Search Results (4,296)

Anxiety disorders affect more than 301 million people worldwide and remain the most prevalent class of mental health conditions. Detection methods have traditionally relied on subjective self-reports, which fail to capture the dynamic physiological signatures of anxiety in daily life. In this longitudinal study, continuous wearable monitoring was conducted with 67 working professionals over nine months, yielding 44,443 h of multimodal data segmented into 890,494 five-minute windows. An unsupervised approach was applied, and ten distinct autonomic states were identified through spectral clustering without the use of emotion labels during clustering. Among these, a rare dysregulated state was discovered, characterized by extreme peripheral cooling ($d=-6.77$), tachycardia ($d=+4.41$), and heightened electrodermal activity, showing a 31-fold enrichment for self-reported anxiety ($p=0.0022$). Beyond this extreme signature, anxiety was expressed heterogeneously across four physiological phenotypes ranging from acute dysregulation to mild perturbation. External validation with the WESAD dataset confirmed generalizability, while the absence of the rare state in laboratory stress paradigms highlighted its specificity to ecological anxiety. By integrating unsupervised discovery with post hoc self-report validation, this work advances our theoretical understanding of autonomic affect and provides a methodological foundation for scalable workplace mental health monitoring. Full article

Background: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy driven by uncontrolled activation of the complement alternative pathway, with pregnancy triggering 10–20% of cases (pregnancy-associated aHUS, p-aHUS). Thalassemia, a chronic hemolytic anemia, creates a state of subclinical complement dysregulation; however, its clinical association with p-aHUS has rarely been reported. Methods: This study presents a 27-year-old primigravida with β-thalassemia intermedia requiring transfusions during pregnancy (CD17 heterozygote) who developed severe postpartum hemorrhage (1760 mL) after vaginal delivery. Over postpartum days 0–4, the patient was monitored for hematological and renal parameters. Laboratory investigations included peripheral smear, ADAMTS13 activity assay, direct Coombs test, and sC5b-9 complement level measurement. Results: Over postpartum days 0–4, the patient developed microangiopathic hemolytic anemia (hemoglobin nadir 46 g/L, lactate dehydrogenase peak 3436 U/L), thrombocytopenia (platelet nadir 31 × 10⁹/L), and acute kidney injury (creatinine peak 663 μmol/L). Peripheral smear showed 4% schistocytes. Subsequent detection revealed normal ADAMTS13 activity (90%), negative direct Coombs test, and elevated sC5b-9 (384.95 ng/mL; normal < 340). The diagnosis of p-aHUS was confirmed, and the patient received hemodialysis and recovered within three months. Conclusions: These findings suggest that chronic complement dysregulation secondary to thalassemia, combined with pregnancy-related complement stress and postpartum hemorrhage, may contribute to the development of p-aHUS. Therefore, thalassemia should be considered a potential sensitizing condition for p-aHUS, warranting close monitoring and complement evaluation in such patients. Full article

Sodium–glucose co-transporter 2 (SGLT2) inhibitors confer cardioprotection in patients with and without diabetes; however, whether SGLT2 is expressed in cardiac tissue and how these drugs act locally in the heart remains unclear. We investigated SGLT2 expression and the effects of empagliflozin in human iPSC-derived cardiac cells exposed to diabetogenic conditions. SGLT2 expression and the effects of empagliflozin were assessed in iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts under acute diabetogenic conditions using protein expression and metabolic activity assays, and in a multicellular 3D cardiac microtissue model using metabolic activity and contraction analyses. SGLT2 was detected in all three iPSC-derived cardiac cell types with nuclear and perinuclear localisation; no membrane-bound expression was observed. Endothelial cell SGLT2 expression was elevated under diabetogenic conditions. Diabetogenic stress reduced metabolic activity in both cardiomyocytes and endothelial cells; empagliflozin partially rescued endothelial cell metabolic activity but had no effect in cardiomyocytes. Empagliflozin reversed diabetogenic stress-induced cardiac fibroblast activation. 3D cardiac microtissues under diabetogenic conditions exhibited prolonged relaxation time, reduced beat rate variability, and reduced metabolic activity. Empagliflozin maintained metabolic activity at levels comparable to those of the control but did not rescue relaxation time or beat rate variability. The responsiveness of non-myocytes (endothelial cells and cardiac fibroblasts) to empagliflozin, in the absence of any effect on cardiomyocytes, suggests that non-myocyte-mediated mechanisms may contribute to the clinically observed cardioprotection of SGLT2 inhibitors. Full article

