Search Results (749)

Research on sex-related differences in child and adolescent neurocognitive development has often been framed around whether boys and girls differ and which group performs better. This framing is increasingly inadequate because it treats developmental timing, observable phenotypes, and clinical recognition as interchangeable forms of evidence. Drawing on developmental neuroscience, cognitive development, research on gendered experience, and clinical studies of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), this integrative narrative review proposes a developmental-visibility framework. The framework interprets sex-related differences across three analytically distinct layers: developmental timing, phenotypic expression, and clinical recognition. Developmental timing refers to age-related trajectories, pubertal coupling, maturation tempo, and variability. Phenotypic expression refers to how developmental differences may appear in language, executive function, emotion, and social cognition under specific task and measurement conditions. Clinical recognition refers to how informants, referral thresholds, compensatory or camouflaging behavior, and diagnostic tools influence which difficulties are identified. ASD and ADHD illustrate the clinical-recognition layer because less externally disruptive or more compensated presentations may remain underrecognized despite meaningful developmental burden. The framework helps explain why modest average effects, inconsistent behavioral findings, and unequal clinical recognition can coexist. It shifts the field from asking whether sex-related differences exist to asking when, how, and under what social and clinical conditions they become visible. Full article

Objective: In this study, Dehydroepiandrosterone (DHEA-induced Polycystic Ovary Syndrome (PCOS) mice were used as models to evaluate the improvement effect of Vitexin (Vit) on ovarian fibrosis and explore the mechanism of action of the NR4A1/NLRP3 signaling pathway. Method: Sixty 4-week-old female ICR mice of the same batch number were selected and their systems were divided into 6 groups (n = 10): normal (Control, Ctrl) group, model (Polycystic Ovary Syndrome, PCOS) group, treatment (Vitexin, The Vit group, normal NR4A1 gene silencing group (Ctrl NR4A1^-/-), NR4A1 gene silencing model group (PCOS NR4A1^-/-), and NR4A1 gene silencing treatment group (Vit NR4A1^-/-). Silencing gene modeling was performed by tail vein injection of adeno-associated virus (serotype AAV-8), and the mouse genotypes were detected by qRT-PCR technology 14 days after injection. After the genotype was determined, the PCOS group and the PCOS NR4A1^-/- group were administered dehydroepandrosterone (6 mg/100 g/d) by gavage for 28 consecutive days for modeling, while the Vit group and the Vit NR4A1^-/- group were treated with dehydroepandrosterone + vitexin (10 mg/kg/d) by gavage for 28 consecutive days. All mice were raised with pure water and regular maintenance food. After 4 weeks of drug intervention, the mice were euthanized and samples were collected. The pathological changes in ovarian tissue were observed by H&E staining, and the degree of ovarian tissue fibrosis was observed by Masson staining. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in mouse serum were detected by biochemical kits. The levels of inflammatory factors (IL-1β, IL-6, IL-18, TNF-α) in mouse serum were determined by enzyme-linked immunosorbent assay. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect oxidative kinase (Gsta4, Prdx3, Mgst1, Gpx3, Gsr), inflammatory factors (Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tnf-α) and fibrotic pathway-related genes (Tgf-β1, Smad3, Collagen1, CTGF, α-SMA, Mmp-13, and β-catenin) in ovarian tissues. The levels of inflammatory factors (NLRP3, Caspase-1, ASC, IL-1β, IL-18, TNF-α, IκBα) and fibrosis in mice were determined by Western blot method, and statistical description and analysis were performed using SPSS software. Result: In the wild-type genotype group, compared with the PCOS group, Vit treatment could effectively regulate the metabolic abnormalities of PCOS mice, including inhibiting excessive weight gain, restoring normal glucose tolerance, and reducing body fat content. After Vit treatment, the levels of MDA, TC, TG, LDL, IL-1β, IL-6, IL-18 and TNF-α in the serum of PCOS mice were significantly reduced, while the levels of SOD and HDL in the serum of PCOS mice were increased. The staining results indicated that Vit treatment could significantly inhibit the process of ovarian fibrosis in PCOS mice. The results of WB and PCR demonstrated that after Vit gavage treatment in mice, inflammatory and fibrotic factors such as Nlrp3, Caspase-1, Asc, Il-1β, Il-18, Tgf-β1, Smad3, Collagen1, CTGF, and α-SMA in ovarian tissues could be significantly down-regulated, and the fibrotic level of ovarian tissues could be reduced. Among the same measurement indicators, the silenced NR4A1 group showed a certain degree of increase compared with the wild genotype group, but there was no significant difference. Conclusions: Vit intervention can restore the sex hormone levels and follicular development in ovarian tissues of PCOS mice, regulate reproductive endocrine disorders and abnormal lipid metabolism levels, and regulate the expression of Collagen I, a-SMA and CTGF in the ovaries by inhibiting the NR4A1/NLRP3 signaling pathway, thereby improving the ovarian fibrosis level of PCOS mice. It is suggested that it may play a key role in the treatment of PCOS and the prevention and delay of its long-term complications. Full article

