Frontiers in bioscience (Scholar edition)最新文献

{"title":"The Role of the Microbiome in the Development of an Autoimmune Reaction in Rheumatoid Arthritis.","authors":"Alexander Blagov, Aleksey A Vatlin, Vsevolod V Pavshintsev, Nikita A Mitkin, Olga N Maltseva, Alexander N Orekhov","doi":"10.31083/FBS44236","DOIUrl":"10.31083/FBS44236","url":null,"abstract":"<p><p>Patients with rheumatoid arthritis (RA), a chronic inflammatory illness, have joint inflammation, increasing tissue damage, and severe disability, all of which negatively impact quality of life. While the precise mechanisms behind RA remain unknown, there is growing evidence that both the onset and development of the illness are closely linked to an imbalance in the intestinal microbiota. Variations in the microbial content of RA patients and healthy people suggest that the gut microbiota plays a part in regulating immunological responses and fostering inflammation. Thus, therapies aimed at restoring the microbiome to its original state have demonstrated encouraging results in terms of increasing therapeutic efficacy, improving patient outcomes, and delaying the progression of disease. However, more research is needed to clarify the intricate interactions between the intestinal microbiota and autoimmunity mechanisms in RA.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 2","pages":"44236"},"PeriodicalIF":0.0,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Dependent Association of <i>SMAD3</i> Gene Polymorphisms With Asthma and Allergy Risk in Russian Children.","authors":"Alexandra V Serezhkina, Olga Yu Bushueva, Maxim B Freidin, Alexey D Bogomazov, Vyacheslav I Puchkov, Alexey V Polonikov","doi":"10.31083/FBS46479","DOIUrl":"10.31083/FBS46479","url":null,"abstract":"<p><strong>Background: </strong>Despite significant advances in identifying susceptibility genes for bronchial asthma (BA), the immunogenetic and other molecular mechanisms underlying disease risk and progression remain incompletely understood. This study aimed to investigate the association between two common single-nucleotide polymorphisms (SNPs), rs17293632 and rs2033784, located within the <i>SMAD3</i> (SMAD family member 3) gene-previously identified in genome-wide association studies-and susceptibility to atopic asthma and allergen sensitivity in Russian children.</p><p><strong>Methods: </strong>This study included DNA samples from 999 unrelated children from the Kursk region, comprising 526 patients with BA (316 boys and 210 girls) and 473 healthy children. SNP genotyping was performed using the MassARRAY-4 system.</p><p><strong>Results: </strong>Both SNPs were associated with an increased risk of BA under the additive genetic model (<i>p</i> ≤ 0.001). In the sex-stratified analysis, the rs17293632 (odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.15-2.77; <i>p</i> = 9.0 × 10^-4) and rs2033784 (OR = 1.80, 95% CI: 1.28-2.52; <i>p</i> = 6.0 × 10^-4) variants were exclusively associated with asthma risk among girls, whereas no significant associations were observed in boys. The rs17293632T-rs2033784G haplotype was associated with an increased risk of asthma in girls (OR = 2.01, 95% CI: 1.38-2.92, <i>p</i> = 3.0 × 10^-4). Notably, <i>SMAD3</i> gene polymorphisms were associated with an increased risk of asthma exclusively among children living in urban environments (<i>p</i> ≤ 0.0001). Polymorphisms in the <i>SMAD3</i> gene have also been linked to specific allergies, including those to horsehair, chicken eggs, beef, wheat, oatmeal, barley, and foxtail.</p><p><strong>Conclusions: </strong>The present study of Russian children confirmed that the rs17293632 and rs2033784 polymorphisms of the <i>SMAD3</i> gene are significant genetic markers associated with BA and allergies. However, an association between these <i>SMAD3</i> variants and asthma was observed only among girls, marking the first time this association has been reported. Further research is necessary to determine whether the <i>SMAD3</i> gene constitutes a viable therapeutic target for treating asthma and allergic diseases.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 2","pages":"46479"},"PeriodicalIF":0.0,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Evaluation of Neurotrophic Receptor Tyrosine Kinase (NTRK) Alterations in Neuroblastomas.","authors":"Nuriya Ismayil, Sefayi Merve Özdemir, Tekincan Çağrı Aktaş, Özde Elif Gökbayrak, Aylin Erol, Deniz Kızmazoğlu, Safiye Aktaş","doi":"10.31083/FBS46963","DOIUrl":"10.31083/FBS46963","url":null,"abstract":"<p><strong>Background: </strong>Neuroblastoma (NB) is the most common extracranial solid tumor among pediatric cancers and accounts for approximately 15% of childhood cancer-related deaths. Neurotrophic receptor tyrosine kinases (NTRKs) are genes that play critical roles in the development and function of the nervous system. Therefore, elucidating the role of NTRKs in NB is important for both understanding basic biological mechanisms and developing novel therapeutic approaches. Specifically, <i>NTRK</i> fusions are being investigated as potential biomarkers and therapeutic targets for targeted therapy strategies. The tumor-agnostic TRK inhibitors larotrectinib and entrectinib are used to treat advanced or metastatic solid tumors with <i>NTRK</i> gene fusions. Accordingly, this study aimed to investigate the clinical significance of <i>NTRK1</i>, <i>NTRK2</i>, and <i>NTRK3</i> point mutations, gene fusions, and protein expression, and to assess the effectiveness of these in guiding targeted therapy decisions in NB.