Coral reef ecosystems of the Egyptian Red Sea face escalating pressure from compounding climate-driven warming and intensifying coastal development, dual stressors whose spatial expression and governance implications remained insufficiently characterized prior to the designation of the Great Fringing Reef Marine Protected Area under Prime Ministerial Decree No. 4419/2025. This study develops an integrated multi-decadal framework combining 32 years of sea surface temperature and surface current velocity records, two decades of satellite-derived chlorophyll-a observations, and four decades of satellite-derived coral reef extent mapping across five monitored coastal sites. Basin-wide SST warming of ≈1.15 °C is spatially heterogeneous, with the northern coastal sector warming nearly 25% above the southern sector rate. Surface circulation diverges structurally at Ras Banas: acceleration in the north is consistent with enhanced advective dilution of anthropogenic inputs, whereas consistent deceleration in the south (mean −0.03 m/s) is associated with an increased ecological footprint of wadi-derived sediment and nutrient discharge. Sharply localized chlorophyll-a anomalies, reaching 0.97 mg/m³ at Hurghada and spatially congruent with documented development chronologies, are consistent with anthropogenic disruption of oligotrophic water quality as an important contributor to reef degradation at northern sites. Field evidence from 2026 repeat surveys, interpreted alongside documented severe regional bleaching affecting southern Egyptian reefs during 2024, suggests that climate-driven thermal stress constitutes a parallel and active pressure, particularly in the southern sector where thermal and anthropogenic stressors appear to have converged during the period of most acute reef contraction. Landsat-derived losses of 24.1–50.2% across all monitored sites since 1985, including a 33.3% contraction at Halaib–Shalateen between 2022 and 2025 alone, reflect the cumulative outcome of these interacting pressures. These findings support the ecological necessity of the 2025 MPA while identifying spatially differentiated, dual-stressor governance priorities essential to translating its policy commitment into measurable conservation outcomes. Full article

Oxybaphus himalaicus Edgew. is a traditional Tibetan medicinal plant used to treat nephritis and edema; however, its active constituents and the molecular mechanisms underlying its renoprotective properties remain poorly elucidated. This study investigated the pharmacological activity and mechanism of Boeravinone A (BA), a major constituent of O. himalaicus, in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A mouse model of LPS-induced AKI and LPS-stimulated RAW264.7 macrophages were used to evaluate the anti-inflammatory and renoprotective effects of BA in vivo and in vitro. Activity-based protein profiling (ABPP) was performed to identify potential molecular targets, followed by validation using isothermal titration calorimetry (ITC), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays. The functional role of the identified target was further examined using shRNA-mediated knockdown and virtual knockout analysis. BA dose-dependently attenuate LPS-induced renal injury and reduced inflammatory responses. Phosphoglycerate kinase 1 (PGK1) was identified as a direct target of BA. Mechanistically, BA activated the Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (Keap1–Nrf2) pathway through PGK1, enhanced the expression of antioxidant enzymes such as Nqo1, and reduced the production of pro-inflammatory cytokines, including IL-1β and IL-6. Virtual knockout of PGK1 in macrophages further supported its regulatory role in this pathway. These findings suggest that BA exerts renoprotective effects by targeting PGK1 and activating the Keap1-Nrf2 pathway, thereby reducing oxidative stress and inflammation. This study provides a pharmacological basis for the traditional use of O. himalaicus and supports BA as a potential candidate for mechanism-based intervention in AKI. Full article

