Search Results (90,154)

Background/Objectives: Heterotopic ossification (HO), the aberrant formation of bone within soft tissues, arises either from rare genetic mutations or more commonly from traumatic insults. It is a major cause of morbidity not only in individuals harboring causative mutations, but also in those undergoing musculoskeletal surgery or trauma and in soldiers sustaining blast or burn injuries. Bone morphogenetic protein (BMP) signaling is a central driver of both hereditary and acquired forms of HO. Primary cilia are nonmotile, antenna-like organelles that extend from the cell surface and serve as crucial sensory and signaling hubs by concentrating key pathway components within a confined volume at the ciliary tip. However, their functional role in the pathogenesis of traumatic HO remains poorly understood. Methods: We investigate the role of primary cilia in traumatic HO using a genetically modified mouse model and cellular model. Results: We demonstrate that BMP signaling is attenuated when primary cilia function is disrupted. Both ciliation frequency and ciliary length were reduced in Scleraxis-CreERT2; Intraflagellar transport 88 ^{floxed/floxed} (Scx-ERT2;Ift88^fl/fl) tenocytes. Deletion of Ift88 effectively suppressed pathological BMP signaling and inhibited HO formation. Conclusions: These findings establish that functional primary cilia are required for traumatic HO development and highlight ciliary regulation as a potential therapeutic avenue for preventing or mitigating post-traumatic HO. Full article

Background: Young adulthood represents a critical period for the emergence of early metabolic disturbances, potentially influenced by dietary shifts toward convenience and ultra-processed foods. However, evidence linking dietary patterns and cooking practices with objective metabolic biomarkers in Romanian university students remains limited. Methods: This cross-sectional study included 693 students aged 18–24 years at the Victor Babeș University of Medicine and Pharmacy, Romania (June–July 2025). Dietary habits, food preferences, and cooking practices were assessed using a structured online questionnaire, while anthropometric and biochemical data were obtained from university health records. The primary outcome was glycated hemoglobin (HbA1c), a marker of average blood glucose levels over the previous 2–3 months. Prediabetes was defined as HbA1c 5.7–6.4%. Dietary patterns were identified using k-means clustering based on fast-food consumption frequency, main meal of the day, fruit and vegetable intake frequency, and predominant cooking method. Multivariable regression models assessed associations between dietary variables and glycemic or lipid outcomes. Results: Prediabetes prevalence was 21.1% (diabetes: 1.4%). Three dietary patterns were identified: health-conscious (prediabetes 15.4%), mixed (20.0%), and fast-food oriented (27.3%; χ² p = 0.003). Fast-food consumption frequency was independently associated with higher prediabetes risk (OR = 1.78 per category; 95% CI 1.38–2.30; p < 0.001) and higher HbA1c levels (β = 0.147; p < 0.001), while fruit and vegetable intake showed an inverse association with HbA1c (β = −0.109; p < 0.001). A dose–response relationship was observed between fast-food frequency and both HbA1c and prediabetes prevalence (p-trend < 0.001). An interaction between high-temperature cooking methods and frequent fast-food consumption was observed for HbA1c (p = 0.023). BMI and sex were the strongest predictors of lipid outcomes, although fast-food intake was associated with higher triglyceride levels (p = 0.034). Conclusions: Among Romanian university students, dietary patterns characterized by frequent fast-food consumption were associated with higher HbA1c levels and greater prediabetes prevalence. A high-temperature cooking method was associated with higher glycemic levels when combined with frequent fast-food intake. These findings suggest that early dietary behaviors during university years may be relevant for metabolic risk profiles in young adults. Full article

