Search Results (427)

Background: The role of age and time-dependent variables in determining the response to disease-modifying therapies (DMTs) has aroused growing interest in the Multiple Sclerosis (MS) field. Although it is a very hot topic, related literature on the subject is considerably lacking. Objectives: The aim of this study is to deepen the understanding of how time-dependent variables influence disability accumulation and drug response in an MS population, assuming DMF as the first-line treatment, and to expand our knowledge of the risk–benefit evaluation of DMF. Methods: We investigated, in a real-world setting, the efficacy of Dimethyl Fumarate (DMF) in naive versus switcher MS patients, correlated with age, in preventing disability accumulation. Starting from an initial population of 234 DMF-treated patients, we selected 169 of them based on their similar time in therapy (TinT) with DMF of 5.9 ± 2.3 year and sex ratio. Of these, 74 were naive and 95 were lateral switchers at the start of treatment. The mean Expanded Disability Status Scale (EDSS), Disease Duration (DD), age and age at onset were compared between groups. Results: The switcher group showed higher EDSS and age compared to the naive group (2.7 vs. 1.8, p < 0.001; 40.2 vs. 35.5, p = 0.005, respectively). Age correlated with DD, EDSS and age at onset in both naive (r = 0.39, p = 0.007; r = 0.53, p = 0.000; r = 0.63, p = 0.000, respectively) and switcher (r = 0.46, p = 0.002; r = 0.49, p = 0.000; r = 0.61, p = 0.000, respectively) groups. Kaplan–Meier curves, adjusted for age, also indicated that the naive group retained an EDSS score status of 0.5–3.5 more frequently (p < 0.001) and reached elevated disability less frequently (p = 0.002) than switchers. The mean EDSS percentage ratio between paired naive and switcher patients, representing the differential neurological impairment (DNI), was 69%, inversely correlating with age in both naive (r = −0.52, p < 0.001) and switcher patients (r = −0.47, p < 0.001). Finally, logistic regression analysis indicated age as an independent and predictive variable with respect to EDSS. Conclusions: We conclude that age is the main contributor to disability progression and the primary predictive factor for treatment effectiveness for DMF in both naive and switcher MS patients. Full article

Background/Objectives: Quasipaa spinosa, a large-sized spiny frog, has high commercial value in the food trade. Although the sexual dimorphism in body size between males and females has been investigated, the sex-determining mechanism in this frog remains unknown. Methods: This study employed a genotyping-by-sequencing (GBS) method to identify sex-associated genomic markers and elucidate the sex determination mechanism in the species. Results: We obtained 853 candidate sex-specific GBS tags, with 811 tags (95.07%) demonstrating a male heterozygous system (XX/XY). The diagnostic specificity of the nine markers was further demonstrated by PCR analysis across multiple adult individuals from seven distinct geographic populations of the frog. Four sex-specific markers were aligned with the DMRT1 gene, representing a master regulator of sex determination and gonadal differentiation across the animal kingdom. Conclusions: Our results deciphered the genetic mechanisms governing sex determination in Q. spinosa and presented effective strategies for mono-sex breeding. Full article

Background: Beverage intake is a consequential yet underappreciated driver of health in Mediterranean settings. Comparative evidence for Spain and Italy based on harmonised measures is scarce. This study addresses that gap by profiling beverage portfolios and their sociodemographic correlates in parallel adult samples from both countries. Methods: We conducted a cross-sectional analysis of adults in Spain (n = 483) and Italy (n = 403) using aligned, validated instruments (NutSo-HH; NutSo-HH-Ita). Outcomes were water (Wtr), sugar-sweetened soft drinks (Sfd), juice (Juc), energy drinks (End), coffee (Cff), alcohol (Alc), and episodes of intoxication (Gtd). Associations were assessed via non-parametric tests, multivariable linear models, and an EBIC-selected Gaussian graphical model (GGM). Main results: Italians reported higher Alc and Gtd; Spaniards reported higher Sfd and Juc. Wtr was comparable across countries, and Cff differences were marginal. Age and sex emerged as the most consistent correlates (older age and male sex with higher Alc; younger age with higher Sfd), whereas education and income were not stable determinants. The GGM suggested behavioural clustering of Sfd–Juc–End, with weak partial correlations for other beverages after adjustment. Implications: Distinct country profiles imply differentiated priorities. In Spain, interventions could prioritise reducing sugar-sweetened beverage intake among younger adults through age-targeted primary care counselling, mandatory water (and unsweetened milk) availability in schools, tiered excise taxes on sugar-sweetened drinks, and restrictions on child- and youth-directed marketing of high-sugar beverages. In Italy, primary care and community health services could routinely screen adults for risky alcohol use and deliver brief, culturally attuned advice that promotes lower-risk patterns of wine consumption during meals. Given the cross-sectional design, self-report measures, and non-probabilistic sampling, findings should be interpreted as context-sensitive markers rather than causal determinants; nevertheless, they highlight concrete prevention approaches and regulatory levers for each country’s beverage-related health risks. Full article