</p><p><strong>Methods: </strong>This study investigated pan-TRK expression, point mutations, and fusions in the <i>NTRK1</i>, <i>NTRK2</i>, and <i>NTRK3</i> genes using next-generation sequencing (NGS) on paraffin-embedded blocks from 173 patients diagnosed with NB. Findings were analyzed in SPSS 29.0 using clinical data, <i>MYCN</i> amplification, and 11q deletion status, with Pearson correlation analysis applied at the <i>p</i> < 0.05 significance level.</p><p><strong>Results: </strong>Immunohistochemistry (IHC) for NTRK revealed that 67.9% of cases were NTRK-positive. NGS analysis identified <i>NTRK1</i> missense point mutations in 20 cases, <i>NTRK2</i> in 9 cases, and <i>NTRK3</i> in 9 cases. In addition, 5 fusions were detected in 4 of the 103 patients who underwent fusion analysis.</p><p><strong>Conclusions: </strong>Owing to the presence of neural tissue, NTRKs are highly positive in IHC, making these genes unsuitable as biomarkers for assessing NTRK inhibitor sensitivity and resistance, which are tissue-agnostic drugs. The observed low fusion rate is consistent with the literature, and the significance of the numerous point mutations identified as agnostic markers warrants further investigation. NTRK expression, fusion, and point mutations were not associated with clinical parameters or survival.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"46963"},"PeriodicalIF":0.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Characterization of the Epstein-Barr Virus in Malignant Tumors of Different Origins: An Emphasis on <i>EBER</i> Promoter Value for EBV Classification.","authors":"Valerija Begić, Petra Šimičić, Kristian Bodulić, Slavko Gašparov, Suzana Hančić, Roberto Galov, Marija Rozman, Paula Gršković, Snježana Židovec-Lepej, Petra Korać","doi":"10.31083/FBS46442","DOIUrl":"10.31083/FBS46442","url":null,"abstract":"<p><strong>Background: </strong>Epstein-Barr virus (EBV) is a well-known cause of infectious mononucleosisand it has also been linked to the development of various malignant tumors. EBV can be classified into two genotypes based on <i>EBNA-2</i> and <i>EBNA-3</i> polymorphisms, with further subclassification predominantly based on <i>BNLF-1</i> and <i>EBNA-1</i> variations. Currently, EBV subtyping has not been performed using <i>EBER</i> genes. Thus, this study aimed to determine EBV subtypes in various malignant tumors and to assess the potential of <i>EBER</i> polymorphisms for EBV classification.</p><p><strong>Methods: </strong>DNA was isolated from tissue samples of patients diagnosed with classical Hodgkin lymphoma (cHL), angioimmunoblastic T cell lymphoma (AITL), and nasopharyngeal carcinoma (NPC). Specific fragments of the <i>BNLF-1</i>, <i>EBNA-1</i>, <i>EBNA-3C</i>, and <i>EBER</i> genes were amplified, and population sequencing was conducted.</p><p><strong>Results: </strong>Based on <i>EBNA-3C</i> sequences, all tumor samples were genotype EBV-1, whereas the <i>BNLF-1</i>, <i>EBNA-1</i>, and <i>EBER</i> sequences indicated that the tumor tissues were infected with different EBV subtypes. The B95-8 subtype predominated in cHL, whereas North Carolina and P-ala were the most frequent subtypes in NPC. In addition, we propose a newly designed algorithm for <i>EBER</i>-based subclassification, which showed that the subtype Cro2 is more frequently present in cHL and AITL than in NPC.</p><p><strong>Conclusion: </strong>The results of this study show characteristic pattern of EBV diversity based on the <i>EBNA-3C</i>, <i>EBNA-1</i>, and <i>BNLF-1</i> gene sequences, as well as the <i>EBER</i> promoter sequence in AITL, NPC, and cHL cohorts specific for the Caucasian population of southeastern Europe; however, these results may not relate to the distribution of EBV variants in other geographic areas.