Search Results (17,309)

Background: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were historically considered contraindicated in severe aortic stenosis (AS) due to theoretical haemodynamic risks. Contemporary evidence increasingly challenges this paradigm, yet data on preoperative use and postoperative outcomes remain limited. We examined the association between preoperative ACEi/ARB use and mortality following aortic valve replacement. Methods: We conducted a retrospective cohort study of 198 consecutive patients undergoing transcatheter (TAVI) or surgical aortic valve replacement (SAVR) at a single tertiary centre between May 2020 and March 2025. Complete one-year follow up was available for 185 patients (93%). The primary outcome was one-year all-cause mortality. Multivariable logistic regression adjusted for age, sex, hypertension, diabetes, LVEF, and procedure type. Results: Of 198 patients, 80 (40%) were receiving ACEi/ARB therapy preoperatively. ACEi/ARB users had a higher prevalence of hypertension (82% vs. 53%, p < 0.001) and diabetes (48% vs. 27%, p = 0.005) but similar age, valve area, and ejection fraction. Unadjusted one-year mortality was lower in the ACEi/ARB group (7% vs. 19%; odds ratio [OR] 0.33, 95% CI 0.12–0.91, p = 0.030). After multivariable adjustment for confounders including age, diabetes, and hypertension, the association did not reach statistical significance (adjusted OR 0.33, 95% CI 0.10–1.12, p = 0.075). Among diabetic patients, unadjusted one-year mortality was numerically lower in the ACEi/ARB group (12% vs. 35%, p = 0.038); however, six subgroup comparisons were performed and this result would not survive Bonferroni correction (threshold p < 0.008). This exploratory finding should be interpreted with caution given the small sample size and absence of adjustment for confounders. Conclusions: Preoperative ACEi/ARB use was associated with lower unadjusted one-year mortality, but this association did not reach statistical significance after multivariable adjustment and residual confounding cannot be excluded. ACEi/ARB use was not associated with increased mortality in this cohort. These hypothesis-generating findings from a single-centre observational study require confirmation in adequately powered prospective trials. Full article

Multicellular cancer cell aggregates, termed spheroids, are anoikis-resistant, avascular, heterogeneous structures responsible for transcoelomic metastasis of ovarian clear cell carcinoma (OCCC). OCCC is a rare subtype of ovarian cancer with high ARID1A gene mutation rates, resulting in genome-wide changes to H3K27Ac levels and histone deacetylase (HDAC) function. Our study investigated the utility of HDAC inhibitor (HDACi) treatment and H3K27Ac dynamics in OCCC spheroids. By comparing KOC-7c and 105C OCCC cell lines, which have opposing abilities to proliferate as spheroids, we revealed that KOC-7c and 105C spheroids differentially regulated H3K27Ac levels, which correlated with the sensitivity of KOC-7c and the resistance of 105C spheroids to H3K27Ac-altering HDACi treatment. RNA-seq of Entinostat-treated versus vehicle-treated spheroids resulted in a dramatic change in the 105C spheroid transcriptome such that it more closely resembled the proliferative KOC-7c transcriptome over the short term. Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent. Full article

Weak alternating electric fields are widely used in neuromodulation techniques such as transcranial alternating current stimulation (tACS), yet the precise biophysical mechanisms underlying neuronal responses remain incompletely understood. Current computational models often neglect the electrical properties of the extracellular microenvironment, limiting their predictive accuracy. Motivated by experimentally observed frequency-dependent modulation of neuronal activity, we developed a two-compartment model of hippocampal CA3 pyramidal neurons in which extracellular resistance is explicitly parameterized and systematically examined as a key factor influencing neuronal response properties under external electric fields. Within a dual-compartment Hodgkin–Huxley framework, the neuron is divided into a “soma–basal dendrite unit” and an “apical dendrite unit,” accounting for voltage polarization induced by external fields. Using phase-locking ratio curves and three-dimensional parameter response surface, we systematically characterized neuronal sensitivity to field parameters and examined how potassium equilibrium potential ($V_K$) and extracellular resistance ($R_{\mathrm{out}}$) modulate these responses. Our results demonstrate that increasing $R_{\mathrm{out}}$ enhances neuronal responsiveness to external fields, while $V_K$ variations primarily regulate intrinsic excitability. These findings provide mechanistic insights into the frequency-dependent modulation of neuronal responses under weak electric fields, consistent with phenomena observed in biological neural systems, and provide a mechanistic and theoretical framework for understanding the joint effects of electric field amplitude and frequency on neuronal sensitivity to weak electric fields, which may help inform future neuromodulation strategies. Full article