Exosomes, nanoscale extracellular vesicles released by virtually all cell types, have emerged as pivotal mediators of intercellular communication and play a crucial role in the pathophysiology of numerous acute and chronic diseases, including a wide spectrum of urological disorders. By acting as sophisticated biological shuttles, exosomes transport a rich and highly specific molecular cargo—comprising proteins, lipids, messenger RNAs, microRNAs, and other nucleic acids—that reflects the physiological or pathological state of their cell of origin. Owing to these unique properties, exosomes are increasingly recognized as promising biomarkers for the diagnosis, prognosis, and monitoring of a broad range of inflammatory, degenerative, and neoplastic diseases. Beyond their diagnostic value, exosomes have attracted considerable attention as therapeutic tools, given their ability to promote tissue regeneration, modulate immune responses, and serve as potential targeted drug-delivery systems for small molecules, biologics, vaccines, and gene-based therapies. Notably, exosomes recapitulate many of the beneficial biological effects traditionally attributed to stem cells, while potentially offering a more practical alternative. As cell-free entities, they may reduce—though not entirely eliminate—several risks associated with cell transplantation, such as uncontrolled proliferation and immune rejection, and they raise fewer ethical concerns, making them attractive candidates for regenerative and precision medicine. In urology, the diagnostic, prognostic, and therapeutic applications of exosomes are rapidly expanding, with particularly promising advances observed in bladder, prostate, and kidney diseases. Growing evidence also supports their relevance in a variety of benign urological conditions, including erectile dysfunction, male infertility, neurogenic bladder, urethral stricture disease, stress urinary incontinence, and bladder pain syndrome. This review synthesizes contemporary knowledge on the biological significance and clinical potential of exosomes in urology, highlighting their emerging role as biomarkers and therapeutics, with a special focus on benign urological disorders. We emphasize that the current evidence base in benign urology is largely preclinical, and that clinical translation, although promising, remains at an early stage. Full article

Chronic stress produces marked individual differences in behavioral adaptation and glucocorticoid sensitivity, but the molecular basis of this variability remains poorly understood. Here, we examined transcriptional responses to glucocorticoid receptor activation after chronic social defeat stress (CSDS) in male C57BL/6J mice. Based on behavioral responses during social interaction, stressed animals were classified into active coping strategy (AS) and passive coping strategy (PS) phenotypes. A total of 24 h after the final stress session, mice received 2 µg/g of dexamethasone (DEX) or a saline injection, and transcriptomic profiling of the prefrontal cortex (PFC) and dorsal raphe nucleus (DRN) was performed 6 h later using RNA sequencing. Chronic stress induced pronounced phenotype- and region-specific transcriptional alterations. The PFC showed extensive stress-associated gene expression changes, particularly in PS animals, whereas the DRN displayed comparatively fewer differentially expressed genes. Functional enrichment analysis nevertheless revealed substantial pathway-level remodeling in both regions. PS animals exhibited extensive pathway reorganization in the DRN, while AS animals showed broader suppression of enriched biological pathways in the PFC. Acute DEX administration further revealed marked phenotype-dependent differences in glucocorticoid-responsive transcriptional programs, with the strongest response observed in AS animals. Together, these findings demonstrate that chronic stress establishes distinct transcriptional states that shape subsequent DEX-induced transcriptional responses in a phenotype- and brain region-specific manner. Our results provide new insight into the molecular mechanisms underlying heterogeneity in stress adaptation. Full article

Background: Intermediate-risk acute pulmonary embolism (PE) is clinically heterogeneous, and early deterioration may occur despite initial normotension. The Endothelial Activation and Stress Index (EASIX) is a readily available laboratory index reflecting endothelial activation, cellular injury, renal-perfusion stress, and platelet-related thromboinflammatory burden. We investigated whether admission EASIX and echocardiographic right ventricular-pulmonary arterial (RV-PA) coupling assessed by the TAPSE/PASP ratio identify intermediate-risk PE patients at increased risk for an early adverse clinical outcome (EACO). Methods: This retrospective cohort study included 900 consecutive intermediate-risk acute PE patients admitted between 1 January 2020 and 10 June 2025. EASIX was calculated as LDH (U/L) × creatinine (mg/dL)/platelet count (10⁹/L). The primary endpoint was EACO within the first seven days after PE diagnosis during the index hospitalization, including hemodynamic decompensation, vasopressor/inotrope requirement, intensive care unit transfer, rescue reperfusion therapy, ventilatory support, cardiac arrest, or PE-related death. Hierarchical logistic regression, ROC analysis, calibration assessment, bootstrap internal validation, and 10-fold cross-validation were performed. Results: EACO occurred in 110 patients (12.2%). Patients with EACO had higher EASIX (2.28 [1.52–3.27] vs. 1.27 [0.86–2.00], p < 0.001) and lower TAPSE/PASP ratio (0.29 [0.23–0.36] vs. 0.42 [0.33–0.57], p < 0.001). log2-EASIX correlated inversely with TAPSE/PASP (Spearman rho = −0.30, p < 0.001). In the final combined model, log2-EASIX (OR 1.55 per doubling, 95% CI 1.14–2.10, p = 0.005) and TAPSE/PASP per 0.1-unit decrease (OR 1.36, 95% CI 1.10–1.68, p = 0.004) remained independently associated with EACO after adjustment for clinical variables, troponin, lactate, D-dimer, and C-reactive protein-to-albumin ratio. The final model showed higher discrimination than the clinical-laboratory model, although the absolute AUC increment was modest (AUC 0.920 vs. 0.904). Bootstrap optimism-corrected AUC was 0.910 and 10-fold cross-validated AUC was 0.904. Conclusions: Admission EASIX and impaired RV-PA coupling may provide complementary prognostic information for early risk stratification in intermediate-risk acute PE. Because this was a retrospective single-center study without external validation, these findings should be considered hypothesis-generating and should not be used as definitive treatment-escalation triggers before independent external validation. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC₅₀ values of 26.7 ± 1.07 µM (Jurkat) and 30.5 ± 1.54 µM (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC₅₀ of 197.9 ± 1.29 µM, corresponding to a 6.5–7.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy. Full article

