Search Results (156)

The growing global threat of antimicrobial resistance (AMR), particularly in cutaneous wound infections, represents a significant clinical and economic challenge. Biofilm formation by multidrug-resistant pathogens, such as Acinetobacter baumannii, often complicates healing and leads to therapeutic failure. Antimicrobial peptides (AMPs) are a promising alternative to conventional antibiotics due to their potent membrane-disrupting mechanism of action and lower propensity to induce resistance. Background/Objectives: This study aimed to evaluate the antibacterial, antibiofilm, and in vivo efficacy of four snake venom-derived cathelicidin-like peptides—Btn (15-34) and BotrAMP14 from Bothrops atrox, and Ctn (15-34) and CrotAMP14 from Crotalus durissus—against multidrug-resistant A. baumannii, Escherichia coli, and Pseudomonas aeruginosa clinical isolates from skin infections, with emphasis on A. baumannii, a WHO priority pathogen. Methods: Minimal Inhibitory Concentration (MIC), Minimal Bactericidal Concentration (MBC), and Minimal Biofilm Inhibitory Concentration (MBIC) were determined against A. baumannii, Escherichia coli, and Pseudomonas aeruginosa. Time-kill kinetics, hemolytic activity, and cytotoxicity assays were performed. A murine skin wound infection model was established to evaluate in vivo antibacterial efficacy and safety. Results: MIC/MBC values ranged from 0.78 to 25 µM against planktonic cells. In comparison, MBIC ranged from 1.56 to 12.5 µM against biofilms. BotrAMP14 eradicated A. baumannii within 4 min, while CrotAMP14 achieved bactericidal action in 20 min at 1.56 µM. Both peptides exhibited no hemolytic activity up to 128 µM and low cytotoxicity (IC₅₀ > 128 µM). In vivo, BotrAMP14 and CrotAMP14 demonstrated significant antibacterial activity at 24 h and 48 h post-infection, respectively, surpassing that of meropenem. Conclusions: These findings suggest that BotrAMP14 and CrotAMP14 are promising topical antimicrobial agents for managing multidrug-resistant skin infections and may help address the urgent need for alternative therapies against antibiotic-resistant pathogens. Full article

This study analyzes the relationship between fires and climate extremes in the Caatinga biome from 2012 to 2023 by integrating Fire Radiative Power (FRP) from VIIRS (S-NPP and NOAA-20), Vapor Pressure Deficit (VPD) and air temperature from ERA5, drought indices (SPI-1 and SPI-6), and heatwave events from the Xavier database. Daily percentiles of maximum (CTX90pct) and minimum (CTN90pct) temperatures were used to characterize heatwaves. Spatial and temporal dynamics of fire patterns were identified using the HDBSCAN algorithm, an unsupervised Machine Learning clustering method applied in three-dimensional space (latitude, longitude, and time). A marked seasonality was observed, with fire activity peaking from August to November, especially in October, when FRP reached ~1000 MW/h. The years 2015, 2019, 2021, and 2023 exhibited the highest fire intensities. A statistically significant upward trend in cluster frequency was detected (+1094.96 events/year; p < 0.001). Cross-correlations revealed that precipitation deficits (SPI) preceded FRP peaks by about four months, while VPD and air temperature exerted immediate positive effects. FRP correlated positively with heatwave frequency (r = 0.62) and negatively with SPI (r = −0.69). These findings highlight the high vulnerability of the Caatinga to compound drought and heat events, indicating that fire management strategies should account for both antecedent drought conditions, monitored through SPI, and real-time atmospheric dryness, measured by VPD, to effectively mitigate fire risks. Full article