Dental caries remains one of the most prevalent chronic diseases worldwide, driven by complex interactions among dietary, hygienic, and biological factors. This study introduces a hybrid predictive framework that integrates mathematical modelling and artificial intelligence (AI) to estimate individual caries risk based on daily sugar intake, oral hygiene index, salivary pH, fluoride exposure, age, and sex. A first-order balance differential equation was applied to simulate demineralisation–remineralisation dynamics, while a feed-forward artificial neural network (ANN) was trained on simulated and literature-derived datasets. The hybrid model demonstrated strong predictive performance, achieving 91.2% accuracy and an AUC of 0.98 in classifying individuals into low-, moderate-, and high-risk categories. Sensitivity analysis identified sugar intake and oral hygiene as dominant determinants, while fluoride and salivary pH showed protective effects. These findings highlight the feasibility of combining mechanistic and data-driven approaches to enhance early risk assessment and support the development of intelligent, personalised screening tools in preventive dentistry. Full article

Exposure to heavy metals from mining activities has been consistently associated with disruptions in hematologic homeostasis, adversely affecting children’s overall development. We aimed to determine population-specific distributions of hematological markers and to compare anemic and nonanemic children in a mining-exposed highland community. A cross-sectional study was conducted with 156 children aged 3 to 7 years from the Peruvian highlands, using non-probability sampling and following CLSI C28-A3 guidelines for this population. Inclusion criteria were children with complete blood count results and residency in mining-contaminated areas. Blood samples were collected via venipuncture and analyzed with a 3-part Sysmex differential hematology analyzer. The mean WBC count was 10.42 ± 1.76 × 10³/µL, with no significant differences between males and females (p = 0.770). Hematological indices, including RBC, hemoglobin, and hematocrit levels, were consistent between sexes. However, significant differences were noted between anemic and nonanemic 3–4-year-old children for RBC (5.56 ± 0.47 vs. 7.06 ± 0.96 × 10⁶/µL) and HCT (33.97 ± 6.89 vs. 35.64 ± 5%) (each p < 0.00001), with lower values in anemic subjects. Also, anemic and nonanemic 5–7-year-old children had significant differences in RBC (5.87 ± 1.02 vs. 7.36 ± 0.79 × 10⁶/µL) and HCT (31.13 ± 1.73 vs. 36.54 ± 4) (each p < 0.00001). Our findings reveal variations in hematological parameter distributions, emphasizing the importance of personalized blood assessments for mining-exposed populations. This approach could enable earlier diagnosis and intervention for anemia among vulnerable pediatric groups. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder worldwide and a key driver of cardiometabolic complications. Despite its growing burden, the underlying metabolic perturbations remain incompletely understood. The Fatty Liver Index (FLI) provides a validated non-invasive tool for stratifying MASLD in large-scale and clinical studies. Methods: This study utilized data from the Qatar Biobank, applying strict exclusion criteria and propensity score matching, to select 110 adults stratified by FLI into the MASLD group (≥60, n = 55) and the control group (<30, n = 55) with balanced age, sex, and BMI. Untargeted serum metabolomics was performed. Differential metabolite profiles were identified using linear regression adjusted for covariates and validated by multivariate modeling. Functional enrichment analyses were conducted to highlight perturbed metabolic pathways. Results: Metabolomic profiling revealed distinct metabolic signatures: the MASLD group was characterized by elevated glutamate and phospholipids, while the control group showed enrichment of gamma-glutamyl amino acids, plasmalogens, and sphingomyelins. Conclusions: This contrasting pattern reflects disruption of the gamma-glutamyl cycle and consistent depletion of antioxidant plasmalogen species, suggesting impaired redox homeostasis and lipid remodeling as hallmarks of MASLD pathogenesis. These findings provide a foundation for future research into targeted metabolic biomarkers and therapeutic strategies. Longitudinal and mechanistic studies are warranted to determine causal relationships and clinical utility. Full article