As in other mammalian species, the complex and specific interactions between internal biological processes and external factors regulate and impact the male dog reproductive system functions. This comprehensive review integrates physiological and molecular mechanisms underlying the reproductive system maintenance throughout the anatomical and histological structure of reproductive organs and their functions from development to aging. Simultaneously, the presentation of fundamental hormonal regulations and functions of the reproductive system is comprised. Special attention is put on e.g., genetic, developmental, age- and environmental-related disorders. The structural and hormonal status of the reproductive organs in response to single or mixed influences: genetic predispositions (e.g., cryptorchidism, sex chromosome aneuploidy syndrome), developmental courses (e.g., cryptorchidism, uterus masculinus, hypospadias), age-related diseases (e.g., tumors), and environmental stressors: e.g., endocrine-disrupting chemicals, toxins, heat stress (possibly leading to e.g., hypogonadism, cryptorchidism, infertility, tumors, precocious aging) is provided. Such multidirectional and comprehensive associations of grouped, selected, clinically significant pathological processes and diseases are broadly considered and linked here for the first time. Based on both epidemiological and experimental findings, the etiologies, current diagnostic approaches, treatment options, and prognostic assessments of these common male dog disorders are presented. This compendium seems useful for young veterinarians, researchers, breeders, and dog owners, enabling them to integrate knowledge on biological principles and processes with clinical practices and research in recent and future canine andrology. Full article

Background and Objectives: Bipolar disorder (BD) is associated with widespread neuroanatomical alterations, particularly within subcortical structures involved in emotional regulation. Conventional magnetic resonance imaging (MRI) approaches may fail to detect subtle microstructural changes. This study aimed to evaluate histogram-based texture characteristics of the putamen in patients with BD and to compare these findings with those of healthy controls. Materials and Methods: This retrospective cross-sectional study included 66 participants (33 BD patients, 33 controls). All subjects underwent standardized cranial MRI. Regions of interest corresponding to the putamen were manually delineated, and histogram-based texture parameters were extracted using custom-developed software. Group comparisons were performed using appropriate statistical tests based on data distribution. Results: The groups were comparable in age and sex (p > 0.05). Significant differences were observed in multiple texture parameters, particularly in the left putamen. Mean and median values were significantly higher in BD patients compared to controls (511.19 ± 106.96 vs. 440.68 ± 102.21, p = 0.008; 511.92 ± 106.71 vs. 440.53 ± 102.74, p = 0.007). Minimum intensity values and root-sum-of-squares levels were also significantly increased (p < 0.001). Skewness differed significantly (p = 0.004), indicating altered distribution asymmetry. Percentile analyses demonstrated consistent differences across nearly all levels, suggesting a shift in intensity distribution. Additionally, Katz fractal dimension was significantly lower in BD patients (p < 0.001), indicating reduced structural complexity. Similar but less pronounced alterations were observed in the right putamen. Overall, the findings suggest the presence of widespread alterations in intensity distribution and structural characteristics. Conclusions: Patients with BD exhibit significant alterations in putamen texture parameters, potentially reflecting alterations in intensity distribution and texture-derived structural characteristics. Histogram-based texture analysis may provide a sensitive, non-invasive approach for detecting subtle brain alterations in BD and may serve as a complementary neuroimaging biomarker. Full article

