Search Results (537)

Background/Objectives: Patients in need of specialized palliative care are clinically highly complex, with pain being the most prevalent problem. Furthermore, in these patients, a self-report for characterization of pain could be difficult to obtain. This cross-sectional, exploratory study investigates the use of clinical parameters and peripheral blood biomarkers for potentially identifying and characterizing pain (assessed using Pain Assessment in Advanced Dementia (PAINAD) and Numeric Scale (NS)) in patients under palliative care, including a population with dementia where pain is often underdiagnosed. Methods: Fifty-three patients with non-oncological diseases were analyzed in a cross-sectional study using medical and nursing records. Among previous biomarkers related to monocytes and platelets assessed by flow cytometry, we selected the most significative ones for pain characterization in a logistic regression analysis (multivariate analysis), alongside patient-specific characteristics such as renal function, nutritional status, and age. Results: Our exploratory findings suggest strong relationships between chronic pain and advanced age, reduced glomerular filtration rate (GFR), and malnutrition within this cohort. Furthermore, the percentage of lymphocytes, total and classical monocytes, the relative expression in monocytes of CD206, CD163, the CD163/CD206 ratio, and the relative expression in platelets of CD59 emerged as potential predictors of pain. Statistical analyses highlighted the challenges of multicollinearity among variables such as age, GFR, and nutritional status. A classification model further suggested that all patients over 65 years in our specific sample reported pain. Conclusions: This pilot study provides preliminary support for prior evidence linking chronic pain to aging, nutritional deficits, and renal impairment, and highlights potential novel peripheral blood biomarkers for pain assessment. This work emphasizes the promise of clinical and molecular biomarkers to improve pain detection and management, contributing to personalized and effective palliative care strategies. Full article

Background: Due to chronic venous insufficiency, venous leg ulcers (VLUs) develop as chronic wounds characterized by impaired healing, persistent inflammation, and endothelial dysfunction. Nitrosative stress, mitochondrial damage, and tissue apoptosis caused by excess nitric oxide (NO) produced by iNOS in macrophages and fibroblasts are contributing factors in the chronic wound environment; therefore, pharmacological modulation of iNOS presents an attractive mechanistic target in chronic wound pathophysiology. Methods: Herein, we present the use of a structure-based computational strategy to assess the inhibition of tavaborole, a boron-based antifungal agent, against iNOS using human iNOS crystal structure (PDB ID: iNOS) by molecular docking using AutoDock 4.2, 500 ns simulation of molecular dynamics (MD), with equilibration within ~50 ns and analyses over full trajectory and binding free energy calculations through the MM-PBSA approach. Results: Docking studies showed favorable binding of tavaborole (–6.1 kcal/mol) in the catalytic domain, which stabilizes contacts with several key residues (CYS200, PRO350, PHE369, GLY371, TRP372, TYR373, and GLU377). MD trajectories for 1 ns showed stable structural configurations with negligible deviations (RMSD ≈ 0.44 ± 0.10 nm) and hydrogen bonding, and MM-PBSA analysis confirmed energetically favorable complex formation (ΔG_binding ≈ 18.38 ± 63.24 kJ/mol) similar to the control systems (L-arginine and 1400W). Conclusions: Taken together, these computational findings indicate that tavaborole can stably occupy the iNOS active site and interact with key catalytic residues, providing a mechanistic basis for further in vitro and ex vivo validation of its potential as an iNOS inhibitor to reduce nitrosative stress and restore endothelial homeostasis in venous leg ulcers, rather than direct therapeutic proof. Full article

