Search Results (4,608)

The epigenetic landscape plays a pivotal role in regulating the functions of both germ and somatic cells (Sertoli and Leydig cells) within the testis, which are essential for male fertility. While somatic cells support germ cell maturation and testosterone synthesis, the epigenetic regulation of germ cells is critical for proper spermatogenesis and function. Epigenetic modifications such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) are crucial for regulating gene expression that is essential for spermatogenesis and reproductive function. Although numerous studies have highlighted the significance of the epigenome and its implications for male reproductive health, a comprehensive overview of the existing literature and knowledge is lacking. This review aims to provide an in-depth analysis of the role of epigenetics in spermatogenesis and reproductive health, with a specific focus on DNA methylation, histone remodeling, and small noncoding RNAs (sncRNAs). Additionally, we examine the impact of lifestyle and environmental factors, such as diet, smoking, physical activity, and exposure to endocrine-disrupting chemicals, on the sperm epigenome. We emphasize how these factors influence fertility, embryonic development, and potential transgenerational inheritance. This review underscores how recent advances in the understanding of the epigenetic modulation of testicular function can inform the pathophysiology of male infertility, thereby paving the way for the development of targeted diagnostic and therapeutic strategies. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Background/Objectives: Pregnancy is associated with increased procoagulant conditions, and when combined with obesity, it can elevate the risk of thrombosis. The study aims to assess thrombosis risk markers during pregnancy in relation to obesity. Methods: Somatically healthy women aged 18–42 years with spontaneous pregnancies who did not receive specific antithrombotic treatment were enrolled in the study (n = 97). The participants were divided into groups based on pregestational BMI: the first group consisted of patients who had a BMI ≤ 25 (n = 42), and the second group consisted of patients who were overweight (BMI > 25) and obese (BMI > 30) (n = 55). The control group comprised healthy, non-pregnant, non-obese women (n = 10). Results: Fibrinogen levels, elevated during pregnancy, were higher in the II and III trimesters, with gestational period having a greater influence than BMI. Moderate D-dimer accumulation was observed regardless of obesity, but higher levels were seen in obese women during the III trimester, indicating the dissolution of intravascular fibrin deposits. Soluble fibrin was significantly higher in obese and overweight women during the II trimester and elevated in both groups during the III trimester, correlating with D-dimer accumulation and indicating thrombus formation. A decrease in platelet aggregation ability was observed correlating with D-dimer and soluble fibrin patterns. Conclusions: A significant accumulation of thrombosis risk markers was observed in the III trimester compared to the II, occurring earlier in obese and overweight pregnant women and indicating a higher risk of thrombotic complications in obesity. Full article

Background/Objectives: Given the heterogeneous nature of long COVID, its treatment and management remain challenging. This study aimed to investigate whether poor pre-pandemic sleep quality, its deterioration during the peak of the pandemic, and circadian preference increase the risk of long COVID symptoms. Methods: An online survey was conducted between 9 October and 12 December 2022, with 384 participants who had recovered from COVID-19 at least three months prior to data collection. Participants were categorized based on the presence of at least one long COVID symptom. Logistic regression models assessed associations between sleep-related variables and long COVID symptoms. Results: Participants with long COVID symptoms reported significantly poorer sleep quality, higher perceived stress, greater somatic and cognitive pre-sleep arousal, and elevated levels of post-traumatic stress symptoms, anxiety, depression, and aggression. Fatigue (39.8%) and memory problems (37.0%) were the most common long COVID symptoms. Sleep deterioration during the pandemic peak was reported by 34.6% of respondents. Pre-pandemic poor sleep quality, its deterioration during the pandemic, and poor sleep at the time of the survey were all significantly associated with long COVID. An extreme morning chronotype consistently predicted long COVID symptoms across all models, while an extreme evening chronotype was predictive only when accounting for sleep quality changes during the pandemic. COVID-19 frequency, severity, financial impact, and somatic pre-sleep arousal were significant predictors in all models. Conclusions: Poor sleep quality before the pandemic and its worsening during the pandemic peak are associated with a higher likelihood of long COVID symptoms. These findings underscore the need to monitor sleep health during pandemics and similar global events to help identify at-risk individuals and mitigate long-term health consequences, with important clinical and societal implications. Full article