This paper develops a probabilistic Available Transfer Capability (ATC) framework that quantifies export headroom for renewables across transmission-distribution interfaces under time-varying uncertainty. Static transmission reliability margins can unnecessarily curtail exports. A dynamic transmission reliability margin (TRM) is embedded within ATC using rolling window statistics and adaptive confidence factor scheduling to release capacity in calm periods and tighten margins during volatile transitions. Uncertainty is modeled as net nodal power imbalance variability from load and renewable deviations, together with stochastic thermal limit fluctuations. Correlated multivariate scenarios are generated via Latin Hypercube Sampling with Iman-Conover correlation preservation and propagated through full AC power flow analysis. Validation on the IEEE 39-bus system and New Zealand’s HVDC inter-island corridor recovers 93.31 MW of usable transfer capacity on the IEEE system relative to the pooled Monte Carlo P95 constant-margin baseline, with 78.11 MW attributable to rolling window volatility tracking and 15.20 MW to adaptive confidence factor scheduling, and 59.51 MW (+7.6%) on the New Zealand corridor relative to the corresponding pooled Monte Carlo P95 baseline, with the gain arising primarily from rolling window volatility tracking. Relative to a 95% one-sided reliability target, achieved coverage is 93.9% for IEEE and 91.8% for New Zealand, translating into increased export headroom and reduced curtailment. Full article

(1) Background: Aristolochia spp. are plants spread around the world and are cautiously used for medicinal purposes due to their toxic compounds. Because of their content of aristolochic acid I (AAI), a major carcinogenic compound, these plant preparations can cause acute and chronic kidney disease, which is associated with cancer. These compounds also contaminate the environment where Aristolochia plants grow, leading to indirect exposure of the population. (2) Methods: The study provides a practical solution for minimizing the toxic effects of AAI using activated charcoal (AC). An ultra-high-pressure liquid chromatography (UHPLC) coupled with a diode array detector (DAD) was used for the AAI qualitative and quantitative evaluation at different time points. Also, the greenness of the chromatographic analysis was evaluated with the AGREE method. (3) Results: A medical pill of 250 mg AC removed 125 µg/mL AAI from a methanolic solution in 30 min with 97.65% efficiency. The greenness for the analytical evaluation was 58%. (4) Conclusions: This study offers, for the first time, a low-cost medical and environmental solution for AAI contamination. The UHPLC–DAD method seems to be an environmentally responsible platform for the AAI routine analysis. AC shows efficient removal, which could be used both for Aristolochia sp. pharmaceutical preparations as well as in environmental decontamination. Full article

Tongue squamous cell carcinoma (TSCC) is clinically heterogeneous, and patients with a similar TNM stage can experience markedly different outcomes. We systematically reviewed omics-driven studies to identify prognostic TSCC biomarkers. Although fundamentally prognostic, we discussed their theoretical translational relevance regarding future clinical decisions—such as treatment stratification or surveillance intensity—while strictly framing them as preliminary, hypothesis-generating targets. PubMed, Scopus, Web of Science, and Cochrane were searched for original human studies published between 2014 and 2024 using high-throughput genomic or transcriptomic profiling. Study selection followed referred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), data were extracted with a structured workbook, and risk of bias was assessed using QUIPS and PROBAST, with reporting completeness appraised using REMARK. Seventeen studies were included, identifying 85 distinct biomarkers. Across biomarkers supported by multivariable overall survival analyses, higher-risk associations were reported for NELL2, PDE4D, CTTN, HBEGF, and CA9, whereas lower-risk associations were reported for AC139530.1, LINC01711, CCDC96, CYP2J2, and SPAG16. Recurrent biological themes included IL-17 signaling, ECM-receptor interaction, and focal adhesion. CA9 was the only biomarker reported in more than one included study, supporting its prioritization for validation. Although the evidence remains heterogeneous and largely hypothesis-generating, these markers may support the future validation of response-oriented therapeutic stratification in TSCC. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the spike receptor-binding domain (RBD) engages angiotensin-converting enzyme 2 (ACE2). Cannabinoid scaffolds have recently been reported to bind S1/RBD, block spike-mediated membrane fusion, and modulate host inflammatory pathways, making them attractive candidates for entry inhibition. Here, we applied an integrated computational pipeline to prioritize cannabis-derived compounds as interfacial blockers of the RBD–ACE2 complex across variants. Eleven phytocannabinoids were docked into the wild-type (WT) RBD–ACE2 interface, identifying three cavities, with ligands preferentially occupying pocket 1. Complexes were subjected to triplicate 200 ns all-atom molecular dynamics (MD) simulations for WT, Delta, and Omicron BA.1 RBD–ACE2. Binding energetics were quantified using molecular mechanics/generalized Born surface area (MM/GBSA) and solvated interaction energy (SIE), and per-residue contributions were analyzed together with solvent-accessible surface area (SASA) and residue interaction networks. Among all compounds, cannabidiol (CBD) and cannabinol (CBN) were the only ligands that remained stably bound in pocket 1 for all variants. CBN showed the most favorable ligand–complex binding in WT, whereas CBD preserved favorable binding in Omicron BA.1 despite reduced interface burial, indicating that van der Waals/electrostatic complementarity and solvation, rather than surface coverage alone, govern affinity. Both ligands weakened modeled RBD–ACE2 binding by perturbing hot-spot residues centered on Y505 or N501Y in RBD and E37, A387, and R393 in ACE2. Overall, our results highlight CBD and CBN as tractable, variant-spanning interface disruptors and illustrate how MD-based free-energy calculations can support computational drug discovery against evolving viral protein–protein interfaces. Full article