Sequential decision-making is critical for applications ranging from personalized recommendations to resource allocation. This study evaluates three decision policies—Greedy, Thompson Sampling (via Monte Carlo Dropout), and a zero-shot Large Language Model (LLM)-guided policy (Gemini-1.5-Pro)—within a contextual bandit framework. To address covariate shift and assess subpopulation performance, we utilize a Collective Conditional Diffusion Network (CCDN) where covariates are partitioned into $B=10$ homogeneous blocks. Evaluating these policies across a high-dimensional treatment space ($K=5$, resulting in $2^5=32$ actions), we tested performance in a simulated environment and three benchmark datasets: Boston Housing, Wine Quality, and Adult Income. Our results demonstrate that the Greedy strategy achieves the highest Model-Relative Optimal (MRO) coverage, reaching 1.00 in the Wine Quality and Adult Income datasets, though performance drops significantly to 0.05 in the Boston Housing environment. Thompson Sampling maintains competitive regret and, in the Boston Housing dataset, marginally outperforms Greedy in action selection precision. Conversely, the zero-shot LLM-guided policy consistently underperforms in numerical tabular settings, exhibiting the highest median regret and near-zero MRO coverage across most tasks. Furthermore, Wilcoxon tests reveal that differences in empirical outcomes between policies are often not statistically significant (ns), suggesting an optimization ceiling in zero-shot tabular settings. These findings indicate that while traditional model-driven policies are robust, LLM-guided approaches currently lack the numerical precision required for high-dimensional sequential decision-making without further calibration or hybrid integration. Full article

Background/Objectives: The objective of this study is to compare nerve-sparing (NS) and non-nerve-sparing (NNS) robot-assisted radical prostatectomy (RARP) techniques used to treat localized prostate cancer. Numerous studies have evaluated the impact of NS techniques on patient-reported outcomes. However, there are unaddressed methodological issues making interpretation of results difficult. Therefore, we performed a comparison of the two techniques, accounting for methodological threats, including patient selection and confounding. Methods: We sampled 120 patients with similar disease burden who underwent RARP by the same surgeon, either with NS (n = 84) or NNS (n = 36) and assessed changes in lower urinary tract (LUT) function and bother, and bowel function/bother using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire and the six-item International Index of Erectile Function (IIEF-6) survey at 6 weeks and 12 months postoperatively. Multivariable linear regression models were used to adjust for differences in age, preoperative PSA levels, pathological tumor stage and Gleason-score of patients receiving either NS or NNS. Results: At 6 weeks postoperatively, the NNS group had a significantly larger decrease in LUT function compared to the NS group (−17.42; 95% Confidence Interval (CI): −31.31, −3.53; p = 0.0145). At 12 months, both groups recovered substantially, and no group differences were observed (p > 0.9). No significant differences were observed between the NS and NNS groups for the EPIC bowel subscores, whereas the IIEF-6 showed borderline significance at 12 months. Conclusions: The results suggest a small impact of NS vs. NNS RARP on important patient-reported outcomes when controlling for tumor biology, surgeon skill, and patient characteristics. These results need to be confirmed by larger studies using similar sampling strategies and design considerations. Full article

Wheat is one of the most important crops contributing to global food and nutritional security. However, the gradual increase in soil salt content significantly impairs wheat growth and development, ultimately resulting in reduced yields. Therefore, enhancing the salt tolerance of wheat is of significant importance. Salt stress commonly induces oxidative stress in plants, and nucleoredoxin (NRX) has been shown to effectively maintain redox homeostasis under stress conditions. However, the functional role and molecular mechanism of the NRX gene in regulating salt tolerance in wheat remain to be elucidated. The results of this study demonstrated that TaNRX1-2D homologous overexpression (OE) lines exhibited significantly enhanced tolerance to salt stress. The survival rate and antioxidant enzyme activities (including superoxide dismutase and catalase) in the OE lines were higher than those in the wild type (WT). In contrast, the levels of superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and malondialdehyde (MDA) in the OE lines were markedly lower than those in the WT. Conversely, the RNA interference (RNAi) lines displayed opposing trends. The results of yeast one-hybrid (Y1H) and dual luciferase assays (D-LUC) demonstrated that the TaERD15L-3B transcription factor positively regulated the expression of the TaNRX1-2D gene by binding to the ABRERATCAL cis-acting element in the TaNRX1-2D promoter. Through luciferase complementation assay (LCA), bimolecular fluorescence complementation (BiFC) assay, and a “mutation capture strategy”, it was found that TaNRX1-2D (C54, 327S) interacted with TaCAT2-B, indicating that TaCAT2-B was the target protein of TaNRX1-2D. The results of data-independent acquisition (DIA) proteomics analysis indicated that TaNRX1-2D may mediate salt tolerance in wheat through the positive regulation of nsLTP protein abundance and the negative regulation of hexokinase protein abundance. In general, the TaERD15L-3B/TaNRX1-2D regulatory module played a crucial role in conferring salt tolerance in wheat. This study provided an important theoretical basis and identified a potential gene target for developing salt-tolerant wheat varieties through molecular breeding approaches. Full article