Background and Objectives: Toe walking (TW) is frequently observed in children with Autism Spectrum Disorder (ASD), yet its clinical significance and association with comorbid conditions remain poorly understood. This study aimed to examine the prevalence of TW in a large Italian cohort of children with ASD and to explore its association with ASD severity, sleep disturbances, feeding behaviors, and gastrointestinal symptoms. Materials and Methods: A total of 289 children with ASD and 289 typically developing controls (TDC), matched for age and sex, were evaluated in a multicentric observational study. TW was assessed during neurodevelopmental evaluations. Sleep quality was assessed using the Sleep Disturbance Scale for Children (SDSC), feeding behaviors via the Brief Autism Mealtime Behavior Inventory (BAMBI), and gastrointestinal symptoms through clinical reporting. Statistical analyses included Chi-square tests, Mann–Whitney U tests, Spearman correlations, and logistic regressions. Results: TW was significantly more prevalent in the ASD group (27.3%) than in TDC (5.5%, p < 0.0001). Within the ASD group, TW occurred in 50.5% of children with Level 3 severity but was absent in Levels 1 and 2 (p < 0.0001). Males exhibited TW more frequently than females. Children with TW had higher SDSC scores (ρ = 0.33, p < 0.0001), though no subscale independently predicted TW. Constipation was reported in 100% of children with Level 3 ASD and was strongly correlated with SDSC total scores (ρ = 0.58, p < 0.0001). The Disorders of Arousal (DA) subscale emerged as an independent predictor of constipation (β = 0.184, p = 0.019). Conclusions: TW in ASD appears to be a marker of greater neurodevelopmental severity and is associated with sleep disturbances and gastrointestinal dysfunction. These findings support the hypothesis that TW may reflect broader dysfunctions involving the gut–brain axis, sensory processing, and motor control. The routine clinical assessment of TW should include the evaluation of sleep and somatic symptoms to better understand the multisystemic nature of ASD phenotypes. Full article

Chronic visceral pain, a significant contributor to morbidity in the United States, affects millions and results in substantial economic costs. Despite its impact, the mechanisms underlying disorders of gut–brain interaction (DGBIs), such as irritable bowel syndrome (IBS), remain poorly understood. Visceral hypersensitivity, a hallmark of chronic visceral pain, involves an enhanced pain response in internal organs to normal stimuli. Various factors like inflammation, intestinal hyperpermeability, and epigenetic modifications influence its presentation. Emerging evidence suggests that persistent colonic stimuli, disrupted gut barriers, and altered non-coding RNA (ncRNA) expression contribute to the pathophysiology of visceral pain. Additionally, cross-sensitization of afferent pathways shared by pelvic organs underpins the overlap of chronic pelvic pain disorders, such as interstitial cystitis and IBS. Central sensitization and viscerosomatic convergence further exacerbate pain, with evidence showing IBS patients exhibit hypersensitivity to both visceral and somatic stimuli. The molecular mechanisms of visceral pain involve critical mediators such as cytokines, prostaglandins, and neuropeptides, alongside ion channels like transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channels (ASICs). These molecular insights indicate potential therapeutic targets and highlight the possible use of TRPV1 antagonists and ASIC inhibitors to mitigate visceral pain. This review explores the neurophysiological pathways of visceral pain, focusing on peripheral and central sensitization mechanisms, to advance the development of targeted treatments for chronic pain syndromes, particularly IBS and related disorders. Full article

B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired hippocampal long-term potentiation (LTP). To elucidate the mechanism(s) underlying diminished synaptic plasticity in B-raf-deficient mice, we performed whole-cell recordings from CA1 pyramidal cells in hippocampal slices of control and B-raf mutant mice. We found that the NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) at the Schaffer collateral—CA1 pyramidal cell synapses was significantly reduced in B-raf mutants, which would at least partially account for their impaired LTP. Interestingly, the reduced NMDA component of field postsynaptic potentials in mutant preparations was partially reinstated by blocking the apamin-sensitive small-conductance Ca²⁺-activated K⁺ (SK) channels, which have also been reported to modulate hippocampal LTP and learning tasks. To determine the impact of B-raf-dependent signaling on SK current, we isolated the apamin-sensitive tail current after a strong depolarizing event and found indeed a significantly bigger SK current in B-raf-deficient cells compared to controls, which is consistent with the reduced action potential firing and the stronger facilitating effect of apamin on CA1 somatic excitability in B-raf-mutant hippocampus. Our data suggest that B-raf signaling readjusts the delicate balance between NMDA receptors and SK channels to promote synaptic plasticity and facilitate hippocampal learning and memory. Full article