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by the interaction between genetic and environmental influences, potentially mediated by epigenetic mechanisms such as DNA methylation. Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC v2.0 array on peripheral blood mononuclear cells (PBMCs) from 100 children with ASD and 50 typically developing controls. Differential methylation analyses were conducted by adjusting for age, sex, and estimated blood-cell-type composition as covariates. Functional enrichment, SFARI gene-overlap analysis, and cross-cohort validation were performed. We identified 3507 differentially methylated positions (DMPs) in the ASD cohort. Functional enrichment revealed pathways involved in neuronal signaling, synaptic activity, and immune regulation, suggesting coordinated neurodevelopmental and immune processes in ASD. Stratification by clinical severity demonstrated common and unique biological characteristics between the moderate and severe ASD groups. Furthermore, DMP-associated genes significantly overlapped with high-confidence ASD risk genes from the SFARI database and established transcriptomic signatures of neurodevelopmental disorders. Comparisons with independent post mortem brain tissue and peripheral blood datasets revealed partial overlap and directional concordance. However, the strength of concordance varied across datasets and was limited in the most directly comparable peripheral blood cohort. Our findings suggested that DNA methylation profiling of PBMCs provided peripheral epigenetic signatures and candidate loci for further validation in larger independent cohorts. Full article

Juvenile Polyposis Syndrome (JPS) is an autosomal dominant disorder characterized by multiple gastrointestinal polyps and an increased risk of cancer, most commonly associated with mutations in the tumor suppressor gene Smad4. However, substantial phenotypic variability exists among individuals carrying identical mutations, suggesting the presence of genetic modifiers. In this study, we used the genetically diverse Collaborative Cross (CC) mouse population crossed with Smad4 knockout mice to identify loci influencing intestinal polyp development. A cohort of 260 F1 mice derived from 14 CC lines was assessed for polyp number and size across intestinal segments. Quantitative trait locus (QTL) mapping revealed several significant loci, including regions on chromosomes 16, 14, and 12, which were designated Ipsl1, Ipsl2, and Ipsl3 for Intestinal Polyposis Susceptibility locus (Ipsl), respectively, in the full population, as well as additional sex-specific loci in male and female cohorts. Pathway enrichment analysis of genes within these regions highlighted functional associations with immune signaling, ubiquitin–proteasome degradation, and metabolic regulation. Candidate genes, including STAM2, PSMD6, NAMPT, and CACNB4, emerged as potential modifiers of polyp susceptibility. These findings highlight the complex genetic architecture underlying JPS phenotypes and provide candidate loci for future functional and translational investigations. Full article

Chemical modifications of RNA add a dynamic regulatory layer to gene expression beyond the genome and epigenome. Among these modifications, 5-methylcytidine (m⁵C) has emerged as a key epitranscriptomic modification that influences RNA stability, translation, localization, and stress responses across diverse biological systems. Recent advances in high-resolution mapping and functional interrogation of m⁵C have revealed its involvement in development, metabolism, immune regulation, and disease pathogenesis. Notably, many of these processes are highly relevant to women’s health, which is shaped by hormone-responsive tissues, reproductive transitions, and pregnancy-associated physiological adaptations. In this review, we provide a comprehensive and integrative overview of m⁵C RNA modification with a focus on its roles in female biology and disease. We summarize the molecular machinery responsible for m⁵C deposition, recognition, and regulation, as well as current detection technologies. We further highlight emerging evidence linking m⁵C dysregulation to early embryonic development, women-specific cancers, gynecologic and reproductive disorders, pregnancy complications, and metabolic and cardiovascular diseases. In addition, we discuss the interplay between m⁵C and sex hormone signaling, as well as the potential of m⁵C as a biomarker and therapeutic target. Finally, we identify key knowledge gaps, including the need for tissue-specific, longitudinal, single-cell, and spatial epitranscriptomic studies in women. By integrating epitranscriptomics into women’s health research, this review underscores m⁵C as a previously underappreciated regulatory layer with significant implications for precision medicine and clinical translation. Full article