Carnosine (CAR), an endogenous histidine-containing dipeptide, exhibits antioxidant and anti-inflammatory activity in various experimental models; however, its molecular mechanism of action remains poorly understood. Here, we demonstrate that the Michael adduct between CAR and 4-hydroxy-2-nonenal (HNE), which has been detected in previous studies in both in vitro and in vivo settings, mediates its bioactivity, particularly its antioxidant and anti-inflammatory responses, through Nrf2 activation. The CAR–HNE adduct was synthesized and its physicochemical, metabolic, and biological properties were evaluated. CAR–HNE exhibited high stability in biological matrices and retained the ability to transfer HNE to thiol nucleophiles at a slow rate under physiologically relevant conditions, consistent with electrophile-mediated Nrf2 activation. This kinetic behavior limits the cytotoxicity typically associated with free HNE while preserving the redox signaling capacity. CAR–HNE induced dose-dependent Nrf2 activation and NF-κB inhibition in cell-based assays without the hormetic toxicity observed for free HNE. Mechanistically, CAR–HNE may act as a redox-tunable electrophilic reservoir, restoring nucleophilic tone and modulating redox-sensitive transcription factors. In vivo, CAR–HNE attenuated DSS-induced colitis more effectively than equimolar doses of either carnosine or HNE alone. Proteomic analyses revealed modulation of canonical Nrf2-dependent antioxidant pathways. Our findings suggest a conceptual shift in carnosine biology: rather than acting as a classical antioxidant or carbonyl quencher, carnosine functions as a precursor of redox-active electrophilic adducts that transduce anti-inflammatory and antioxidant responses via controlled RCS signaling. Full article

The present study investigates the dry sliding wear behaviour of pure Zn, Zn–3Mg, and Zn–3Mg–0.5Y biodegradable alloys using mass loss measurements, friction torque monitoring on an Amsler tribometer, and optical profilometry of wear tracks. The microstructure of the Zn–Mg–Y alloy exhibited an α-Zn matrix comprising Zn–Mg intermetallic constituents and dispersed Y-rich phases. Tribological testing at 20 N and 30 N revealed a marked enhancement in wear resistance for Zn–3Mg in comparison to pure Zn, attributable to matrix strengthening by intermetallic phases. Despite the stabilising effect of Y on the friction response, there was no consistent reduction in wear volume under higher loads. Surface investigations have revealed a multifaceted wear mechanism, characterised by a combination of abrasion, oxide tribolayer formation, and localised adhesion. The measured wear rates were found to fall within the range documented in the available literature concerning biodegradable Zn-based alloys, thereby confirming the experimental validity of the findings. In summary, Zn–3Mg exhibited the optimal equilibrium between friction stability and wear resistance under the examined dry sliding conditions. However, further research in physiological environments is necessary to evaluate its biomedical applicability. Full article

Background/Objectives: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is linked to poorer overall survival and a higher risk of brain metastases compared to HER2-negative breast cancer. Current preclinical studies lack robust HER2+ metastatic syngeneic mouse models for investigating targeted and immunomodulatory therapies. This study aims to develop effective HER2+ mouse models to investigate response dynamics to HER2-targeted therapy and immunotherapy. Methods: The human HER2 gene (WT or mutant p.A775_G776insYVMA, GFP-tagged at the C-terminus) was introduced into triple-negative breast cancer (TNBC) mouse mammary carcinoma cells with known metastatic potential (4T1 and EO771) via lentiviral transduction. HER2 expression and phosphorylation were analyzed using Western blotting and immunohistochemistry. Tumors were treated with HER2-targeted therapy (trastuzumab and tucatinib), immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), and anti-HER2 antibody–drug conjugate (ADC) to evaluate treatment efficacy. Metastatic potential was assessed with brain fluorescence imaging. Statistical analysis included ANOVA and Kaplan–Meier tests. Results: Newly established lines demonstrated expression of HER2+, with HER2^YVMA lines showing higher phosphorylation than HER2^WT lines. Cells were tumorigenic, demonstrating in vivo tumor take rates at 100% for 4T1-HER2 and 15–30% for EO771-HER2. HER2 overexpression led to a 30% increase in spontaneous brain metastasis in the 4T1-HER2 models. Trastuzumab alone did not reduce primary tumor size but significantly reduced brain GFP signal by 17% ± 8% and 26% ± 7% in the 4T1-HER2^WT and 4T1-HER2^YVMA models, respectively. Combinational therapies with anti-HER2 therapy and immune checkpoint blockade effectively suppressed primary tumor growth and prolonged survival in EO771-HER2^YVMA model. T-Dxd, but not T-DM1, demonstrated partial treatment response in the EO771-HER2^WT model. Conclusions: HER2+ syngeneic tumor models were developed that spontaneously metastasize to the brain and demonstrate variable responses to immunotherapies and ADCs. These models are valuable for advancing molecular imaging modalities for HER2+ brain metastasis, studying blood–brain barrier penetration of HER2-targeted drugs, and exploring the combination of therapies, including immunotherapy. Full article