The catalytic mechanism of the Zn(II)-dependent chlorothalonil dehalogenase from Pseudomonas sp. CTN-3 (Chd) was examined using molecular dynamics (MD) simulations, Bayesian network analysis, and Markov state model analysis to quantify its motions. Chd selectively substitutes an aromatic chlorine-carbon bond in chlorothalonil (TPN; 2,4,5,6-tetrachloroisophtalonitrile) with an aromatic alcohol (4-hydroxytrichloro-isophthalonitrile; 4-OH-TPN). It is a homodimer with two solvent-accessible channels in each monomer, which are proposed to provide different routes for substrate and products to access/leave the catalytic Zn(II) site. Based on MD simulations, Chd exhibits allosteric behavior wherein a “Y”-shaped substrate channel exhibits a “flip flop” mechanism, where the “right” substrate channel opens to allow TPN to enter, after which it closes, followed by the “left” channel opening. The “right” channel then reopens, likely to allow the product, 4-OH-TPN, to leave the active site, but this reopening of the right channel drives the “left” channel to close. Coupled with the substrate channels alternately opening and closing, a corresponding possible Cl⁻ channel opens and closes. Although the dynamics of this process are fast, Chd needs to overcome a 5 kT free-energy barrier for this transition and to relax after opening. Additionally, exposed “wing” residues, hydrophilic residues at the ends of protruding α-helices, act as allosteric indicators, signaling the complex allosteric motions required to open the substrate channel. We propose, for the first time, a dynamic mechanism that drives substrate binding and product release, providing new insight into Chd’s catalytic mechanism. Full article

A universal HPLC method with diode array detection was developed for the separation and determination of the lactone and acid forms of monacolin K in the presence of other active ingredients (vitamins B₁, B₆, B₁₂, and folic acid) found in selected dietary supplements. The method also enables the quantitative determination of citrinin in monacolin K. Chromatographic separation was performed on an ACE 5 C18-PFP column (250 × 4.6 mm) thermostated at 25 °C. The mobile phase consisted of 0.005 M phosphate buffer (pH 2.60) and acetonitrile under linear gradient elution conditions. Detection was carried out spectrophotometrically at 230 nm for monacolin K and 325 nm for citrinin. The total run time was 28 min. The method was validated and met the acceptance criteria for specificity, linearity, sensitivity, accuracy, and precision. Linearity was achieved over a broad concentration range: 12.48–37.44 μg·mL⁻¹ for MK and 3.48–5.22 μg·mL⁻¹ for CTN. The method is sufficiently sensitive, with LOD and LOQ values of 0.91–2.85 μg·mL⁻¹ and 2.18–3.48 μg·mL⁻¹ for MK and CTN, respectively. Good precision (RSD < 0.70%) and intermediate precision (RSD < 1.33%) were observed. The accuracy of the method, expressed as percentage recovery at three concentration levels, ranged from 98.73% to 100.64%. The analysis revealed that the monacolin K content in randomly selected dietary supplements did not comply with the manufacturer’s declaration in any case. Full article

Background/Objectives: Academically sponsored cancer clinical trials (ACCTs) are essential for advancing patient-centered care, particularly in areas underserved by commercial research. The Canadian Cancer Clinical Trials Network (3CTN) was established to support high-quality multi-center ACCTs through coordinated infrastructure and funding. Over ten years, funders provided an average of CAD 4.3 million annually (~CAD 0.11 per capita), primarily from federal and provincial sources. This study evaluates the outcomes and impact of trials supported by 3CTN between 2015 and 2024. Methods: We conducted a descriptive analysis of 350 ACCTs that stopped recruiting and had primary completion dates within the study period. Trial characteristics, results, publication rates, and incorporation into clinical guidelines were assessed using registry data, peer-reviewed publications, and structured searches of oncology guidelines. Results: Among these 350 closed trials, 116 were Phase III studies. Of these, 36% were incorporated into clinical practice guidelines, and 7% were likely to be incorporated. Overall, 81% of trials were published in journals, and 45% posted results in public registries. Trials addressed diverse cancer types, with notable contributions in rare cancers and vulnerable populations. Conclusions: 3CTN-supported ACCTs had high completion and reporting rates, with substantial influence on clinical practice. These findings highlight how sustained infrastructure and modest public investment can deliver meaningful improvements in cancer care and inform evidence-based policy. Full article