Gonadectomy is performed in bitches to prevent unwanted reproduction and reduce the risk of sex hormone-related conditions. However, growing evidence suggests that the timing of spaying may influence long-term susceptibility to non-reproductive diseases. This retrospective case–control study (2013–2023) evaluated the association between timing of spaying and the development of orthopedic and neoplastic disorders in a Belgian referral-hospital population. Cases included bitches diagnosed with cranial cruciate ligament rupture, hip dysplasia, elbow dysplasia, lymphoma, mast cell tumor, osteosarcoma, or hemangiosarcoma, while disease-free bitches served as controls. Associations between disease occurrence and spaying status were assessed using multivariable logistic regression adjusted for age, weight category, and body condition score. Age at gonadectomy (<12 vs. ≥12 months) and timing relative to the first estrus were evaluated in separate models. Spaying <12 months of age was associated with increased odds of all conditions compared with intact females. Spaying ≥12 months of age was associated with lower odds of several orthopedic and neoplastic outcomes compared with early spaying, although odds were not always comparable to those in intact females. Large body size and higher body condition score were independently associated with increased odds of orthopedic outcomes. These findings support individualized spaying strategies rather than a universal age threshold. Full article

Central auditory processing efficiency is considered a predictor of how well children can learn to read, with the Frequency Following Response (FFR) serving as a sensitive biomarker of neural speech encoding ability. However, data regarding the 170 ms [da] stimulus in children who are native speakers of Brazilian Portuguese (BP) remain limited. This study investigated FFR results in 37 typically developing, normal-hearing children aged 8 to 10 years. Participants underwent audiological, behavioral, and academic performance screenings, followed by monaural FFR recording (using a 170 ms [da] stimulus at 80 dBnHL). Linear mixed models (LMM) were used to examine the effects of age, sex, and ear on the latencies of waves V, A, D, E, F, and O. The analysis revealed a medium effect size for waves D, E, and F, regarding the Ear factor, though statistical significance was specifically observed for wave E. For this wave, sex was also associated with a medium effect size, characterized by longer latencies in female participants. While the results for age did not reach broad statistical significance, the presence of medium effect sizes in wave E may suggest ongoing refinement of neural synchrony and asymmetric maturation during this developmental period. This study contributes to the characterization of neural speech encoding in the Brazilian Portuguese-speaking children and may support future investigation involving auditory processing disorders and learning difficulties. Full article

Betaine-homocysteine methyltransferase (BHMT) is an enzyme involved in one-carbon metabolism and plays a crucial role in maintaining liver health. In this study, we investigated the impact of liver-specific deletion of BHMT on liver dysfunction using a mouse model. We generated BHMT floxed mice and bred them with albumin Cre to generate liver-specific BHMT knockout (BHMT LKO) mice. Liver tissues harvested from six-month-old chow-fed BHMT floxed and LKO mice were characterized through histological, biochemical, and molecular analyses. BHMT LKO mice displayed a complete loss of hepatic expression of BHMT mRNA, protein and enzyme activity. Histopathological analysis revealed the development of hepatic steatosis in BHMT LKO mice compared to the floxed mice. These morphological changes were supported by biochemical analysis showing elevated levels of hepatic triglycerides in conjunction with a profound decrease in the methylation potential (i.e., reduced S-adenosylmethionine (SAM): S-adenosylhomocysteine (SAH) ratio), which was mainly driven by a six- to sevenfold increase in SAH levels. BHMT LKO mice also exhibited increased lipid peroxidation and lysosomal dysfunction compared to floxed mice. Early signs of inflammation were seen in the livers of BHMT LKO mice of both sexes, as evident from significant increase in CD68-positive cells and interleukin 1β levels. Additionally, there was a moderate increase in fibrosis, as evidenced by the upregulated expression of α-smooth muscle actin and collagen II levels and the histological assessment of picrosirius red-stained liver sections of BHMT LKO mice of both sexes compared to their respective counterparts. These findings demonstrate that hepatic BHMT deficiency promotes lipid accumulation, lysosomal/proteasomal dysfunction, and early inflammatory and fibrotic changes in the liver by reducing the methylation potential. Collectively, our results underscore BHMT as a critical regulator of liver homeostasis and a potential therapeutic target in liver-related disorders. Full article