The human cerebral cortex is organized into distinct area-specific regions along the rostral–caudal axis, yet current human brain organoid models incompletely recapitulate this regional diversity. Here, we establish an area-specific brain organoid platform by leveraging transcription factors (TFs) identified through re-analysis of in vivo human cortical transcriptomic datasets. Publicly available single-cell RNA sequencing datasets from human developing cortex were re-analyzed to identify differentially expressed genes associated with rostral and caudal cortical identities. From this analysis, we identified SP9 (rostral-enriched) and DMRTA2 (caudal-enriched) as candidate TFs governing regional specification. To model cortical area identity, these TFs were overexpressed in an inducible manner during human cerebral organoid (hCO) generation. Overexpression of SP9 resulted in hCOs exhibiting rostral cortical characteristics, whereas DMRTA2 overexpression promoted caudal cortical features. The resulting hCOs showed distinct regional identities, reflected by differential expression of area-specific markers. In addition, these regional identities were accompanied by distinct functional phenotypes, as calcium imaging revealed divergent patterns of spontaneous neural activity between rostral and caudal hCOs. Altogether, our findings demonstrate that overexpression of TFs enables the controlled generation of area-specific hCOs. This approach provides a scalable and reproducible platform for studying human cortical regionalization and offers a framework for investigating region-specific mechanisms underlying neurodevelopmental and neurological disorders. Full article

Background/Objectives: Increasing training demands in women’s football have heightened interest in female-specific health characteristics, including menstrual health. The aim of this study was to describe menstrual-cycle characteristics and injury history in adult amateur female football players using selected items of the Low Energy Availability in Females Questionnaire (LEAF-Q), with particular focus on prolonged absence of menstrual bleeding and training-associated menstrual changes. Methods: A cross-sectional survey was conducted in 118 adult amateur (non-elite) female football players (mean age 24.41 ± 4.50 years). Participants reported mean weekly training hours of 4.88 ± 2.45, consistent with amateur-level competitive and recreational participation. Selected items of the LEAF-Q were used, rather than the complete questionnaire; therefore, findings should be interpreted as descriptive indicators of menstrual health and injury history rather than a comprehensive LEA screening. Results: Most participants reported normal menstruation (95.76%), and menarche most commonly occurred between 12 and 14 years of age (92.37%). A history of ≥3 consecutive months without menstrual bleeding (clinically meaningful amenorrhea) was reported by 12.71% of players, while 4.24% reported such an episode at the time of the survey. Training-associated changes in menstrual bleeding were reported by 52.54% of participants, most commonly shorter and lighter bleeding; less frequently, cessation of bleeding (8.93%) or heavier and prolonged bleeding (1.79%) was reported. Injuries in the preceding 12 months were common, with 71.19% reporting one or two injuries and 28.81% reporting three or four injuries. Conclusions: Despite a high prevalence of self-reported regular menstrual cycles, a notable proportion of adult amateur female football players reported episodes of prolonged absence of menstrual bleeding and training-associated changes in bleeding characteristics. These findings highlight the variability of menstrual-cycle characteristics in the context of football training and support the inclusion of routine, confidential menstrual-health monitoring as part of broader athlete health management in women’s football. Football-related injuries were common over the preceding 12 months, reflecting the substantial musculoskeletal demands of the sport. Full article