Background/Objectives: High-fat diets (HFDs) are widely used to induce obesity, but cost-effective and reproducible formulations remain challenging. Moreover, the reversibility of metabolic and gut microbiota alterations following HFD withdrawal is not fully understood. This study evaluated a low-cost HFD model in mice and investigated metabolic, oxidative, and gut microbiota changes during a subsequent 12-week dietary normalization phase. Methods: Male C57BL/6 mice were fed a standard diet (CTN) or a lard-supplemented HFD for 12 weeks (Phase 1), followed by 12 weeks dietary normalization to a standard diet (Phase 2). Body weight, adiposity, blood glucose, biochemical parameters, and oxidative markers were assessed. Fecal samples were analyzed for short-chain fatty acids (SCFAs), microbiota composition (16S rRNA sequencing), and predicted functions using FAPROTAX and PICRUSt2. Results: The HFD significantly increased body weight, abdominal circumference, the Lee index, and adipose tissue mass compared to CTN. Following diet normalization, both groups exhibited weight loss, but the previously obese mice maintained a higher Lee index and distinct lipid and uric acid profiles. No hepatic oxidative stress was detected after normalization. SCFA profiles underwent a temporal shift: CTN showed higher fecal acetate, while HFD mice exhibited elevated butyrate. Functional prediction revealed one pathway associated with an unclassified Rickettsiales bacterium that was exclusively found in HFD mice. The CTN group exhibited a higher abundance of the thiamine diphosphate formation pathway (PWY-7357), suggesting enhanced oxidative metabolism. Conclusions: This low-cost HFD successfully induced obesity and dysbiosis. Dietary normalization resulted in a partial modulation of metabolic and microbial balance, thereby highlighting host–microbe metabolic plasticity. Full article

Cardiac troponins (cTn) T and I are biochemical markers of myocardial injury. In this review article, we aim to summarize the mechanisms and significance of cardiac troponin (cTn) elevation unrelated to acute myocardial infarction (AMI) in the most frequently occurring non-cardiac conditions, where the accurate interpretation of elevated cTn levels is often challenging. Different mechanisms in non-cardiac conditions can cause non-ischemic myocardial injury. Understanding the pathophysiology of cTn release is an essential precondition for minimizing unnecessary, costly, and potentially risky (cardiac) interventions and for providing timely and appropriate medical care. Elevated cTn in critically ill patients and in patients with chronic disease/conditions is an independent predictor (risk factor) of cardiovascular and overall mortality. Treatment of underlying conditions is of primary importance, and close monitoring for the occurrence of cardiovascular complications during hospitalizations should be considered in these patients. Also, when the patient recovers from the underlying disease, clinical judgement should be employed to decide whether and to what extent further cardiological evaluation is indicated. Full article

The benefit of neoadjuvant chemotherapy (NAC) over upfront surgery (UFS) for resectable pancreatic ductal adenocarcinoma (PDAC) is increasingly recognized, yet prognostic biomarkers remain undefined. We evaluated tumor–stroma ratio (TSR), β-catenin (β-CTN) expression, and tumor budding (TB) in 84 resected PDACs (35 NAC, 49 UFS) using digital image analysis of multi-cytokeratin (m-CK) and β-CTN immunohistochemistry. TSR was defined as the proportion of malignant epithelial area within the tumor, and the β-CTN/m-CK index as the ratio of β-CTN to m-CK immunoreactivity in tumor tissue relative to intralobular ducts. TB was significantly less frequent in NAC than UFS (p = 0.003), suggesting that NAC may indirectly modulate epithelial–mesenchymal transition, with TB regarded as its morphological correlate. In the NAC cohort, low TSR was associated with more favorable histological response (Evans IIa/IIb, median 7%; Evans I, 16%; p = 0.009), likely reflecting NAC-induced tumor shrinkage with relative stromal predominance. In multivariable analysis, low β-CTN/m-CK index (<0.5) predicted shorter relapse-free survival in both NAC (HR = 2.516, p = 0.043) and UFS (HR = 2.230, p = 0.025) subgroups. High TSR (≥13%) was associated with shorter cancer-specific survival (HR = 2.414, p = 0.034) in the overall cohort, indicating prognostic value complementing its association with NAC response. These results identify the β-CTN/m-CK index and TSR as prognostic biomarkers in PDAC. Full article