Background/Objectives: Research has shown a high prevalence of co-occurring trauma-related disorders and cocaine use disorder (CUD). However, there remains a need for preclinical studies to determine how traumatic event exposure influences vulnerability to CUD development and relapse. In this study, we assessed the impact of traumatic event exposure using a threat conditioning (TC) paradigm, which models traumatic event exposure through associative threat learning on cocaine-seeking behavior in adult male and female rats. Methods: Adult male and female rats were exposed to a single TC session. After TC, the rats underwent cocaine self-administration (SA), extinction training, cue-primed reinstatement, and cocaine-primed reinstatement testing. A parallel cohort was subjected to a sucrose SA cohort to assess whether TC altered non-drug reward seeking in the form of sucrose SA. Results: In the cocaine cohort, stressed male rats exhibited greater cue- and cocaine-primed reinstatement relative to non-stressed males, whereas no reinstatement differences emerged in female rats. In the sucrose cohort, stressed females displayed increased sucrose pellet delivery during self-administration compared to non-stressed females, but no differences were observed during sucrose reinstatement in either male or female rats. Conclusions: These findings indicate that trauma exposure prior to cocaine use influences cocaine relapse-related behavior, as well as non-drug reward reinforcement earning, in a sex-specific manner. Overall, these results highlight the value of associative stress models such as TC for studying trauma–addiction comorbidity and the need to investigate the neurobiological mechanisms driving these sex-specific outcomes. Full article

Background/Objectives: Idiopathic epilepsy is a lifelong neurologic disorder in dogs, but its genetic basis remains incompletely understood in many breeds. This study aimed to identify risk-associated markers in Siberian Huskies, quantify their effects, assess potential risk modifiers, and characterize the shared haplotype background of the associated signal. Methods: A genome-wide association study was conducted in 113 Siberian Huskies genotyped on the Illumina CanineHD array, integrating association, regression, and haplotype/IBD analyses. An independent follow-up cohort of 57 additional dogs was genotyped at the lead marker by Sanger sequencing. Sex and gonadectomy status/timing were also evaluated as potential modifiers of risk, using multivariable regression and time-to-event analyses. Results: A strong, localized association was identified on canine chromosome 3 (CFA3) within KCNIP4. The lead intronic marker was significantly enriched in cases, with all risk-allele homozygotes affected, most heterozygotes affected, and no control homozygotes observed. Risk-associated chromosomes shared extended haplotypes across the region, consistent with carriers inheriting a common risk haplotype from a relatively recent shared ancestor. Among carriers, male sex was associated with higher odds of epilepsy and earlier seizure onset, with more tentative evidence for a similar association with gonadectomy before 5 years of age. Conclusions: These findings prioritize a CFA3 region encompassing KCNIP4 as a major risk locus for idiopathic epilepsy in Siberian Huskies. Fine-mapping with high-coverage sequencing and functional follow-up will be required to pinpoint the causal variant(s) and support development of risk assessment tools. Until those studies are completed, this marker should be regarded as a research finding rather than a predictive test. Full article

Gender medicine represents a key paradigm for advancing equitable and effective healthcare by systematically integrating sex- and gender-related differences into medical research and clinical practice. Despite regulatory efforts and international guidelines, significant gaps persist in the consideration of sex and gender across medical disciplines, including nephrology. Biological factors—including genetic, hormonal, and metabolic differences—interact with social, cultural, and environmental determinants to influence chronic kidney disease (CKD) susceptibility, clinical presentation, progression, and response to therapy. Insufficient consideration of sex and gender contributes to persistent disparities in CKD progression, cardiovascular outcomes, access to kidney transplantation, adverse drug reactions, dialysis outcomes, and pregnancy-related kidney complications. This narrative review outlines the historical development of gender medicine and critically appraises its relevance and unresolved challenges in kidney disease, with a focus on sex-specific differences in selected conditions, including autosomal dominant polycystic kidney disease, glomerular diseases, acute kidney injury, and pregnancy-associated kidney disorders. Integrating sex- and gender-informed approaches into nephrology is not merely an ethical requirement but a scientific necessity to improve risk stratification, personalize therapeutic strategies, and promote truly equitable and effective kidney care. Full article