The double-sex and mab-3-related transcription factors (Dmrt) are widely distributed in the animal kingdom and play a crucial role in sex determination and differentiation. In this study, we identified eight Dmrt transcription factors in the genome of the centipede Scolopendra mutilans, including five Dsx-related genes (as Dsx1, Dsx2 (five splice variants), Dsx3, Dsx4 and Dsx5) and three Dmrt-related genes (as Dmrt11E, Dmrt99B, and Dmrt93B). Phylogenetic analysis revealed evolutionary conservation across arthropods, with Dsx genes clustered into class-specific clades (Chilopoda, Insecta, Crustacea, Arachnida). Structural analysis confirmed conserved DM domains and sex-specific motifs, with tandem duplication of Dsx2 on chromosome 4. Expression profiling demonstrated significant sexual dimorphism: Dsx5 was female-biased, whereas Dsx2, Dsx3, and Dsx4 were male-biased, suggesting their functional divergence in sexual differentiation. Correlation analysis linked the expression of Sxl and Fem-1C to the regulation of Dsx isoforms, suggesting the presence of a conserved upstream regulatory cascade for sex-specific splicing. These findings elucidate the structural and functional landscape of Dmrts in S. mutilans, and provide insights into how sex-determination mechanisms evolved in Myriapoda. Full article

Atrial fibrillation (AF) is the supraventricular tachy-arrhythmia most commonly detected in the general population, with significant sex-related differences in epidemiology, pathophysiology, and treatment outcomes. Emerging evidence highlights the role of sex hormones—particularly estrogen and testosterone—in modulating left atrial electrophysiologic substrate, structural remodeling, inflammation, and thromboembolic risk. Hormonal fluctuations across different lifespan influence AF onset, progression, and therapeutic response, yet current management approaches largely overlook such determinants. This narrative review integrates data from basic, translational, and clinical research to examine hormonal effects on atrial substrate, disease progression, and differential results of treatments, including stroke prevention, pharmacological options, and transcatheter ablation. It also explores the potential of hormone-targeted interventions, antifibrotic therapies, and precision strategies tailored to hormonal status. Addressing these mechanisms could optimize patient-specific management, improve outcomes and guide future clinical practice recommendations. Advancing toward sex-specific, hormone-informed AF care requires further mechanistic studies, hormonal profiling, and sex-stratified clinical trials. Full article

The Nile tilapia (Oreochromis niloticus), a key aquaculture species, displays marked sexual growth dimorphism, with males growing faster than females. This process is governed by intricate interactions between antagonistic regulators, including transcription factors, growth factors, and steroid hormones, operating through sex-specific developmental pathways. While circular RNAs (circRNAs) are known to modulate gene expression by sponging microRNAs (miRNAs), their role in teleost sex differentiation remains poorly understood. To address this gap, we profiled circRNA expression in tilapia gonads by constructing six circRNA libraries from testes and ovaries of 180 days after hatching (dah) fish, followed by high-throughput sequencing. We identified 6564 gonadal circRNAs distributed across all 22 linkage groups, including 226 differentially expressed circRNAs (DECs; 108 testis-biased, 118 ovary-biased). Functional enrichment analysis linked their host genes to critical pathways such as cAMP signaling, cell adhesion molecules, and—notably—sexual differentiation processes (e.g., estrogen signaling, oocyte meiosis, and steroid hormone biosynthesis). Furthermore, we deciphered competing endogenous RNA (ceRNA) networks, uncovering circRNA–miRNA–mRNA interactions targeting germ cell determinants, sex-specific transcription factors, and steroidogenic enzymes. This study provides the first systematic exploration of circRNA involvement in tilapia sex differentiation and gonadal differentiation, offering novel insights into the post-transcriptional regulation of sexual dimorphism. Our findings advance the understanding of circRNA biology in fish and establish a framework for future studies on aquaculture species with similar reproductive strategies. Full article