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has revealed a complex interplay between respiratory and neurological manifestations. This study utilized K18-hACE2 transgenic mice to investigate the morphological, ultrastructural, and transcriptomic changes induced by SARS-CoV-2 infection in both lungs and brain tissues. Histopathological analysis at seven days post-infection revealed significant pulmonary damage characterized by interstitial pneumonia, alveolar septal thickening, with a marked inflammatory infiltrate predominantly consisting of neutrophils and lymphocytes, and an abnormal profile of type II pneumocytes. Concurrently, in the brain, we observed vasculitis, gliosis, and edema, indicating an inflammatory response and vascular compromise that can disturb the blood–brain barrier. In addition, gene expression in lung tissue presented increased CCL2, IL10, and GDDA45D in infected mice and the downregulation of proinflammatory genes. However, in brain tissue, the increased expression of CCL2, CASP1, IL6, IFNB1, and GDDA45G inflammatory genes was observed in infected K18-hACE2 mice. Full article

Acute coronary syndrome patients undergoing percutaneous coronary intervention remain at high risk for major adverse cardiovascular events (MACE: cardiovascular mortality, non-fatal myocardial infarction, and stroke). Inflammatory–oxidative stress biomarkers are potential prognostic tools; however, the influence of sampling timing—pre-procedural versus post-procedural—remains unclear. This meta-analysis evaluated six biomarkers: sST2, GDF-15, OPG, sLOX-1, H-FABP, and Galectin-3. Pooled Hazard Ratios (HRs) for time-to-event outcomes and Standardized Mean Differences (SMDs) between event and non-event groups were synthesized using random-effects models involving 40 studies (18,933 patients). Elevated pre-procedural levels of sST2 (HR = 3.32, p < 0.0001), GDF-15 (HR = 3.00, p < 0.0001), sLOX-1 (HR = 2.61, p = 0.0023), and OPG (HR = 1.79, p = 0.0206) significantly predicted MACE. Notably, pre-PCI sST2 strongly predicted heart failure hospitalization (HR = 6.30, p < 0.0001). Additionally, pre-PCI H-FABP demonstrated a moderate significant effect on adverse outcomes (SMD = 0.67, p < 0.0001). While pre-PCI Galectin-3 was not significant, its post-procedural levels showed a large significant effect (SMD = 1.15, p < 0.0001). In conclusion, inflammatory and oxidative stress biomarkers, particularly sST2 and GDF-15, demonstrate consistent associations with adverse outcomes in ACS patients undergoing PCI, offering more reliable baseline risk stratification than post-procedural measurements. Full article