Background/Objectives: The OPA1 gene encodes a dynamin-related GTPase essential for mitochondrial fusion. Variants in OPA1 are a major cause of autosomal dominant optic atrophy (DOA). A subset of DOA patients exhibits hearing loss, often manifesting as auditory neuropathy spectrum disorder (ANSD). In this study, we aimed to describe the frequency of OPA1-related hearing loss in a large cohort of patients with hearing loss and to explore the genotype–phenotype correlations and appropriate interventions. Methods: A total of 18,475 Japanese patients with hearing loss were recruited. Targeted massively parallel sequencing of 158 deafness-related genes was performed, and individuals with OPA1 variants were identified. Clinical data, including age of onset, audiological findings, and systemic features, were retrospectively reviewed. Results: Ten individuals from eight independent families carrying OPA1 variants were identified. Three variants were classified as pathogenic or likely pathogenic, while five were variants of uncertain significance. Hearing loss was typically post-lingual in onset and progressive, with predominantly mild-to-moderate severity. Missense variants tended to be associated with DOA-plus phenotypes and ANSD. Five patients obtained only limited benefit from hearing aids, whereas one patient who received a cochlear implant achieved good speech perception. Conclusions: OPA1 is a rare causative gene for hearing loss and is frequently associated with the ANSD phenotype. Affected individuals exhibited phenotypic heterogeneity, which may reflect incomplete penetrance or the influence of mitochondrial DNA-related factors. Full article

The accelerating frequency of emerging infectious diseases (EIDs) in livestock poses a significant threat to global food security, as well as to animal and public health. While wastewater-based surveillance (WBS) has advanced significantly for human health surveillance, its application to livestock production systems remains fragmented and lacks standardization. This review synthesizes current evidence on livestock wastewater-based surveillance (L-WBS) as an early-warning sentinel for emerging viral pathogens, evaluating their dynamics, economic impacts, biosecurity measures, and One Health implications. Existing studies demonstrate that L-WBS effectively detects emerging viral pathogens in agricultural effluent, swine manure, and municipal wastewater systems serving livestock regions, frequently preceding clinical outbreak recognition. We further conceptualized a multifactorial framework linking environmental drivers such as climate and ecological disruption and agricultural intensification to pathogen emergence dynamics. Economic assessments show substantial direct losses (approximately US$ 950 per H5N1-infected dairy cow and US$ 25.9 billion in African swine fever virus (ASFV)-related damages across China) alongside indirect costs from biosecurity implementation, workforce disruption, and supply-chain instability. We recommend prioritizing methodological standardization through unified sampling and extraction protocols, integration of next-generation sequencing for genomic surveillance, and cross-sectoral policy frameworks to operationalize L-WBS as a global early-warning infrastructure for mitigating zoonotic spillover and livestock-dependent community resilience. Full article

Background: Long COVID is characterised by persistent symptoms after SARS-CoV-2 infection, and its impact on cardiovascular health is a growing concern. This study aimed to evaluate the association between the presence and severity of metabolic syndrome and vascular structural and functional in patients with long COVID. Methods: We conducted a cross-sectional study of 304 adults diagnosed with long COVID. Vascular health was assessed using carotid intima–media thickness to evaluate arterial structure, and pulse wave velocity to assess arterial stiffness. Metabolic syndrome was defined according to international criteria. Multiple regression models were performed to analyse the association between the number of metabolic syndrome components and vascular parameters, adjusting for age, sex, lifestyle and pharmacological treatments. Results: All vascular measures show a positive association with artery pressure. All measures except cardio–ankle vascular index were positively associated with the number of metabolic syndrome components. Carotid intima–media thickness, carotid–femoral pulse wave velocity and vascular ageing index were positively associated with waist circumference. Brachial–ankle pulse wave was positively associated with all metabolic syndrome components and showed an inverse association with HDL-cholesterol. Cardio–ankle vascular index was inversely associated with waist circumference. Conclusions: In conclusion, among adults with long COVID, metabolic syndrome and the accumulation of its components are associated with poorer vascular structure, function, and vascular ageing. Full article

