Background: 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 RTEL1 and COL6A1 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. Methods: 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. Results: 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 EPAS1 and EGLN1 genes, which may have a positive effect under hypoxic conditions, as well as variants in TCAP, F5, GP1BA, and other genes involved in muscle activity and blood coagulation. Conclusions: This study identified rare variants in the EPAS1 and EGLN1 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.
BACKGROUND: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 EBNA-2 and EBNA-3 polymorphisms, with further subclassification predominantly based on BNLF-1 and EBNA-1 variations. Currently, EBV subtyping has not been performed using EBER genes. Thus, this study aimed to determine EBV subtypes in various malignant tumors and to assess the potential of EBER polymorphisms for EBV classification. METHODS: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 BNLF-1, EBNA-1, EBNA-3C, and EBER genes were amplified, and population sequencing was conducted. RESULTS:Based on EBNA-3C sequences, all tumor samples were genotype EBV-1, whereas the BNLF-1, EBNA-1, and EBER 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 EBER-based subclassification, which showed that the subtype Cro2 is more frequently present in cHL and AITL than in NPC. CONCLUSION:The results of this study show characteristic pattern of EBV diversity based on the EBNA-3C, EBNA-1, and BNLF-1 gene sequences, as well as the EBER 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.
Interfamilial hybridization between American paddlefish (Polyodon spathula) 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.
Background: 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, NTRK 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 NTRK gene fusions. Accordingly, this study aimed to investigate the clinical significance of NTRK1, NTRK2, and NTRK3 point mutations, gene fusions, and protein expression, and to assess the effectiveness of these in guiding targeted therapy decisions in NB. Methods: This study investigated pan-TRK expression, point mutations, and fusions in the NTRK1, NTRK2, and NTRK3 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, MYCN amplification, and 11q deletion status, with Pearson correlation analysis applied at the p < 0.05 significance level. Results: Immunohistochemistry (IHC) for NTRK revealed that 67.9% of cases were NTRK-positive. NGS analysis identified NTRK1 missense point mutations in 20 cases, NTRK2 in 9 cases, and NTRK3 in 9 cases. In addition, 5 fusions were detected in 4 of the 103 patients who underwent fusion analysis. Conclusions: 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.
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.
Background: 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 Drosophila larvae, including Glucose transporter 1 (Glut1), which encodes a glucose uniporter. Previous studies have identified metabolic functions of Glut1 in the whole fly brain; however, the specific neurons in which Glut1 acts to regulate nutrient storage remain unknown. Methods: To determine the neuronal populations in which Glut1 regulates lipid and carbohydrate storage, Glut1 levels were decreased in specific neurons, and triglycerides (TAGs) and glycogen levels were measured. We specifically decreased Glut1 expression in corazonin (Crz)-expressing neurons, a neuronal population that expresses the corazonin gene (Crz), which encodes a neuropeptide involved in carbohydrate metabolism. Results: Targeting RNAi against Glut1 in Crz 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, glycogen phosphorylase (Glyp) and glycogen synthase (Glys) as well as the Crz transcript. Notably, knocking down Glut1 in Crz-expressing neurons increased Glys and Crz transcript levels. Conclusions: These data suggest that Glut1 acts in the Crz-expressing neurons to regulate Crz levels and organismal glycogen metabolism.
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.
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.
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 (pperm ≤ 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.
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.
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: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: 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.
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: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.
Background: Histone deacetylase 1 (HDAC1) is a critical epigenetic regulator involved in chromatin remodeling and transcriptional repression, making it a valuable target for cancer therapy. Selective inhibition of HDAC1 represents a promising approach to cancer treatment, as it modulates gene expression and induces apoptosis in tumor cells. Methods: Two novel hydroxamate-based HDAC1 inhibitors, compounds 4 and 6, were designed and evaluated using molecular docking, molecular dynamics (MD) simulations, and enzymatic inhibition assays. Molecular docking assessed binding interactions, while MD simulations evaluated the stability of the ligand–protein complexes. Enzymatic inhibition assays were used to determine the IC50 values and evaluate the potency of the compounds. Results: Molecular docking revealed that both compounds exhibited significant interactions with HDAC1, including hydrophobic contacts, hydrogen bonding, and zinc coordination. Compound 4 demonstrated a stronger binding affinity (–6.2 kcal/mol) compared to compound 6 (–5.7 kcal/mol). The MD simulations confirmed that compound 4 exhibited greater stability, with divalent zinc coordination (4.3 Å and 4.8 Å), whereas compound 6 showed weaker monovalent coordination (4.4 Å). Enzymatic assays demonstrated that compound 4 had an IC50 of 2.96 ± 0.4 μM, while compound 6 exhibited an IC50 of 4.76 ± 0.5 μM; thus, compound 4 possesses superior inhibitory potency. Conclusions: Compound 4 exhibits enhanced binding affinity, stability, and enzymatic inhibition compared to compound 6, suggesting that this compound may serve as a promising lead for the development of selective HDAC1 inhibitors.