The integration of silica nanoparticles (NS) into cementitious composites has emerged as a promising strategy to refine the microstructure and enhance concrete performance. Beyond their chemical role in accelerating hydration and promoting additional C–S–H gel formation, silica nanoparticles act as physical fillers, reducing porosity and improving interfacial bonding within the matrix. These dual effects result in a denser and more resilient composite, whose mechanical and dynamic responses differ from those of conventional concrete. However, studies addressing the vibrational and modal behavior of nano-reinforced concretes, particularly under elastic and viscoelastic foundation conditions, remain limited. This study investigates the dynamic response of NS-reinforced concrete slabs using a refined quasi-3D plate deformation theory with five (05) unknowns. Different foundation configurations are considered to represent various soil interactions and assess structural integrity under diverse supports. The effective elastic properties of the nanocomposite are obtained through Eshelby’s homogenization model, while Hamilton’s principle is used to derive the governing equations of motion. Navier’s analytical solutions are applied to simply supported slabs. Quantitative results show that adding 30 wt% NS increases the Young’s modulus of concrete by about 26% with only ~1% change in density; for simply supported slender slabs, this results in geometry-dependent increases of up to 18% in the fundamental natural frequency. While the Winkler and Pasternak foundation parameters reduce this frequency, the damping parameter of the viscoelastic foundation enhances the dynamic response, yielding frequency increases of up to 28%, depending on slab geometry. Full article

The COVID-19 pandemic exposed critical vulnerabilities in single-target antiviral strategies, highlighting the urgent need for multi-mechanism therapeutic approaches against emerging viral threats. Here, we present an integrated computational framework systematically evaluating natural fatty acids as potential dual ACE2 (Angiotension Converting Enzyme 2)-inflammatory modulators; compounds simultaneously disrupting SARS-CoV-2 viral entry through allosteric ACE2 binding while suppressing host inflammatory cascades; through allosteric binding mechanisms rather than conventional competitive inhibition. Using molecular docking across eight ACE2 regions, 100 ns molecular dynamics simulations, MM/PBSA free energy calculations, and multivariate statistical analysis (PCA/LDA), we computationally assessed nine naturally occurring fatty acids representing saturated, monounsaturated, and polyunsaturated classes. Hierarchical dynamics analysis identified three distinct binding regimes spanning fast (τ < 50 ns) to slow (τ > 150 ns) timescales, with unsaturated fatty acids demonstrating superior binding affinities (ΔG = −6.85 ± 0.27 kcal/mol vs. −6.65 ± 0.25 kcal/mol for saturated analogs, p = 0.002). Arachidonic acid achieved optimal SwissDock affinity (−7.28 kcal/mol), while oleic acid exhibited top-ranked predicted binding affinity within the computational hierarchy (ΔG_bind = −24.12 ± 7.42 kcal/mol), establishing relative prioritization for experimental validation rather than absolute affinity quantification. Energetic decomposition identified van der Waals interactions as primary binding drivers (65–80% contribution), complemented by hydrogen bonds as transient directional anchors. Comprehensive ADMET profiling predicted favorable safety profiles compared to synthetic antivirals, with ω-3 fatty acids showing minimal nephrotoxicity risks while maintaining excellent intestinal absorption (>91%). Multi-platform bioactivity analysis identified convergent anti-inflammatory mechanisms through eicosanoid pathway modulation and kinase inhibition. This computational investigation positions natural fatty acids as promising candidates for experimental validation in next-generation pandemic preparedness strategies, integrating potential therapeutic efficacy with sustainable sourcing. The framework is generalizable to fatty acids from diverse biological origins. Full article