Background and Clinical Significance: Inherited thrombocytopenia (IT) is a heterogeneous group of disorders caused by mutations in over 45 genes. Among these, ANKRD26-related thrombocytopenia (ANKRD26-RT) accounts for a notable subset and is associated with variable bleeding tendencies and an increased risk of myeloid malignancies. However, the extent of this oncogenic risk appears to vary between specific gene variants. Understanding the genotype–phenotype relationship is essential for patient counseling and management. This report presents a multigenerational family carrying the rare c.−118C > G variant in the 5′ untranslated region of ANKRD26, contributing to the discussion on variant-specific cancer predisposition. Case Presentation: Two sisters aged 57 and 60 presented with lifelong bleeding diathesis and moderate thrombocytopenia. Their symptoms included easy bruising, menorrhagia, and excessive postoperative bleeding. Genetic testing confirmed heterozygosity for the ANKRD26 c.−118C > G variant. Bone marrow analysis revealed abnormal megakaryopoiesis without evidence of dysplasia or somatic mutations. One sister underwent major surgery without complications when managed with prophylactic hemostatic therapy. Their family history included multiple female relatives with similar symptoms, although formal testing was limited. Notably, none of the affected individuals developed hematologic malignancy, and only one developed esophageal cancer, with no current evidence linking this variant to solid tumors. Conclusions: This case underscores the importance of distinguishing between ANKRD26 variants when assessing malignancy risk. While ANKRD26-RT is associated with myeloid neoplasms, the c.−118C > G variant may confer a lower oncogenic potential. Variant-specific risk stratification and genetic counseling are crucial for optimizing surveillance and avoiding unnecessary interventions in low-risk individuals. Full article

Background: Preparing patients for surgery considers assessing the patient’s somatic health, for example by the American Society of Anesthesiology (ASA) scale or the Revised Cardiac Risk Index (RCRI), known as the Lee index. This process usually ignores mental functioning (personality and anxiety), which is known to influence health. The purpose of this study is to analyze the existence of a relationship between personality traits (the Big Five model and trait-anxiety) and anesthesia scales (ASA scale, Lee index) used for the preoperative evaluation of patients. Methods: The study group comprised 102 patients (59 women, 43 men) scheduled for hip replacement surgery. Patients completed two psychological questionnaires: the NEO-FFI (NEO Five Factors Inventory) and the X-2 STAI (State-Trait Anxiety Inventory) sheet. Next, the presence and possible strength of the relationship between personality traits and demographic and medical variables were analyzed using Spearman’s rho rank correlation coefficient. Results: Patients with a high severity of trait anxiety are classified higher on the ASA scale (rs = 0.359; p < 0.001). Neuroticism, defined according to the Big Five model, significantly correlates with scales of preoperative patient assessment: the ASA classification (rs = 0.264; p < 0.001) and the Lee index (rs = 0.202; p = 0.044). A hierarchical regression model was created to test the possibility of predicting ASA scores based on personality. It explained more than 34% of the variance and was a good fit to the data (p < 0.05). The controlled variables of age and gender accounted for more than 23% of the variance. Personality indicators (trait anxiety, neuroticism) additionally accounted for slightly more than 11% of the variance. Trait anxiety (Beta = 0.293) proved to be a better predictor than neuroticism (Beta = 0.054). Conclusions: These results indicate that inclusion of personality screening in the preoperative patient evaluation might help to introduce a more individualized approach to patients, which could result in better surgical outcomes. Full article

Somatic and epigenetic alterations contribute to myeloid leukemogenesis and play an important role in risk stratification and the optimization of treatment for myeloid malignancies. The significance of rare genetic alterations, such B-cell lymphoma-6 corepressor (BCOR) and B-cell lymphoma-6 corepressor-like protein 1 (BCORL1) mutations, in pediatric acute myeloid leukemias (AML) and myelodysplastic syndrome (MDS) is unknown. We present a case series of pediatric and adolescent patients, with de novo AML, harboring BCOR/BCORL1 mutations. Studies involving larger cohorts of patients are needed to further elucidate the role of BCOR/BCORL1 mutations in pediatric AML and MDS. Full article

Background/Objectives: Body Mass Index (BMI) is a widely used indicator of children’s nutritional status and helps identify risks of being underweight and overweight during development. Understanding how BMI classifications evolve over time is crucial for early intervention and public health planning. This study aimed to determine the scope and direction of changes in BMI classification among children between the ages of 6 and 10. Methods: This longitudinal study included 1026 children (497 boys and 529 girls) from Gdansk, Poland. Standardized anthropometric measurements were collected at ages 6 and 10. BMI was calculated and classified using international reference systems (IOTF and OLAF). BMI classification changes were analyzed using rank transformations and Pearson correlation coefficients (p < 0.05) to explore relationships between body measurements. Results: Most children (76.51%) retained their BMI classifications over the four-year period. However, 23.49% experienced changes, with boys more often moving to a higher BMI category (15.29%) and girls more frequently shifting to a lower category (14.03%). The prevalence of children classified as living with obesity declined between ages 6 and 10, while both overweight and underweight classifications slightly increased. Strong correlations were observed between somatic features and BMI at both ages. Conclusions: The stability of BMI classification over time underscores the importance of early identification and sustained monitoring of nutritional status. The sex-specific patterns observed highlight the importance of targeted health promotion strategies. In this context, incorporating dietary interventions—such as promoting balanced meals and reducing unhealthy food intake—could play a significant role in maintaining healthy BMI trajectories and preventing both obesity and undernutrition during childhood. Full article