In the chicken industry, sex determination significantly affects production efficiency and raises ethical concerns in poultry farming. As a key economic species, maximizing the advantages of each sex is vital in modern intensive breeding. Therefore, understanding the mechanisms of sex determination and regulation is critical to advancing the poultry industry. Transcriptome analysis of 3.5-day-old White Leghorn chicken embryonic genital ridges (n = 30, 15 males and 15 females) was performed using sex-pooled samples (five embryos/replicate, three replicates/sex). Sequencing generated 39.6 GB of high-quality reads for inter-sex comparative analysis, revealing 283 significantly differentially expressed genes (DEGs). The DEGs were primarily enriched in pathways such as ribosome biogenesis, glycan biosynthesis and metabolism, and TGF-β signaling, which are potential candidate pathways for the differentiation of chicken embryonic gonads. Key DEGs (including SMAD2Z, FREM1, NR2F1, SEMA6A, NFIB, RNF165, SMAD7B, SMAD2W, SPIN1W, and HINTW) were validated by RT-qPCR, confirming the transcriptome sequencing results. Among the DEGs, we predict binding sites for NR2F1 and NFIB within the DMRT1 gene promoter and suggest that these factors may serve as potential upstream activators for the expression of DMRT1, and they may initiate high DMRT1 expression in the subsequent stages of male embryos and regulate testicular development. In conclusion, this study investigated DEGs in the gonads of male and female chicken embryos after 3.5 days of incubation and found that NR2F1 and NFIB may serve as potential upstream activators for the expression of DMRT1, which is involved in the early determination of chicken sex. Full article

Spinach is a dioecious vegetable and an excellent model for investigating plant sex differentiation. Exogenous gibberellin treatment induced sepal hypoplasia and sex reversal, converting 42% of stamens into pistils in male plants. Transcriptome analysis identified 112 male-biased genes enriched in stamen and pollen development, while hormone profiling revealed coordinated changes in GA, cytokinins, auxin, jasmonic acid, and abscisic acid. Functional assays demonstrated that silencing SpAMS or SpPGIP caused extensive carpelization, and in situ hybridization localized their expression to developing anthers. Dual-luciferase assays confirmed that SpAMS directly activates the B-class gene SpPI, and genomic mapping placed SpAMS in the pseudo-autosomal region of the Y chromosome. These results indicate that GA disrupts hormonal homeostasis and anther wall integrity, while the SpAMS–SpPI pathway regulates tapetal development to maintain male identity. Our findings identify SpAMS as a key male-promoting factor in spinach and provide a framework for elucidating sex determination mechanisms in dioecious plants. Full article

In Nile tilapia, one of the most important aquaculture species, males are larger than females, and an all-male monosex culture offers significant economic benefits. Although the pituitaries of genetic female (XX) and genetic male (XY) tilapia have identical expression levels of follicle-stimulating hormone (fsh), FSH receptor (fshr) expression remains relatively low in XY-undifferentiated gonads and then increases following morphological sex differentiation. The expression patterns of genes related to androgen biosynthesis in XY-undifferentiated gonads are similar to those of fshr during testis differentiation. This might imply that FSH has a potential function in testis differentiation through regulating the expression of genes related to androgen biosynthesis. To determine whether FSH signaling regulated androgen biosynthesis, we microinjected recombinant FSH (rFsh) into XY larvae during the early sex-differentiation stage. We compared the expression of various genes related to testis differentiation after injection. The genes hsd3b, cyp17a1, dmrt1, and gsdf were found to have higher expression in the rFsh treatment group. These results suggest that FSH signaling can activate androgen biosynthesis by regulating steroidogenic enzymes, including hsd3b and cyp17a1. Moreover, injected rFsh can upregulate dmrt1, which has a positive effect on the expression of gsdf. Therefore, during testis differentiation and development, FSH plays a role in both androgen synthesis and the expression of genes related to testis differentiation in Nile tilapia. Full article