Background/Objectives: The current strategy for seasonal influenza prophylaxis relies on updating the vaccine components annually to account for the rapid antigenic drift of viruses and the low cross-protective efficacy of available vaccines. Mutant influenza viruses with truncated or deleted NS1 protein are known to stimulate cross-specific T-cell immune response and provide protection against heterosubtypic influenza A and B viruses. Methods: We generated NS1ΔC influenza A and B viruses with C-terminal NS1 deletions by reverse genetics. In a mouse model, we assessed the safety and immunogenicity of the B/Lee/NS1ΔC strain upon intranasal administration, as well as the mechanism of its cross-protective efficacy against sublethal B/Victoria and B/Yamagata challenges. We then investigated the potential of the intranasal Flu/NS1ΔC vaccine–a trivalent formulation of NS1ΔC A/H1N1, A/H3N2, and B influenza viruses–to protect mice from lethal influenza infection with homologous, heterologous, and antigenically drifted influenza A and B viruses. Results: Intranasal immunization with the B/Lee/NS1ΔC strain was safe in mice. It activated cross-specific T-cell responses in the lungs and protected animals against heterologous challenge by reducing viral load, inflammation, and lung pathology. Immunization with the trivalent Flu/NS1ΔC vaccine formulation improved survival and reduced weight loss and viral load upon challenge with A/H1N1pdm, A/H2N2, A/H5N1, and B/Victoria viruses. Conclusions: The trivalent intranasal Flu/NS1ΔC influenza vaccine is a promising tool to improve seasonal influenza protection and preparedness for an influenza pandemic. Full article

Previous reports suggest that the progression from subacute to chronic non-specific low back pain (nsLBP) involves functional changes in both the nervous and immune systems. The purpose of the present study was to characterize the gene expression profiles of circulating immune cells that affect the interaction between these two systems when subacute nsLBP turns into chronic nsLBP. Participants aged 18–55 were included based on the presence or duration of LBP, with peripheral blood mononuclear cells collected for RNA sequencing from 20 healthy controls (no nsLBP), 20 subclinical patients (intermittent nsLBP), and 19 chronic patients (long-term nsLBP). The data revealed that chronic nsLBP is linked to a distinct gene expression profile, with 139 uniquely differentially expressed genes (DEGs), differing from those in the subclinical and control groups. Interestingly, comparing chronic and subclinical groups showed minimal overlap in DEGs, indicating a clear inflammatory distinction between subclinical nsLBP and chronic nsLBP. The findings also indicated that patients with chronic nsLBP were different from other individuals regarding axon guidance, indicating neuroplastic changes when intermittent nsLBP turns into chronic nsLBP. Hence, early recognition of the transition from subclinical to chronic nsLBP using RNA profiling may pave the way for more precise therapeutic strategies targeting neuroplastic changes and inflammatory processes. Full article