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"46442"},"PeriodicalIF":0.0,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glut1 Acts in Corazonin-Producing Neurons to Regulate Glycogen Storage in <i>Drosophila</i>.","authors":"Prem Patel, Justin R DiAngelo","doi":"10.31083/FBS47458","DOIUrl":"10.31083/FBS47458","url":null,"abstract":"<p><strong>Background: </strong>Metabolic homeostasis is regulated by numerous genes, whose dysregulation leads to metabolic diseases such as obesity and diabetes. Several genes important for lipid storage were identified in a buoyancy-based screen in <i>Drosophila</i> larvae, including <i>Glucose transporter 1</i> (<i>Glut1</i>), which encodes a glucose uniporter. Previous studies have identified metabolic functions of <i>Glut1</i> in the whole fly brain; however, the specific neurons in which Glut1 acts to regulate nutrient storage remain unknown.</p><p><strong>Methods: </strong>To determine the neuronal populations in which <i>Glut1</i> regulates lipid and carbohydrate storage, <i>Glut1</i> levels were decreased in specific neurons, and triglycerides (TAGs) and glycogen levels were measured. We specifically decreased <i>Glut1</i> expression in corazonin (<i>Crz</i>)-expressing neurons, a neuronal population that expresses the corazonin gene (<i>Crz</i>), which encodes a neuropeptide involved in carbohydrate metabolism.</p><p><strong>Results: </strong>Targeting RNAi against <i>Glut1</i> in <i>Crz</i> neurons reduced glycogen levels in males but did not alter TAG levels. To further characterize this nutrient storage phenotype, we measured the expression of two genes involved in glycogen storage, <i>glycogen phosphorylase</i> (<i>Glyp</i>) and <i>glycogen synthase</i> (<i>Glys</i>) as well as the <i>Crz</i> transcript. Notably, knocking down <i>Glut1</i> in <i>Crz</i>-expressing neurons increased <i>Glys</i> and <i>Crz</i> transcript levels.</p><p><strong>Conclusions: </strong>These data suggest that Glut1 acts in the <i>Crz</i>-expressing neurons to regulate <i>Crz</i> levels and organismal glycogen metabolism.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"47458"},"PeriodicalIF":0.0,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Genetic Feasibility of Gonadal Development and Fertility in Polyodon-Acipenserid Interfamilial Hybrids: An Opinion on the Chromosomal Basis.","authors":"Jenő Káldy, Gyula Kovács, Katalin Bogár, Balázs Kovács, Eszter Várkonyi","doi":"10.31083/FBS47666","DOIUrl":"10.31083/FBS47666","url":null,"abstract":"<p><p>Interfamilial hybridization between American paddlefish (<i>Polyodon spathula</i>) and Acipenserid (sturgeon) species produces viable hybrid offspring. However, the potential fertility of these hybrids is a critical issue for understanding sex determination mechanisms within Acipenseriformes, as well as for aquaculture and species conservation programs. Investigating the fertility of such hybrids requires an integrative focus on the genetic basis of sex determination and gonadal differentiation. Based on current knowledge of sturgeon sex determination systems, the fundamental genetic framework for gonadal development is assumed to be at least partially retained in Polyodon-Acipenserid hybrids. Nevertheless, the meiotic processes governing gametogenesis may be affected by chromosomal or regulatory incompatibilities. To date, the available evidence does not indicate complete disruption of meiosis. However, further cytogenetic and molecular analyses are needed to clarify the extent of functional gametogenesis and the reproductive potential of these hybrids.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"47666"},"PeriodicalIF":0.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-impact Genetic Variants in <i>EGLN1</i>, <i>EPAS1</i>, and Other Genes Identified in Mountaineers by Exome Sequencing.","authors":"Evgeniia M Maksiutenko, Valeriia А Merkureva, Yury A Barbitoff, Mikhail V Aseev, Tatyana E Lazareva, Andrey S Glotov, Oleg S Glotov","doi":"10.31083/FBS38966","DOIUrl":"10.31083/FBS38966","url":null,"abstract":"<p><strong>Background: </strong>Investigating the genetic basis of adaptation to environmental stresses, such as hypoxia, can enhance our understanding of human biology and resilience. High-altitude adaptation provides a valuable model for studying the genetic mechanisms of the hypoxic response. Indeed, most known loci associated with hypoxic adaptation have been identified in indigenous mountain populations; however, research on elite climbers remains limited. In our previous study, we conducted exome sequencing of experienced mountaineers and identified two pathogenic variants in the <i>RTEL1</i> and <i>COL6A1</i> genes, both of which are linked to respiratory failure. These findings encouraged this study, which conducted exome sequencing to explore genetic variation in a larger cohort.</p><p><strong>Methods: </strong>We performed exome sequencing for a cohort of 114 mountaineers with varying levels of experience. Variant calling was performed in the sequencing data using a pipeline based on the Genome Analysis Toolkit (GATK) v.4.1.9. Annotated variants were used to identify rare and common variants with possible effects on high-altitude adaptation.