Background: The cardiotoxic effects of doxorubicin (DOX), a powerful chemotherapeutic drug, are widely recognized. Cuproptosis, a unique copper-dependent form of controlled cell death, may be involved in DOX-induced cardiomyopathy, according to recent findings. This study employs both in vivo and in silico procedures to investigate the protective effects of the copper chelator penicillamine (PEN) and the role of cuproptosis in DOX-related cardiotoxicity. Methods: Thirty-two adult Sprague Dawley rats were allocated into four groups (n = 8): control, DOX, DOX+PEN, and PEN. Cardiac function was assessed via echocardiography. Serum cardiac biomarkers (LDH, CK-MB, CTnI), oxidative stress markers (SOD, GPX, MDA), and expression levels of cuproptosis-related genes (FDX1, LIAS, SLC31A1, ATP7A) were evaluated. Histopathological examinations and immunohistochemical staining for FDX1, SLC31A1, and DLAT were performed. Molecular docking simulated PEN’s interaction with cuproptosis-related proteins. Network pharmacology and molecular docking studies were also conducted to identify core molecular targets and simulate PEN’s binding interactions with key cuproptosis regulators. Results: DOX administration induced significant cardiac dysfunction, oxidative stress, and upregulation of cuproptosis markers. PEN treatment mitigated these effects, improved cardiac function, reduced fibrosis, and suppressed the expression of cuproptosis-related genes and proteins. Docking results confirmed strong interactions between PEN and cuproptosis-regulatory proteins. Network pharmacology revealed 14 key overlapping targets linking PEN with cuproptosis and DOX-induced cardiotoxicity. Conclusion: This study provides experimental evidence implicating cuproptosis in DOX-induced cardiomyopathy. PEN exerts cardioprotection, potentially by targeting this pathway, offering a promising therapeutic strategy. Full article

Crop pathogens threaten global agriculture by causing severe yield and economic losses. Conventional detection methods are often slow and inaccurate, limiting timely intervention. This study introduces a pentagon-shaped terahertz photonic crystal fiber (THz PCF) biosensor, optimized with the decision cascaded 3D return dilated secretary-bird aligned convolutional transformer network (DC3D-SBA-CTN). The biosensor is designed to detect a broad spectrum of pathogens, including fungi (e.g., Fusarium spp.) and bacteria (e.g., Xanthomonas spp.), by identifying their unique refractive index signatures. Integrating advanced neural networks and optimization algorithms, the biosensor achieves a detection accuracy of 99.87%, precision of 99.65%, sensitivity of 99.77%, and specificity of 99.83%, as validated by a 5-fold cross-validation protocol. It offers high sensitivity (up to 7340 RIU⁻¹), low signal loss, and robust performance against morphological variations, making it adaptable for diverse agricultural settings. This innovation enables rapid, precise monitoring of crop pathogens, revolutionizing plant disease management. Full article

With the global aging population increasing, promoting psychological well-being (PWB) in later life has become critical. This study employed a cross-sectional design to examine the impact of connectedness to nature (CtN) on PWB among Chinese older adults, focusing on the mediating role of self-perceptions of aging (SPA) and the moderating effect of meaning in life (MIL). Data from 401 participants were analyzed using a moderated mediation model, controlling for demographic variables. The results indicate that CtN is positively associated with PWB, partially through reducing negative SPA. Moreover, MIL strengthens both the direct effect of CtN on PWB and its indirect effect via SPA. These findings underscore the importance of fostering nature connection and meaning in life to enhance well-being in older adults and offer valuable insights for interventions promoting healthy aging. Full article