Background/Objectives: The Zika virus (ZIKV) represents an ongoing threat to public health due to its neurological and congenital complications. Even after 10 years since the first major outbreak, correlated with an increase in congenital ZIKV syndrome, there is still no vaccine or treatment for this infection. Among the various existing platforms, DNA vaccines combined with the use of immunoinformatics tools allow for the efficient selection of immunogenic epitopes and immunostimulatory molecules with greater flexibility, in addition to being simple to manufacture and having a higher cost–benefit ratio in production. Methods: In this work, we conducted an integrated approach, combining in silico analyses and in vivo experimental validations, for the development of multi-epitope DNA vaccines against ZIKV. The computational analyses confirmed structural stability, adequate solubility, absence of toxicity, and immune induction potential for constructs based on epitopes from the Envelope (E) and NS1 proteins. Therefore, we evaluated DNA constructs containing the ENV + NS1 epitopes, both with and without fusion to the ssPGIP signal peptide, in BALB/c mice. Results: Both vaccines increased the population of CD4⁺ and CD8⁺ T lymphocytes, in addition to the production of IgG antibodies associated with the Th1 profile. The fusion with ssPGIP broadened the response, stimulating the release of Th1, Th2, and Th17 cytokines, as well as enhancing antibody formation. In contrast, its absence was associated with a slight increase in CD4⁺ and CD8⁺ T cells, accompanied by restricted cytokine production. Conclusions: These results indicate that epitope-targeted techniques offer a viable and safe method for inducing robust immune responses, demonstrating that combining immunoinformatics methods with early preclinical testing is an effective strategy for ZIKV vaccine development. Furthermore, although the present study focused on initial immunogenic characterization, future studies involving viral challenge in a suitable animal model will be essential to conclusively determine the protective efficacy of these vaccine candidates. Full article

Receiver-initiated MAC protocols, such as the IEEE 802.15.4e RIT scheme, are promising for energy-efficient communication in multi-hop wireless sensor networks. However, their practical use requires a better understanding of how multiple contention-avoidance mechanisms interact under realistic network conditions. This study develops an ns-3 implementation of an RIT-compliant receiver-initiated MAC protocol together with a flexible evaluation framework that enables selective activation of representative enhancement strategies, including carrier-sensing options for data and beacon transmissions and randomization of beacon intervals. Four realistic network scenarios were designed to simulate practical deployment settings. Simulation results revealed that the effectiveness of these enhancement strategies varied significantly depending on network load and topology. In particular, beacon interval randomization, although often assumed to improve robustness, was found to degrade performance under low-load conditions, indicating that even widely adopted mechanisms may behave differently depending on operational environments. Conversely, CSMA-based approaches provided consistent improvements in transmission reliability. These observations highlight the importance of considering environmental factors and parameter configurations when enabling enhancement mechanisms. Overall, the proposed platform provides a reproducible and unified environment for fair comparison of receiver-initiated MAC protocols and their optional mechanisms, offering practical insights for selecting appropriate configurations in real sensor network deployments. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung disease characterized by progressive scarring of the lungs. The available therapeutic strategies are limited and primarily focus on slowing disease progression rather than achieving fibrosis reversal. Cardamonin (CDN), a food-derived natural chalcone, has exhibited anti-fibrotic activity in liver and kidney fibrosis models; however, its role and underlying mechanism in IPF remain unelucidated. Herein, we integrated network pharmacology, machine learning, molecular simulations, and in vitro experiments. Network pharmacology identified 135 overlapping targets between CDN and IPF, which demonstrated a significant enrichment in the Phosphatidylinositol 3-Kinase/Protein Kinase B signaling pathway (PI3K/AKT). Machine learning further prioritized 6 core targets, with IGF1 emerging as a key candidate. Molecular docking revealed a favorable binding energy of −7.9 kcal/mol for the CDN-IGF1 complex. Subsequent 100 ns molecular dynamics simulations further confirmed its robust binding stability, yielding a mean binding free energy of −150.978 kcal/mol. In vitro, CDN significantly mitigated fibrosis in bleomycin (BLM)-challenged A549 cells, downregulating the expression of α-smooth muscle actin (α-SMA) and fibronectin. This effect was accompanied by a beneficial reversal of epithelial–mesenchymal transition (EMT), as indicated by increased E-cadherin levels and decreased vimentin expression. Mechanistically, CDN significantly suppressed the IGF1/PI3K/AKT axis; this inhibitory effect was partially reversed by exogenous IGF1 supplementation and further enhanced by the PI3K-specific inhibitor LY294002. This work provides the evidence that CDN alleviates BLM-induced pulmonary fibrosis by targeting the IGF1/PI3K/AKT-EMT axis. These findings lend support to a robust mechanistic basis for developing CDN as a potential therapeutic candidate for IPF. It should be noted that these conclusions are drawn from in vitro experiments using A549 cells, and further validation in primary alveolar epithelial cells and animal models is warranted to confirm their physiological relevance. Full article