Background/Objectives: MiRNAs have demonstrated promising roles in the diagnosis of pancreatic cancer and in the prognostic assessment of affected patients. Methods: We conducted a prospective pilot study including 23 patients diagnosed with advanced-stage pancreatic cancer and 10 healthy controls, matched by age and sex. In the screening phase, we evaluated the expression of 176 miRNAs in pooled plasma samples from both groups using real-time PCR. Subsequently, we validated the overexpression of selected miRNAs in individual plasma samples using the same technique. Statistical analysis was performed using IBM SPSS Statistics version 29. Results: During the screening phase, 22 miRNAs exhibited differential expression in patients with pancreatic cancer compared to healthy controls. Among these, hsa-miR-100-5p (27.8-fold increase), hsa-miR-122-5p (7.5-fold), hsa-miR-885-5p (7.2-fold), hsa-miR-34a-5p (5.7-fold), and hsa-miR-193a-5p (4.4-fold) showed the most pronounced upregulation. In the validation phase, all five candidates demonstrated significant overexpression in individual plasma samples (p < 0.001). Their circulating levels also showed associations with tumor stage (p < 0.05). Conclusions: Our findings highlight a distinct circulating miRNA signature associated with advanced pancreatic cancer, supporting the potential role of hsa-miR-100-5p, hsa-miR-122-5p, hsa-miR-885-5p, hsa-miR-34a-5p, and hsa-miR-193a-5p as minimally invasive biomarkers for disease detection and staging. Larger, multicenter studies including early-stage patients and disease control groups will be required to validate these biomarkers and determine their clinical utility. Full article

Sex determination, the developmental process that directs embryos toward male or female fates, is controlled by master sex-determining genes whose origins and evolutionary dynamics remain poorly understood outside of a few model systems. In contrast to the highly differentiated sex chromosomes of mammals, birds, and Drosophila, most anurans (frogs and toads) maintain homomorphic sex chromosomes that exhibit a rapid turnover, even among closely related species. Master sex-determining genes evolve via gene duplication or via allelic diversification, and sex chromosome turnover is driven by gene translocation or novel mutations in the existing genes involved in the sexual developmental pathway. To uncover the mechanisms underlying the emergence of master sex-determining genes and sex chromosome turnover, we analyzed 53 published anuran genomes and one caecilian genome (>200 Mya divergence) and available transcriptomes. We asked how often master sex-determining genes arise by gene duplication, whether and how often gene translocation associates with sex chromosome turnover, and if master sex-determining genes evolve under positive selection. We find that chromosome-level synteny is remarkably conserved, with only a few fusions or fissions and no evidence for translocation of four candidate master sex-determining genes (Dmrt1, Foxl2, Bod1l, and Sox3). Only Dmrt1 duplicated in 3 out of 50 species (excluding tetraploid Xenopus), and it showed strong testis-biased expression in all 8 species with available gonadal expression data. While Dmrt1 has evolved under purifying selection, Dmrt1 duplicates exhibit elevated nonsynonymous substitution rates and tendency towards positive selection. Lineage-specific amino acid changes were observed in the conserved DM domain of Dmrt1. These results demonstrate that, in anurans, master sex-determining genes rarely arise via gene duplication, and more likely evolve via allelic diversification. Sex chromosome turnover is not associated with gene translocation and is more likely driven by mutations on genes involved in sexual developmental pathways. All candidate sex-determining genes were under strong purifying selection, with the exception of duplications which are linked to positive selection. Our results suggest future research on anuran sex determination and sex chromosome evolution should focus on identifying allelic diversification and novel mutations on genes involved in sexual developmental pathways. Full article

Gekko hokouensis is a gecko species widely distributed across East Asia. Although most of the Japanese populations possess ZW sex chromosomes (female heterogamety), the degree of sex chromosome differentiation varies among populations. The gene encoding for Dmrt1, a transcription factor involved in testis development in vertebrates, is located on the Z and W sex chromosomes of this species and is therefore a candidate of the sex-determining gene. In this study, we investigated the gene structure of the Z and W homologs of Dmrt1 in two populations of Gekko hokouensis from the Ishigaki Island and Okinawa Island. In the Ishigaki population, the ZW chromosome pair is morphologically undifferentiated, whereas in the Okinawa population the ZW pair is heteromorphic. In the Okinawa population, promoter and exon sequences were nearly identical between the Z and W homologs, and no non-synonymous substitution was detected. In contrast, the W homolog in the Ishigaki population exhibited 42 bp and 12 bp deletions in exon 2. The predicted three-dimensional protein structure revealed a rearrangement of the C-terminal region in the W homolog that may interfere with target site binding. These results indicate that differentiation between Z and W homologs of Dmrt1 has occurred independently in each population. Our findings highlight the diversity of sex chromosome evolution and sex-determining mechanisms even within a single species. Full article