Background: A prior direct clinical and morphological comparison between non-coronavirus disease (COVID) myocarditis diagnosed before the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) pandemic and post-COVID myocarditis has not been performed. Purpose: To compare morphological activity, Toll-like receptor distribution, and response to immunosuppressive therapy in patients with non-COVID and post-COVID myocarditis. Methods: In total, 77 patients (52 male and 25 female, 48.7 ± 11.7 years old) with biopsy-proven myocarditis, New York Heart Association (NYHA) class 2 or higher heart failure diagnoses, and an ejection fraction (EF) <45% were included. The exclusion criteria comprised a history of myocardial infarction, verified cardiomyopathies, systemic autoimmune diseases, and viral DNA in the myocardium, except parvovirus B19. A right ventricular endomyocardial biopsy was performed using hematoxylin and eosin and Van Gieson staining assays, alongside the polymerase chain reaction (PCR) for viruses (herpes viruses, parvovirus B19, adeno-, enteroviruses, and SARS-CoV-2). Moreover, immunohistochemical assays were conducted for CD3, CD45, CD68, CD20, nucleocapsid/spike proteins of SARS-CoV-2, and the subcellular distribution of Toll-like receptors (TLRs) type 4 and 9 (in 38 patients). The steroids (methylprednisolone 24–40 mg per day), azathioprine, and mycophenolate mofetil were prescribed. This study was observational and non-interventional. The mean follow-up was 15.0 [6.0; 35.5] months. Results: Myocarditis was diagnosed in 45 patients before the SARS-CoV-2 pandemic (giant cell in one case and lymphocytic in the others). Another 32 patients had post-COVID myocarditis that was positive for RNA or/and proteins of SARS-CoV-2 (giant cell in one case, eosinophilic in three cases, and lymphocytic in the others). There were no differences in age, NYHA classification, C-reactive protein (CRP) and anti-heart antibodies levels, echocardiographic parameters (mean EF: 30.2 ± 7.8 vs. 28.7 ± 6.7%), parvovirus B19 positivity (22 vs. 34%), methylprednisolone dosages (24–40 mg/day), and death/transplantation rate (11.1 vs. 9.4%). Differences between non-COVID and post-COVID myocarditis focused on higher CD3, CD 45*, and toll-like receptors (TLR)-4 (4+ vs. 6+) and TLR-9 (0 vs. 2+) levels, alongside subcellular distribution and a better response to therapy ((10% or more increase in EF in 53 vs. 86%* of patients, mean EF (43.9 ± 12.3 vs. 49.8 ± 7.6%*) by the end of follow-up); *p < 0.05). Conclusion: Post-COVID myocarditis is characterized by different morphological types, higher morphological activity, the tendency to increase TLR expression, and an improved response to immunosuppressive therapy compared to non-COVID myocarditis.
BACKGROUND:The general assumption that spirochetemia does not occur at the early localized stage of Lyme disease is due to a lack of sensitive and specific methods for molecular diagnosis. METHODS:During a Lyme disease season in 2023, the platelet-rich plasma specimens of 145 people residing in Lyme disease-endemic areas in the United States were immediately separated from the blood cells following venous blood collection to prevent the spirochetes, if any, from invading the lymphocytes in the test tube. The entire DNA content was extracted from the platelet pellet and used for split sample polymerase chain reaction (PCR) amplification; Sanger sequencing was performed on the nested PCR products to detect the Borrelia burgdorferi flaB and 16S rRNA genes. RESULTS:In 98 of the people who were clinically suspected of having early localized Lyme disease irrespective of the presence or absence of a skin lesion, 33 of their blood specimens (33.7%) were positive for Borrelia burgdorferi (B. burgdorferi), including 17 positive for flaB gene only, 15 positive for both the flaB and 16S rRNA genes, and one positive for 16S rRNA gene only. Eight (17.0%) of the 47 asymptomatic resident controls were positive for flaB PCR only. CONCLUSIONS:The flaB gene is a more sensitive chromosomal target than the 16S rRNA gene for molecular detection of one to three B. burgdorferi cells due to spirochetes gaining or retaining flaB paralogs at the early localized stage of Lyme disease.
BACKGROUND:Staphylococcus aureus is a significant human pathogen. Therefore, differentiating Staphylococcus aureus (S. aureus) from coagulase-negative staphylococcal species is an important step in the diagnostics procedure. The coagulase tube test assay is used as a preliminary identification test; however, there are instances of S. aureus isolates testing negative. We hypothesized that this might affect clinical outcomes and that particular staphylocoagulase genotypes are not detected by the coagulase tube test. METHODS:In total, 122 clinical bloodstream S. aureus isolates with clinical metadata were examined for coagulating ability. The coa genotype was determined for each isolate using whole genome sequencing, and regions flanking the coa gene in the genome sequence were examined for synteny to identify differences that may indicate possible differences in coa gene regulation. In addition, a subset of isolates was assessed for coa gene expression using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS:All 122 isolates were found to have the coa gene, and all but one tested positive in the coagulase slide test. Comparatively, 18.9% of the isolates tested negative in the coagulase tube test assay. There was no association between an isolate having a negative tube test and having a complicated bloodstream infection. Among the 122 isolates, 11 coa genotypes were present, with similarities between the coa gene and comparative genome phylogenies and grouping of multilocus sequence types (MLST, abbreviated to ST), indicating that the coa gene may be vertically inherited. Staphylocoagulase type X and XI isolates were more likely to test negative in the coagulase tube test despite evidence of an intact functional coa gene. CONCLUSIONS:The S. aureus lineages may be negative in the coagulase tube test, especially ST15 and ST3911 (from staphylocoagulase genotype X). Our analysis suggests that the observed negativity in the coagulase tube test is due to the inability of particular coagulase types to coagulate the substrate provided in the commercial test. This has implications for using the tube test in differentiating Staphylococcus aureus isolates from other species. The Illumina genome sequencing read-set for each isolate was submitted to the National Center for Biotechnology Information (NCBI) under the accession number PRJNA611667.