Human respiratory syncytial virus (RSV) remains a leading cause of severe lower respiratory tract infections in infants and immunocompromised populations, causing approximately 160,000 annual deaths globally. Despite recent approvals of prefusion F (pre-F) protein-based vaccines (Arexvy, Abrysvo) for older adults and pregnant women, pediatric vaccine development faces unique challenges including enhanced respiratory disease (ERD) risks, maternal antibody interference, and immature infant immune responses. Meanwhile, G protein glycosylation variability and NS1/NS2-mediated interferon suppression remain the outstanding difficulties in structure-based vaccine design. Additionally, current animal models demonstrate notable constraints in virus replication, host susceptibility, immune responses, clinical symptoms, and ERD phenomena. This review synthesizes current obstacles and innovative strategies, highlighting that the selection of multi-antigen strategies, appropriate adjuvants, and the development of more precise preclinical animal models are critical elements that will determine the efficacy and safety of future RSV vaccines. Full article

Hazardous galvanic sludge waste (GSW) from the electroplating industry, produced at 100,000–150,000 tonnes/year in the EU and containing high concentrations of Cr and Ni was successfully treated using metakaolin-based geopolymers via Stabilization/Solidification (S/S). The experimental design incorporated chelating (sodium diethyl dithio carbamate, C₅H₁₀NS₂Na, DTC), reducing (sodium sulfide, Na₂S), and adsorbing (hydroxyapatite, Ca₅(PO₄)₃(OH), Hap) agents separately to improve heavy metal immobilization. The results demonstrated that Na₂S drastically decreased Cr release by −98.7% by reducing mobile Cr(VI) to insoluble Cr(III). DTC reduced Ni leaching by −93.4%, forming sparingly soluble Ni(II)(DTC)₂ complexes that precipitated within the matrix. Hap enhanced Ni retention by 55.5% via cation exchange but was ineffective for Cr due to electrostatic repulsion with the anion Cr(VI)O₄²⁻ at the geopolymer’s high pH. This work is the first to apply geopolymerization coupled with these chemical agents for S/S of as-received galvanic waste, offering a highly efficient, low-carbon strategy to manage this hazardous industrial residue. Full article

Climate change in the Pannonian region is accelerating a shift toward autumn sowing of cool-season grain legumes (pea, faba bean, lentil, chickpea, lupine) to achieve higher yields, greater biomass production, enhanced nitrogen fixation, improved soil cover, and superior resource use efficiency compared with spring sowing. However, successful overwintering depends on the availability of robust winter-hardy cultivars. This review synthesizes recent breeding advances, integrating traditional approaches—such as germplasm screening, hybridization, and field-based selection—with genomics-assisted strategies, including genome-wide association studies (GWAS), quantitative trait locus (QTL) mapping, marker-assisted selection (MAS), and CRISPR/Cas-mediated editing of CBF transcription factors. Key physiological mechanisms—LT₅₀ determination, cold acclimation, osmoprotectant accumulation (sugars, proline), and membrane stability—are assessed using field survival rates, electrolyte leakage assays, and chlorophyll fluorescence measurements. Despite challenges posed by genotype × environment interactions, variable winter severity, and polygenic trait control, the release of cultivars worldwide (e.g., ‘NS-Mraz’, ‘Lavinia F’, ‘Ghab series’, ‘Pinklevi’, and ‘Rézi’) and ongoing breeding programs demonstrate substantial progress. Future breeding efforts will increasingly rely on genomic selection (GS), high-throughput phenomics, pangenomics, and G×E modeling to accelerate the development of climate-resilient legume cultivars, ensuring stable and sustainable production under increasingly unpredictable winter conditions. Full article