Background and Objectives: Rates of obesity have been consistently increasing in recent years across all age groups, with a notable rise among young people. Obesity represents a persistent inflammatory condition and a key contributor to various chronic health problems, such as cardiovascular disorders, metabolic abnormalities, cancer, and psychological conditions. The move from high school to university is a transitional phase accompanied by specific pressures that can affect both body weight control and mental health in students. This cross-sectional investigation aimed to investigate potential associations between excess weight and the presence of depressive and anxiety symptoms in university populations. Methods: This cross-sectional analysis included 5298 students enrolled at universities across ten geographic areas of Greece. Participants filled out questionnaires concerning demographic information and lifestyle behaviors. Levels of depression and anxiety were measured using the Beck Depression Inventory (BDI-II) and the short form of the State Anxiety Inventory (STAI-6), respectively. Measurements of height and body weight were obtained to compute Body Mass Index (BMI). Results: The presence of overweight or obesity among students was significantly and independently related to female sex, urban residence, living independently, tobacco use, and lower academic performance (p = 0.0103, p = 0.0102, p = 0.0203, p = 0.0075, and p = 0.0168, respectively). Individuals reporting insufficient physical activity had 85% higher odds of being overweight or obese (p = 0.0068). Similarly, participants experiencing depressive or anxious symptomatology had more than double odds of excess body weight compared with those without such symptoms (p = 0.0015 and p = 0.0012, respectively). Furthermore, poor Mediterranean diet adherence was linked to more than a twofold increase in the odds of overweight or obesity (p = 0.0005). Conclusions: These findings offer considerable evidence that symptoms of depression and anxiety may serve as significant contributors to the development of overweight and obesity among university students. Additional longitudinal studies are strongly encouraged to substantiate these observations. Full article

Background/Objectives: Sarcopenia is a progressive decline in skeletal muscle strength and mass, leading to decreased functionality, metabolic disorders, morbidity, and mortality. There are a number of sarcopenia screening tools, such as the SARC-F questionnaire (that includes noting strength, assistance with walking, ability to raise from the chair, climb stairs, and falls), with its augmented forms that have added calf circumference (SARC-CalF), BMI and age (SARC-F + EBM), and the Ishii score, which show variable performance across populations. However, these were developed and validated mostly in Asian cohorts. To evaluate the diagnostic accuracy of these tools for the European Working Group on Sarcopenia in Older People (EWGSOP2), as well as define sarcopenia in hospitalized East European older adults, with sex and obesity stratification. Methods: Sarcopenia was diagnosed using the EWGSOP2. ROC analyses with DeLong tests assessed SARC-F, SARC-CalF, SARC-F + EBM, and the Ishii score in 278 Romanian inpatients (probable sarcopenia n = 201/278, 72.3%; confirmed n = 77/278, 27.7%). Results: Probable sarcopenia was noted as good-excellent discrimination against across all tools (AUCs 0.764–0.812); confirmed sarcopenia was noted as SARC-CalF superior (AUC = 0.743), followed by SARC-F + EBM (0.697), the Ishii score as moderate (0.667), and SARC-F was limited (0.591; p < 0.001 vs. augmented). SARC-CalF optimal cut-offs varied significantly: 4–6 (probable) vs. ≥11 (confirmed). Sex-stratified outcomes had excellent probable detection in both sexes, and this was confirmed to be superior in men. The Ishii score thresholds were 152/244 vs. Asian ≥ 105/120. Obesity required higher cut-offs with high NPVs (77–100%), confirming rule-out utility and SARC-F + EBM performing the best, both in the obesity and sarcopenic obesity subgroups (AUCs 0.742, 0.964). Conclusions: Augmented SARC-F scores outperformed the original SARC-F for confirmed sarcopenia in multimorbid Europeans, with SARC-F CalF having the best performance overall. Population-specific (sex/obesity) data-driven thresholds are essential, especially for the Ishii score, as this first Romanian validation reveals limitations of Asian norms in European cohorts, thus advocating for European recalibration. Full article