</p><p><strong>Results: </strong>The analysis did not identify any common adaptive variants in these individuals; however, nine variants were identified as potentially relevant to high-altitude adaptation and climbing performance. These included novel variants in the <i>EPAS1</i> and <i>EGLN1</i> genes, which may have a positive effect under hypoxic conditions, as well as variants in <i>TCAP</i>, <i>F5</i>, <i>GP1BA</i>, and other genes involved in muscle activity and blood coagulation.</p><p><strong>Conclusions: </strong>This study identified rare variants in the <i>EPAS1</i> and <i>EGLN1</i> genes, which had previously been associated with high-altitude adaptation. Additionally, we describe several potentially pathogenic variants in genes not previously linked to hypoxia, highlighting the value of studying elite mountaineers as a unique cohort for broader interpretation of genetic variation.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"38966"},"PeriodicalIF":0.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Review of Potential Diagnostic and Therapeutic Developments in Systemic Lupus Erythematosus (SLE).","authors":"Alexander Blagov, Vladislav Kalmykov, Alikhan Asoyan, Olga Maltseva, Alexander Orekhov","doi":"10.31083/FBS39493","DOIUrl":"10.31083/FBS39493","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE), a complex autoimmune disease, affects multiple tissues and organs, presenting substantial challenges for both diagnosis and treatment. Both innate and adaptive immune cells are involved in the intricate pathophysiology of SLE. The characteristics of SLE include the production of autoantibodies and the formation of immune complexes that accumulate within the vasculature, leading to organ damage. Although progress in understanding the pathogenesis of SLE has lagged behind that of other autoimmune rheumatic diseases, recent findings have highlighted promising therapeutic targets and raised the prospect of personalized treatment strategies. This narrative review was conducted through a comprehensive analysis of recent literature focused on the pathogenesis, diagnosis, and treatment of SLE. Prospective experimental and clinical studies with well-documented results were selected for analysis. Diagnostic biomarkers were evaluated for their sensitivity, specificity, and correlation with disease activity indices, such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Therapeutic agents, including monoclonal antibodies, interferon, and interleukin inhibitors, as well as emerging small molecules, were assessed based on clinical trial outcomes and potential future applicability in clinical practice. Several promising biomarkers, such as pentraxin 3 (PTX3), S100 calcium-binding protein A8 (S100A8), B cell differentiation factor (BCDF), interferon gamma-induced protein 10 (IP-10), urinary activated leukocyte cell adhesion molecule (ALCAM), vascular cell adhesion molecule 1 (VCAM-1), and platelet factor 4 (PF4), have shown strong correlations with disease activity and lupus nephritis (LN). Among treatments, monoclonal antibodies, such as belimumab and anifrolumab, are already approved by the United States Food and Drug Administration. Meanwhile, others, including obinutuzumab and sifalimumab, have demonstrated encouraging results in Phase II trials. These developments reflect growing potential for precision diagnostics and targeted therapy in SLE. Recent advances in understanding the immunological underpinnings of SLE have led to the identification of sensitive and specific biomarkers, as well as novel biologics, which may overcome the limitations of traditional therapies. Biomarkers such as PTX3 and S100A8 can facilitate early diagnosis and may also predict treatment efficacy, offering the foundation for tailored therapeutic strategies. The continued evaluation of emerging biologics, particularly those targeting B cells and the interferon pathway, holds promise for enhancing disease management and improving long-term patient outcomes.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"18 1","pages":"39493"},"PeriodicalIF":0.0,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Path to Precision Medicine in Leigh Syndrome Spectrum: A Four-Decade Chronicle of Genetic Discovery and Targeted Treatment.","authors":"Lishuang Shen","doi":"10.31083/FBS45427","DOIUrl":"10.31083/FBS45427","url":null,"abstract":"<p><p>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 <i>Ndufs4</i> ^-/-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.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"17 4","pages":"45427"},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Regulation of DNA Double-Strand Breaks and Repair Pathways.","authors":"Lucián Zastko","doi":"10.31083/FBS46225","DOIUrl":"10.31083/FBS46225","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":73070,"journal":{"name":"Frontiers in bioscience (Scholar edition)","volume":"17 4","pages":"46225"},"PeriodicalIF":0.0,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}