identify such enterotypes. Therefore, this pilot study primarily aimed to compare different algorithms for enterotype definition and to estimate the factors that correlate with the differentiation of the gut microbiota in adolescents with different body weights.

Methods: Adolescents with normal body weight (N) and obesity (O) (aged 11-17 years) were included in this pilot study. Based on the analysis of the V3-V4 variable regions of the 16S ribosomal RNA gene amplicon libraries, the main enterotypes of the gut microbiota of adolescents were characterized using three approaches (E-typing A, B, and C) according to the bacterial taxa that were chosen for differentiation. For sample clustering, we used Bray-Curtis, Jensen-Shannon divergence, and weighted and unweighted UniFrac distance metrics. Clustering was assessed using the silhouette index. Meanwhile, the Kruskal-Wallis test was used to determine the relationship between enterotype and biochemical parameters.

Results: The O and N groups comprised 18 and 22 adolescents, respectively, and, according to anthropometric data, differed significantly only in weight and body mass index (BMI). The linear discriminant analysis effect size (LEfSe) plot showed that the presence of minor and rare phylotypes in the gut microbiota differed between the two groups of adolescents. The distribution of individual samples based on the principal coordinates analysis (PCoA) showed that the gut microbiomes in the adolescents were not grouped in the N or O groups but were distributed according to the composition of the main bacterial taxa. We assessed the contribution of the Bacteroides, Prevotella, Subdoligranulum, and Ruminococcus phylotypes to the microbiota of the adolescents in the two groups. The Subdoligranulum enterotype was significantly more represented in the N group than in the O group when the E-typing A approach to enterotyping was applied. Pairwise comparisons were performed with corrections for multiple testing between the biochemical parameter levels of the different enterotypes. Bilirubin levels were lower in adolescents with the gut microbiota enterotype Ruminococcus-Subdoligranulum than in those with the enterotype Bacteroides when the E-typing B approach was used for differentiation.

Conclusions: This pilot study comprised a small group of adolescents with normal body weight and obesity; we identified Bacteroides as the main enterotype, regardless of body weight. A stable microbial community is formed in the gut during adolescence, which determines its stratification by enterotype.

Background: Varicocele, a common condition affecting male fertility, has been linked to impaired semen quality and elevated sperm DNA fragmentation (SDF). This study aimed to evaluate the epidemiological prevalence of varicocele and SDF in infertile men and compare the effectiveness of microsurgical varicocelectomy and antioxidant therapy in improving semen parameters and reducing SDF.

Methods: This multi-center study included 3632 subfertile and 276 fertile men in the epidemiological phase (retrospective) and 182 infertile men in the comparative analysis phase (prospective). Patients were stratified into three groups: Group 1 (microsurgical varicocelectomy, n = 86), Group 2 (antioxidant therapy, n = 63), and Group 3 (control, n = 33). Varicocele prevalence, semen parameters, and SDF levels were assessed, with follow-up evaluations conducted three months post-intervention. Semen parameters were evaluated using the World Health Organization (WHO) Fifth Edition guidelines, and SDF was measured using the sperm chromatin dispersion test.

Results: Varicocele was observed in 29.5% of subfertile men and 27.2% of fertile men, with no statistically significant difference noted (p = 0.18). However, subfertile men with varicocele exhibited significantly higher median SDF levels (20.8%, interquartile range (IQR): 14.1-27.9) compared to fertile men (12.3%, IQR: 9.1-16.5; p < 0.001). Microsurgical varicocelectomy significantly improved semen parameters, with the median sperm concentration increasing by +25.0 million/mL (IQR: 18.4-31.5; p < 0.001) and progressive motility by +67.0% (IQR: 50.0-83.5; p < 0.001). Antioxidant therapy yielded moderate improvements in sperm concentration (+11.0 million/mL, IQR: 8.0-14.5; p < 0.001) and motility (+6.0%, IQR: 4.0-8.5; p = 0.01). The control group showed no significant changes.

Conclusion: This study reveals comparable varicocele prevalence between subfertile (29.5%) and fertile men (27.2%), with impaired semen quality and elevated SDF levels in subfertile cases. Microsurgical varicocelectomy proved most effective, while antioxidant therapy offered a viable alternative or adjunct for non-surgical candidates, underscoring the need for tailored varicocele infertility treatments.

Background: Leaf rust caused by Puccinia triticina Erikss. is a widely distributed wheat (Triticum aestivum L.) disease. Using wild relatives, such as Triticum spelta L., as a source of desirable traits represents a good strategy for developing wheat varieties, as T. spelta L. has shown tolerance to various types of biotic and abiotic stresses. This study aimed to determine the genetic basis of resistance to leaf rust in the accession Triticum spelta 109 (PI 355580).

Methods: The resistant genotype T. spelta 109 was crossed with the bread wheat variety Roelfs F2007, and 135 F₃ families were generated to analyze the genetics of resistance to the MBJ/SP leaf rust race. The families were classified into three groups: (i) homozygous-resistant; (ii) homozygous-susceptible; (iii) segregating. A χ² test was performed to compare whether the expected and observed segregation ratios fit and to determine the number of genes involved in the resistance of T. spelta 109.

Results: The seedling tests in the F1 generation showed susceptibility in all plants, indicating that the resistance is conferred by a recessive gene(s). The results of the χ² test revealed that the observed segregation ratios of the F3 families followed the expected values, suggesting that a recessive gene confers the leaf rust resistance present in T. spelta 109. According to our results and the reported recessive genes identified among the T. spelta accessions, the identified recessive gene in T. spelta 109 (PI355580) is different and most likely a novel leaf rust resistance gene.

Conclusions: The genetic resistance to leaf rust of T. spelta 109 (PI 355580) is conferred by a single recessive gene. The importance and usefulness of searching for rust resistance genes from different sources and incorporating them into the genetic base of wheat breeding programs to provide diversity is confirmed.