Curcumin, a natural polyphenol with well-established antioxidant and anti-inflammatory properties, was evaluated for its protective effects against glyphosate (GLY)-induced mammary toxicity. Pregnant mice received GLY (50 or 250 mg/kg/day) with or without curcumin (150 mg/kg/day) by oral gavage; GLY dose-dependently disrupted alveolar architecture, caused marked inflammatory infiltration, and downregulated tight-junction proteins. In parallel, goat mammary epithelial cells (GMECs) were treated with GLY (1 or 7 mM) and curcumin (1 µM) to dissect acute cellular stress pathways. These complementary models address distinct aspects of GLY toxicity: the in vivo system reflects defined oral exposure, whereas the in vitro setting employs high concentrations to probe mechanistic events. Transcriptomic profiling combined with functional assays demonstrated that GLY triggered oxidative stress, endoplasmic reticulum stress, and intracellular Ca²⁺ overload, activated the TNFα/MAPK axis, suppressed STAT3 phosphorylation, and ultimately promoted apoptosis. Curcumin co-treatment alleviated these alterations at both structural and molecular levels. These findings indicate that curcumin can combat GLY-induced mammary injury by restoring cellular homeostasis and inhibiting apoptotic and inflammatory signaling, thereby protecting breast health. Full article

Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer’s disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)—a hallmark of stroke, hypoxia, TBI, and migraine—modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis. Full article

Background: Acute liver injury (ALI) is commonly caused by acetaminophen (APAP) overdose, which drives oxidative stress alongside activation of innate immune signaling. Casticin, a naturally occurring flavonoid, has anti-inflammatory and antioxidant properties. Focusing on the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/tumor necrosis factor receptor-associated factor 6 (TRAF6)/nuclear factor kappa B (NF-κB) pathway, this study assessed casticin’s ability to protect mice from APAP-induced hepatotoxicity. Methods: APAP-induced ALI was established in mice randomly assigned to the following six groups: normal control, casticin control, APAP, APAP plus N-acetylcysteine (NAC), APAP plus low-dose casticin, and APAP plus high-dose casticin. Casticin was administered for three consecutive days before APAP to evaluate its preventive rather than therapeutic potential. Biochemical and histological analyses were performed, with molecular assessments using Western blotting, ELISA, quantitative real-time PCR (qPCR), and immunohistochemistry. Results: APAP significantly elevated serum ALT, AST, and ALP and markedly deteriorated hepatic architecture, confirming hepatotoxicity. APAP also induced lipid peroxidation and depleted antioxidant defenses. Hepatic TNF-α and IL-6 increased, IL-10 decreased, and the abundance of TLR4, MyD88, TRAF6, and NF-κB p65 was elevated. Casticin reduced these pathway components, lowered TNF-α and IL-6, and increased IL-10 dose-dependently, with effects approaching those of NAC. Conclusions: Casticin protected the liver against APAP toxicity, restraining oxidative injury while damping TLR4/MyD88/TRAF6/NF-κB signaling. Full article