This study utilizes high-resolution X-ray computed tomography (CT) to evaluate the reservoir characterization in heterogenous carbonate rocks. These rocks show a diagenetic alteration that influences the reservoir quality in the Cretaceous Qamchuqa–Bekhme formations in outcrop and subsurface sections (Gali-Bekhal, Bekhme, and Taq Taq oilfields, NE Iraq). The scanning of fifty-one directional line analyses was conducted on three facies: marine, early diagenetic (non-hydrothermal), and late diagenetic (hydrothermal dolomitization, or HTD). The facies were analyzed from thousands of micro-spot analyses (up to 5250) and computed tomographic numbers (CTNs) across vertical, horizontal, and inclined directions. The surface (outcrop) marine facies exhibited CTNs ranging from 2578 to 2982 Hounsfield Units (HUs) (Av. 2740 HU), with very low average porosity (1.20%) and permeability (0.14 mD) values, while subsurface marine facies showed lower CTNs (1446–2556 HU, Av. 2360 HU) and higher porosity (Av. 8.40%) and permeability (Av. 1.02 mD) compared to the surface samples. Subsurface marine facies revealed higher porosity, lower density, and considerably enhanced conditions for hydrocarbon storage. The CT measurements and petrophysical properties in early diagenesis highlight a considerable porous system in the surface compared to the one in subsurface settings, significantly controlling the quality of the reservoir storage. The late diagenetic scanning values coincide with a saddle dolomite formation formed under high temperature conditions and intensive rock–fluid interactions. These dolomites are related to a hot fluid and are associated with intensive fracturing, vuggy porosities, and zebra-like textures. These textures are more pronounced in the surface than the subsurface settings. A surface evaluation showed a wide CTN range, accompanied by an average porosity of up to 15.47% and permeability of 301.27 mD, while subsurface facies exhibited a significant depletion in the CTN (<500 HU), with an average porosity of about 14.05% and permeability of 91.56 mD. The petrophysical characteristics of the reservoir associated with late-HT dolomitization (subsurface setting) show two populations. The first one exhibited CTN values between 1931 and 2586 HU (Av. 2341 HU), with porosity ranging from 3.10 to 18.43% (Av. 8.84%) and permeability from 0.08 to 2.39 mD (Av. 0.31 mD). The second one recorded a considerable range of CTNs from 457 to 2446 HU (Av. 1823 HU), with porosity from 6.38 to 52.92% (Av. 20.97%) and permeability from 0.16 to 5462.62 mD (Av. 223.11 mD). High temperatures significantly altered the carbonate rock’s properties, with partial/complete occlusion of the porous vuggy and fractured networks, enhancing or reducing the reservoir quality and its storage. In summary, the variations in the CTN across both surface and subsurface facies provide new insight into reservoir heterogeneity and characterization, which is a fundamental factor for understanding the potential of hydrocarbon storage within various geological settings. Full article