Background/Objectives: Acute coronary syndromes (ACS) encompass a spectrum of clinical entities from unstable angina to non–ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI), all associated with significant morbidity and mortality. Inflammation plays a central role in the pathophysiology of ACS, contributing to atherosclerotic plaque destabilization, myocardial injury, and adverse clinical outcomes. Inflammatory biomarkers, together with N-terminal pro–B-type natriuretic peptide (NT-proBNP), are increasingly used for risk stratification, yet their prognostic value across different ACS presentations remains unclear. This study aimed to assess the prognostic value of inflammatory status in patients with acute coronary syndromes in a single-center cohort. Methods: This prospective observational study included 100 consecutive patients with ACS and elevated inflammatory biomarkers, enrolled in 2024–2025 at a tertiary cardiovascular center. Inflammatory status was assessed by using C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII); NT-proBNP was also measured. The primary endpoint was in-hospital MACE, defined as cardiovascular death, recurrent myocardial infarction, stroke, urgent coronary revascularization, or acute heart failure requiring escalation of therapy. Multivariable logistic regression and ROC analyses were performed. Results: Among the 100 ACS patients, half experienced in-hospital MACE. Compared with those without events, patients with MACE were older (p = 0.003) and had higher inflammatory biomarkers—CRP (p < 0.001; strongest association), NLR (p = 0.030), and SII (p = 0.042)—as well as higher NT-proBNP (p = 0.002). Patients with MACE also showed reduced renal function (p < 0.001) and lower left ventricular systolic function, reflected by reduced LVEF (p = 0.001), indicating concomitant renal impairment and ventricular dysfunction. Hypertension was more prevalent in the MACE group (p = 0.028), and new-onset atrial fibrillation was significantly more common among these patients (p < 0.001). In multivariable analysis, LVEF emerged as an independent predictor of short-term outcomes (OR 0.934 per 1% increase; p = 0.047). Conclusions: Inflammatory activation appears closely linked to the occurrence of in-hospital adverse events in patients with acute coronary syndromes. While left ventricular ejection fraction remained an independent determinant of short-term outcomes, inflammatory biomarkers may provide complementary insight into the inflammatory burden accompanying ACS. Full article

Background/Objectives: Allergic conjunctivitis (AC) is the most common inflammatory disease affecting the ocular conjunctiva. Tacrolimus (TCR), a potent calcineurin inhibitor, is limited by poor aqueous solubility and low ocular bioavailability. This study aimed to develop TCR-loaded cubosomes (TCR-Cubs) incorporated into HPMC/PVP K90 dissolving microneedles (MNs) to enhance their therapeutic efficacy. Methods: TCR-Cubs were prepared using a modified top-down fragmentation method with glyceryl monooleate and poloxamer 407, optimized via Box–Behnken design, and incorporated into dissolving MNs. The system was evaluated in vitro, ex vivo, and in vivo using a rabbit model of allergic conjunctivitis. Results: The optimized formulation exhibited the smallest particle size (210 ± 0.91 nm), polydispersity index (0.29 ± 0.03), zeta potential (−21 ± 0.87 mV), and the highest entrapment efficiency (% 93.3 ± 0.45). The optimized formulation was incorporated into MNs via micro molding. Scanning electron microscopy (SEM) confirmed well-defined, sharp microneedles, with low height reduction (<10%) by mechanical testing and high penetration efficiency (>85–90%). In vitro release studies revealed sustained drug release of (~75–80%) over 24 h, compared to (~40%) from the TCR suspension, following diffusion-controlled kinetics. Ex vivo permeation studies showed a (~2–3-fold) enhancement in corneal drug flux. In vivo pharmacodynamic evaluation using an ovalbumin-induced allergic conjunctivitis model demonstrated significant reductions in inflammatory mediators, including inflammatory markers (TNF-α, IL-1β, IL-6, NLRP3), which were reduced by (~50–75%), with modulation of CPA3, BCL2, and TGF-β1 by qRT-PCR. Histopathology and TLR4 analysis confirmed reduced inflammation without irritation. Conclusions: This dual-delivery system offers a promising, non-invasive platform for enhanced ocular delivery of tacrolimus with superior anti-inflammatory efficacy in allergic conjunctivitis. Full article

In recent years, typhoon activity over the South China Sea (SCS) has intensified, and interactions between typhoons and mesoscale eddies profoundly regulate the regional oceanic environment and air–sea energy exchange. To systematically investigate the position- and polarity-dependent eddy responses to typhoon forcing, we developed a typhoon–eddy spatial matching algorithm and analyzed the global mesoscale eddy dataset (2006–2020) combined with China Meteorological Administration (CMA) best-track typhoon records. Composite and correlation analyses were employed to examine variations in the eddy surface available potential energy (SAPE) and sea-surface temperature (SST) within a 7-day window before and after typhoon passage, with the typhoon power dissipation index (PDI) used to quantify storm intensity. Composite results reveal distinct dual-asymmetric responses: (1) Energetically, eddies on the left side of typhoon tracks exhibit overall weakening, with anticyclonic eddies (ACEs) showing more pronounced energy decay; in contrast, right-side eddies undergo significant intensification, and cyclonic eddies (CEs) display stronger enhancement than ACEs. (2) Thermally, all eddy types experience net cooling after typhoon passage, with right-side eddies showing stronger SST reductions than left-side ones, and CEs exhibiting more intense cooling than ACEs. Time-scale correlation analyses further demonstrate that the eddy energy change rate (EECR) of left-side CEs, right-side CEs, and right-side ACEs is positively correlated with PDI, whereas left-side ACEs show no significant correlation. For the SST change rate (SSTCR), all types of eddy events exhibit significant negative correlations with PDI, with weaker correlations for CEs and stronger correlations for ACEs. This study demonstrates that the track-relative position of tropical cyclones and the polarity of pre-existing mesoscale eddies exert a systematic control on the observed eddy responses to tropical cyclone forcing in the SCS. These results provide observational constraints on the asymmetric oceanic responses induced by tropical cyclones and offer insights into the interpretation of typhoon–ocean interaction diagnostics in marginal seas. Full article