Grass carp is an economically important cultured species in China. Triploid embryo production is widely applied in aquaculture to achieve reproductive sterility, improve somatic growth, and reduce ecological risks associated with uncontrolled breeding. In this study, a simple cold shock method for inducing triploid grass carp was developed. The triploid induction rate of 71.73 ± 5.00% was achieved by applying a cold treatment at 4 °C for 12 min, starting 2 min after artificial fertilization. Flow cytometry and karyotype analysis revealed that triploid individuals exhibited a 1.5-fold increase in DNA content compared to diploid counterparts, with a chromosomal composition of 3n = 72 (33m + 36sm + 3st). Additionally, embryonic transcriptome analysis demonstrated that, in the cold shock-induced embryos, genes associated with abnormal mesoderm and dorsal–ventral axis formation, zygotic genome activation (ZGA), and anti-apoptosis were downregulated, whereas pro-apoptotic genes were upregulated, which may contribute to the higher abnormal mortality observed during embryonic development. Overall, this study demonstrates optimized conditions for inducing triploidy in grass carp via cold shock and provides insights into the transcriptomic changes that take place in cold shock-induced embryos, which could inform future grass carp genetic breeding programs. Full article

This study investigated the changes in protein composition and DNA content in damaged somatic nerves when exposed to insulin-like growth factor-1 (IGF-1). Using electrophoretic protein separation in polyacrylamide gel (PAG) and spectrophotometry, the transection was shown to be accompanied by a significant decrease in the quantitative content of total protein, certain protein fractions and DNA, both in the proximal and distal segments of the nerve conductor. Against the background of the intramuscular administration of IGF-1, intensive DNA synthesis and the protein composition stabilization of somatic nerves at the earlier post-traumatic stages were observed. By means of Raman scattering (RS-spectroscopy) and recording action potentials (APs), the enhanced recovery of the physicochemical condition of the nerve fiber membrane and its functional activity, indicating regeneration activation in the somatic nerves after damage, was revealed. IGF-1 was most likely to stimulate cytoskeleton protein synthesis through launching the mitogen-activated protein kinase signal pathway (MAPK/ERK), resulting in the increased expression of the genes related to the remyelination and functioning recovery of damaged nerve conductors. Full article

Ornamental fish shipped by road or rail may spend days in transit without food, leading to a reduction in somatic growth after transportation and during acclimatization. In the present study, a time-series (0, 2, 4, 6, 8, 10, and 12 days) experiment was conducted to investigate the growth recovery of male Siamese fighting fish (Betta splendens, 1.56 ± 0.02 g body weight, n = 15 per group) transported by road for two days. Biometric changes, nesting activity, skin pigmentation, digestive enzyme activity, muscle quality, and whole-body composition, were compared across all fish groups. The recovery in growth, as indicated by final body weight, increased with post-transportation time (p < 0.05), causing a significant reversal of weight loss with a proportionally stable condition factor from day 8 until the end of observation (p > 0.05). During this time period, the fish exhibited similar bubble-nest building activity to the control group that was not transported (p > 0.05). Color parameters, digestive enzyme activities, muscle quality, and whole-body composition of fish 8 days after shipping were comparable to the control fish group (p > 0.05). Our findings indicate that an 8-day recovery time is an appropriate protocol for Siamese fighting fish acclimatization following overland shipping. Full article

Lung adenocarcinoma exhibits a heterogeneous molecular landscape shaped by key oncogenic drivers and tumor suppressor gene alterations. Mutation frequencies vary geographically, influenced by genetic ancestry and environmental factors. However, the molecular profile of lung adenocarcinoma in Bulgarian patients remains largely uncharacterized. We conducted a prospective study of 147 Bulgarian patients with metastatic lung adenocarcinoma, analyzing clinicopathologic features and somatic mutation frequencies using next-generation sequencing. Key mutations and their prevalence were assessed and compared with published data from other populations. The cohort included predominantly male patients (68.0%) with a median age of 67 years. TP53 mutations were most frequent (41.5%), followed by EGFR alterations (19.0%) and KRAS c.34G>T (p.Gly12Cys) (17.0%). Over half of the patients (51.0%) harbored two or more gene mutations. Mutation frequencies aligned closely with European cohorts, exhibiting a lower prevalence of EGFR mutations compared to East Asian populations. This study characterizes the molecular landscape of lung adenocarcinoma in Bulgaria, highlighting the predominance of TP53 and KRAS mutations. The findings emphasize the need for comprehensive molecular profiling to inform targeted therapies and support precision oncology approaches tailored to the Bulgarian population. Further research is needed to validate these results and improve clinical outcomes. Full article