SIRT7is an NAD⁺-dependent deacetylase predominantly localized in the nucleolus, where it plays important roles in chromatin regulation, transcriptional control, and cellular stress response. Accumulating evidence has revealed that SIRT7 participates in multiple molecular processes, including ribosomal RNA transcription, histone modification, DNA damage repair, metabolic regulation, and inflammatory signaling pathways. Through these mechanisms, SIRT7 contributes to the pathogenesis of various human diseases, particularly cancer and metabolic disorders. In recent years, emerging studies have begun to uncover the roles of SIRT7 in the central nervous system (CNS). Although research in this area remains limited, available evidence suggests that SIRT7 may be involved in neuronal homeostasis, glial function, neuroinflammation, and responses to brain injury. Furthermore, dysregulation of SIRT7 has been implicated in CNS-related pathologies. In this review, we summarize the understanding of SIRT7 molecular mechanisms and its implications in human disease, with special emphasis on its emerging roles in the CNS. We also address unresolved questions and propose future research directions to facilitate a deeper understanding of SIRT7 in neurological physiology and pathology. Full article

Polyether ether ketone (PEEK) is a high-performance polymer with exceptional mechanical properties, durability and lightweight. 3D printing of PEEK can be very beneficial in the medical industry to manufacture patient-specific implants; however, there is a lack of studies regarding the fatigue behavior of 3D-printed PEEK, especially under compression, which is closely related to its potential applications. This paper investigates the static and dynamic mechanical performance of 3D-printed PEEK. Tensile and compression tests were conducted on specimens with ±45° raster orientation. Annealing at 270 °C for 5 h increased crystallinity from 34.4% to 41.4% yet unexpectedly reduced tensile strength from 60.8 MPa to 47.3 MPa, while increasing Young’s modulus from 2.51 GPa to 3.51 GPa. Micro-CT analysis revealed increased pore size after annealing. Static compression strength showed improvement post-annealing, increasing from 80.1 MPa to 126.7 MPa, with modulus rising from 1.64 GPa to 2.28 GPa. Compression–compression fatigue tests, performed at 5 Hz and 2.5 Hz with stress amplitudes of 70–95% of maximum strength (R = 0.1), enabled the construction of the first S-N curve for 3D-printed PEEK under compressive loading. Annealed specimens exhibited superior fatigue life, with infinite life achieved at 83.3 MPa (70% of static strength). Thermal imaging highlighted the role of temperature in fatigue failure, showing that annealed specimens endured higher thermal loads. These findings support the suitability of 3D-printed PEEK for load-bearing biomedical applications under cyclic compressive loads. Full article