Citrinin (CTN), a mycotoxin commonly found in contaminated food and animal feed, impairs intestinal barrier integrity through oxidative stress and cytotoxicity. However, its link to ferroptosis, an iron-dependent form of regulated cell death, remains unclear. This study investigated whether CTN induces ferroptosis in intestinal epithelial cells and evaluated the protective role of Euphorbia hypericifolia (EH) against CTN-induced oxidative damage and tight junction (TJ) disruption. Using IPEC-J2 cells exposed to CTN, intracellular ferrous ion (Fe²⁺) levels, reactive oxygen species (ROS) accumulation, and TJ integrity were assessed using FerroOrange and DCFH-DA staining, RT-qPCR, immunofluorescence, and WST-1 assays. Additionally, a high-throughput screen of 459 natural products identified EH extract as a top candidate in mitigating CTN toxicity. The CTN treatment significantly elevated intracellular Fe²⁺ and ROS levels, downregulated antioxidant genes (notably CAT), and disrupted ZO-1 expression and TJ morphology in IPEC-J2 cells, all hallmarks of ferroptosis-like cell death. Co-treatment with EH extract effectively reversed these effects, restoring antioxidant gene expression, reducing Fe²⁺ and ROS accumulation, and preserving TJ structure. Phytochemical profiling of EH extract revealed several bioactive compounds potentially responsible for its protective effects. These findings suggest that CTN induces ferroptosis-related cytotoxicity in IPEC-J2 cells, but EH alleviates this toxicity by modulating oxidative stress and iron homeostasis, supporting its potential use as a natural feed additive for intestinal protection Full article

Background: Elevated cardiac troponin (cTn) levels in patients with paroxysmal supraventricular tachycardia (PSVT) often prompt coronary artery disease evaluation, though the clinical relevance of this finding remains unclear. This study aimed to identify risk factors for cTn elevation after a PSVT episode and assess its clinical significance, including the role of coronary artery disease (CAD) and long-term outcomes. Methods: We retrospectively collected data on demographics, presenting symptoms, comorbidities, chronic antiarrhythmic medication use, tachycardia duration, admission systolic blood pressure (SBP), heart rate (HR), laboratory findings, and cardioversion method in patients presenting to the Emergency Department (ED) with PSVT over a 4-year period. Patients were stratified into two groups based on the presence or absence of troponin elevation. Individuals with elevated cTn levels and at least one cardiovascular risk factor were further evaluated for CAD. One-year outcomes included SVT recurrence, rehospitalization, ablation, and mortality. Results: Among 120 patients with PSVT, 58 (48.3%) exhibited elevated cardiac troponin (cTn) levels. Independent predictors of cTn elevation included retrosternal chest pain, absence of prior SVT history, higher admission HR, and lower SBP. A heart rate cut-off of 165 bpm was identified as optimal for predicting cTn elevation (sensitivity 62.1%, specificity 72.6%). Of the 58 cTn (+) patients, 25 underwent CAD evaluation, with only 1 case (4%) confirming significant coronary disease. At one-year follow-up (n = 118), troponin elevation was not associated with increased SVT recurrence, rehospitalization, ablation, or mortality. Similarly, CAD evaluation in troponin-positive patients did not predict outcomes. Conclusions: Troponin elevation after PSVT is frequent but not prognostically significant. It is likely due to transient myocardial stress rather than CAD, supporting a conservative, individualized approach to further testing. Full article

The road transport sector is currently facing significant challenges, due in part to CO₂ emissions, high fuel prices, and a shortage of staff. These issues are partially caused by more than 40% of truck journeys being “empty runs” in some member states of the European Union and heavy under-utilization of deck space for non-empty runs. In order to overcome said inefficiency, this paper proposes a decentralized platform to facilitate collaborative transport networks (CTNs), i.e., to enable horizontal collaboration to increase load factors and reduce costs and CO₂ emissions. Our solution leverages secure multi-party computation (MPC) to guarantee that no sensitive business information is leaked to competing hauliers. The system optimizes truck assignments by modeling logistics as a weighted graph that considers orders and truck capacities while maintaining strict confidentiality. Our approach addresses key barriers to CTN adoption, such as lack of trust and data privacy. Implemented using MPyC without extensive optimizations, we demonstrate the efficiency and effectiveness in increasing the average load factor, while achieving acceptable running times (in the order of hours) for arguably meaningful instance sizes (up to 1000 orders). After leveraging a rather simplistic modeling inspired by previous work, we finally give an outlook of possible extensions toward more realistic models and estimate their impact on efficiency. Full article