The development of novel antiviral nanomaterials is an important approach for addressing emerging viral threats. In this study, glycyrrhizic acid-modified gold nanoparticles (GA-Au NPs) were successfully synthesized and characterized, and their inhibitory effects against porcine reproductive and respiratory syndrome virus (PRRSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus were systematically evaluated. At non-cytotoxic concentrations, GA-Au NPs showed inhibitory activity against PRRSV in vitro. Stage-specific assays suggested that intracellular replication-related events were prominently affected, with additional inhibitory effects observed during adsorption, invasion, and release, whereas no direct virucidal activity was detected under the tested conditions. Furthermore, GA-Au NPs dose-dependently reduced SARS-CoV-2 pseudovirus infection-associated reporter signals in HEK-293T-ACE2 cells, supporting inhibitory activity in an additional viral model. In conclusion, GA-Au NPs represent a biocompatible antiviral nanomaterial with multi-stage inhibitory activity against PRRSV and inhibitory effects in a SARS-CoV-2 pseudovirus model, supporting their further evaluation as antiviral nanomaterials in enveloped virus-related models. Full article

Soil salinity severely constrains strawberry production by disrupting ion homeostasis and provoking oxidative injury. This study investigated whether soluble silicon (Si) and activated carbon (AC) act to enhance salt tolerance in strawberry (Fragaria × ananassa). Under NaCl stress, plants showed pronounced growth inhibition, increased Na⁺ accumulation and a deteriorated K⁺/Na⁺ balance, accompanied by elevated reactive oxygen species (ROS) and lipid peroxidation. In contrast, combined AC + Si treatment consistently provided the strongest protection, improving seedling vigor and survival. Relative to NaCl alone, AC + Si increased shoot and root fresh weight by 67.5% and 78.5%, reduced shoot Na⁺ by 59.1%, and lowered shoot H₂O₂ and MDA by 62.6% and 66.5%, respectively, indicating marked improvement in ion–redox homeostasis. Beyond plant responses, AC-containing treatments alleviated salt-induced increases in soil electrical conductivity, coinciding with a clear restructuring of the rhizosphere bacterial community and enrichment of putatively beneficial taxa. Transcriptome profiling further supported coordinated reprogramming of ion transport, redox control and stress-responsive signaling pathways under the AC + Si regime. Collectively, the results indicated that Si and AC co-application enhances strawberry salt tolerance through an integrated soil–plant–microbiome mechanism that stabilizes ion homeostasis and reinforces redox homeostasis. Full article

Rising population pressures have intensified the need to reuse wastewater, which increases exposure to microbial and heavy metal contamination, negatively impacting ecosystems and human health. Heavy metals in wastewater present a major environmental concern. This study examines the adsorption capacities and efficiencies of individual and combined adsorbents—activated carbon (AC), biochar (BC), and kaolinite (KA)—for removing heavy metals, organic matter, salinity, and pathogens from wastewater. Wastewater samples were treated in column adsorption systems and analyzed before and after treatment using physicochemical and microbiological methods. The composite adsorbent (AC + BC + KA) performed best, reducing electrical conductivity by 75% (from 4.0 to 1.0 mS/cm), total dissolved solids from 2560 mg/L to 915.2 mg/L, and sodium adsorption ratio from 27.14 to 7.06. The pH remained within the optimal irrigation range (7.66). The system removed up to 85.87% of heavy metals (Cu²⁺, Cd²⁺, Mn²⁺, Zn²⁺) and 100% of pathogenic bacteria (E. coli, Shigella spp., and B. cereus). The microporous structure of AC provides large surface areas for pollutant trapping through adsorption, while BC introduces functional groups that enhance contaminant capture. The combination of these materials offers an eco-friendly and effective method for wastewater purification. Full article