European wild ungulates are captured for different purposes, requiring the assessment of animal welfare and health. Specific guidelines to assess stress and pathophysiological compromise in captured wild ungulates are lacking. This review aims to set the bases for establishing standardised protocols allowing the evaluation of capture and handling stress in wild European ungulates. Physical and chemical capture and handling elicit stress, a physiological response activating sympathetic–adrenal medulla and hypothalamic–pituitary–adrenal cortex axes, releasing catecholamines and corticosteroids, respectively. While being an adaptive response, if prolonged over time, the effects become harmful and life-threatening, increasing body temperature and heart rate, and provoking muscular and renal ischemia. This clinical outcome is known as capture myopathy, which encompasses four sequential syndromes: Hyper acute or capture shock, Acute or ataxic-myoglobinuric, Sub-acute or ruptured muscle, and Chronic debility or delayed per-acute. Monitoring temperature, heart rate, serum muscular enzyme (CK, AST, ALT, and LDH) activities and lactate, creatinine, urea, and potassium concentrations characterises pathophysiological compromise. Wild ungulate capture and handling protocols should include not only methodology but also monitoring, data recording, sample collection, and analyses. This information should serve to improve protocols and eventually develop specific guidelines for stress and welfare assessment when capturing and handling wild ungulates. Full article

High-dose intravenous vitamin C (HDIVC) has been investigated as a potential adjunctive therapy in critical illness, including sepsis, acute respiratory distress syndrome (ARDS), and COVID-19. Despite a strong mechanistic rationale, clinical trials have yielded inconsistent results. From a clinical pharmacology perspective, this variability may reflect, at least in part, differences in pharmacokinetic exposure, timing of administration, and patient selection rather than a lack of biological activity. Intravenous administration enables plasma concentrations in the millimolar range (≈1–5 mM), far exceeding those achievable with oral dosing (<100 µM), thereby reaching thresholds required for pharmacodynamic effects on oxidative stress, immune signaling, and endothelial function. This exposure-dependent transition distinguishes vitamin C as a pharmacological agent rather than a nutritional supplement in critically ill populations. Therapeutic response may be influenced by timing relative to disease progression, with earlier administration representing a biologically plausible strategy that warrants prospective evaluation rather than a clinically established therapeutic window. Interindividual variability in transporter function, redox status, and genetic background may further contribute to heterogeneous responses. Biomarkers such as interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, and markers of endothelial injury provide a framework for patient stratification and monitoring of pharmacodynamic effects. Integrated with pharmacokinetic principles, these markers support a shift toward biomarker-guided, precision-based therapeutic strategies. This review synthesizes current clinical and mechanistic evidence through an exposure–response conceptual framework, framing HDIVC as a context-dependent pharmacological intervention and advancing a shift toward biomarker-guided, precision-based therapeutic strategies in critical illness. Full article

Background: Mechanical work is traditionally defined by the pressure–volume loop, but its invasive nature limits routine clinical use. The myocardial work index (MWI) has emerged as a non-invasive alternative, combining strain and estimated pressure to assess cardiac performance. However, MWI does not account for ventricular geometry and treats the ventricle as a dimensionless chamber. According to Laplace’s law, wall stress and the true myocardial load depend on both pressure and ventricular geometry. Therefore, this study aims to develop and evaluate a geometry-informed myocardial work framework that provides a more physiologically representative estimate of mechanical energy expenditure. Method: In this proof-of-concept study, mechanical work was calculated using the one-fiber model of the left ventricle (LV) with Laplace-based geometric correction, integrating fiber stress over strain to derive the tension-adjusted myocardial work (TAMW) model. Strain was obtained from speckle tracking echocardiography along with pressure data while LV volumes and wall geometry were obtained from cardiac MRI. Two acute myocarditis patients with compact and dilated ventricles were analyzed, comparing cumulative and instantaneous work between MWI and TAMW. Performance gaps were quantified as the percentage difference in peak cumulative work. Results: Conventional MWI differed substantially between two cases (2576 vs. 1795 mmHg%, performance gap: 33.3%) whereas TAMW reduced this discrepancy to 7.5% (10,806 vs. 9789 mmHg%). TAMW also highlighted differences in temporal distribution of instantaneous work relative to MWI, reflecting the influence of ventricular geometry on contraction dynamics. Conclusions: TAMW incorporates the influence of geometry in the myocardial work framework revealing a more physiologically consistent reflection of myocardial effort across different ventricular geometries. Full article