Objectives: To confirm the utility of barometric whole-body plethysmography (BWBP) as a non-invasive, clinical diagnostic test for brachycephalic obstructive airway syndrome (BOAS) in cats. Methods: Client-owned cats belonging to brachycephalic breeds were enrolled and classified into two clinical severity grades of upper airway obstruction (UAO). Brachycephalic cats with high-grade UAO severity (Brachy-H-UAO) represented those with clinically evident effects on clinical signs or physical examination findings, whereas brachycephalic cats with low-grade UAO severity (Brachy-L-UAO) represented those without clinically evident problems. A group of non-brachycephalic (NB) cats that were respiratory disease-free and with neither a history of cardiac or systemic diseases nor exposure to cigarette smoke was used as the control group. Cats were placed in the BWBP chamber, and breathing signals were obtained after an adaptation period in a quiet and silent environment. The ventilatory variables obtained were respiratory rate (RR; [bpm]), tidal and minute volume per kilogram bodyweight (MV/BW and TV/BW; [mL/kg]), inspiratory (Ti; [s]) and expiratory (Te; [s]) intervals, airway obstruction index enhanced pause (Penh), and peak inspiratory and expiratory flows per kilogram (PIF and PEF; [mL/s/kg]). Results: Forty-three client-owned cats (11 Brachy-H-UAO, 7 Brachy-L-UAO, and 25 NB) were included. Brachycephalic cats (Brachy-H-UAO: 311 mL/kg; Brachy-L-UAO: 253 mL/kg) showed significantly lower median MV/BW than NB cats (503 mL/kg) (p = 0.01). Brachy-H-UAO cats demonstrated significantly higher median PEF/PIF ratios (Brachy-H-UAO: 1.46, minimum–maximum 0.82–2.48; Brachy-L-UAO: 0.76, 0.52–1.11; NB: 0.73, 0.56–1.00) and Penh (Brachy-H-UAO: 2.37, minimum–maximum 0.57–23.82; Brachy-L-UAO: 0.57, 0.27–1.11; NB: 0.53, 0.21–0.68) than Brachy-L-UAO and NB cats (p < 0.001). No significant differences were observed among the three groups for RR, TV/BW, Ti, Te, or Te/Ti. Conclusions and Relevance: Cats affected by BOAS demonstrate impaired ventilatory function, with reduced minute ventilation and a distinctive flow pattern and parameters reflecting limited inspiratory flow and increased upper airway resistance. BWBP can serve as a useful tool to diagnose and characterize the severity of BOAS in cats. Full article

Yeast infections are a major concern in clinical settings, and several known species are recognized for their antifungal drug resistance, especially the multidrug-resistant pathogen Candidozyma auris. It is of increasing importance to identify pathogenic yeasts to improve treatment outcomes. We present a technique to identify these yeast pathogens using machine learning with a neural network (DenseNet-201) on images obtained from laser light scattering and conventional microscopy. We performed the binary classification of seven species of pathogenic yeast based on their light scattering patterns and their microscopy images. We achieved an average classification accuracy of 95.3% for light scattering patterns and 96.6% for microscopy images of the yeast cells. We also demonstrate high classification accuracy when isolating Candidozyma auris images from all other species combined, at an average of 95.1% for light scattering patterns and 96.7% for microscopy images. The high average classification accuracies suggest that both light scattering and microscopy image data can be combined with machine learning models to classify pathogenic yeasts. Full article

Inflammation is widely viewed as a driver of hepatocellular carcinoma (HCC), yet inflammatory signaling also reshapes hepatic xenobiotic metabolism. Here, we established transgenic (Tg) IKKβ^Δhep mice (Tg-IKKβ^Δhep), which combine hepatocyte-specific IKKβ deletion with liver expression of a nuclear, kinase-inactive IKKβ mutant (NLS-IKKβKN). Tg-IKKβ^Δhep mice developed spontaneous chronic hepatitis and progressive fibrosis but were strikingly resistant to diethylnitrosamine (DEN)-induced hepatocarcinogenesis, with markedly reduced tumor multiplicity and total tumor burden. Despite persistent inflammatory injury, DEN-triggered oxidative DNA damage and p53 activation were markedly attenuated, compatible with reduced tumor initiation. Transcriptomic and biochemical analyses revealed broad repression of xenobiotic-metabolizing cytochrome P450 genes, including the pericentral enzyme CYP2E1, accompanied by reduced CYP2E1 protein abundance. This was associated with impaired HNF4α–PXR–CAR transcriptional output and reduced HNF4α occupancy at target promoters. Acute TNFα or IL-1β exposure recapitulated this repression, in part through reduced PGC-1α expression and decreased RNA polymerase II recruitment to target promoters. In parallel, pericentral xenobiotic metabolism was blunted, a change that could plausibly diminish DEN bioactivation and genotoxic stress. Together, these findings support a “metabolic gatekeeping” model in which chronic inflammation can constrain chemical hepatocarcinogenesis by attenuating carcinogen-metabolizing capacity. Full article