Search Results (4,419)

This experiment investigated the effects of two rearing systems, cage and free-range, on growth performance, serum biochemical parameters, slaughter performance, cecal microbiota, and hepatic metabolism of yellow-feathered broilers. A total of 240 healthy 21-day-old Liangfenghua yellow-feathered male broilers with similar body weight were randomly assigned to a cage group (LY) and a free-range group (SY), with 10 replicates per group and 12 birds per replicate. All birds were fed the same diet until 63 days of age. Compared with the LY group, the SY group had significantly lower final body weight, average daily gain, and abdominal fat percentage (p < 0.05), while average daily feed intake and feed-to-gain-ratio were significantly higher (p < 0.05). The Shannon and Simpson indices of the cecal microbiota were significantly higher in the SY group (p < 0.05), and the genera Bacteroides, Lactobacillus, Rikenella, and Oscillibacter were specifically enriched. A total of 560 differential metabolites were identified by liver non-targeted metabolomics, and these metabolites were significantly enriched in the necroptosis, cysteine and methionine metabolism, thiamine metabolism, and amino sugar and nucleotide sugar metabolism pathways (p < 0.05). Correlation analysis between cecal microbiota and liver metabolites revealed that the differentially abundant bacterial genera showed significant negative correlations with multiple amino acid metabolites in the liver. In conclusion, the free-range rearing system reduced the growth performance of yellow-feathered broilers but enriched specific bacterial genera, increased gut microbiota diversity, and modulated host amino acid metabolism and energy homeostasis through the “gut microbiota–liver” axis, ultimately inducing an adaptive metabolic state characterized by reduced abdominal fat deposition and remodeling of hepatic metabolic pathways. Full article

Urban flood vulnerability is increasingly shaped by the interaction between climate change, urbanization, and spatial planning practices, particularly in Mediterranean metropolitan areas. This study develops an integrated GIS–AHP framework to assess the susceptibility component of flood vulnerability in the urban area of Thessaloniki, Greece. Using open-access geospatial data, ten indicators representing soil, hydrological, and environmental conditions are derived and spatially analyzed. The Analytic Hierarchy Process (AHP), based on expert judgment, is applied to estimate the relative importance of these indicators and to support their integration into a composite flood susceptibility index. The results reveal strong spatial heterogeneity, with high susceptibility concentrated in low-lying, densely urbanized areas and zones near drainage pathways. Among the examined factors, the Topographic Wetness Index emerges as the most influential, highlighting the persistent role of terrain-driven hydrological processes even in highly built environments. The proposed framework provides a transparent and transferable methodology for identifying flood-prone areas and supports evidence-based urban planning and climate resilience strategies. The findings contribute to the broader discussion on vulnerability and resilience in urban systems by linking spatial analysis with decision-support tools in a policy-relevant context. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

Introduction: Pedestrians lying on the road—collapsed through medical emergency, intoxication, or displacement following a prior collision—represent a disproportionately lethal and underaddressed category in road traffic safety. Forensic database analyses derived from Japan’s national police records document a fatality rate of 33.0% for collisions involving pedestrians lying on the road, more than double the rate for upright pedestrian collisions. Standard Advanced Driver-Assistance Systems (ADAS) yield a True Positive Rate (TPR) of only 21.4% for detecting pedestrians lying on the road under night conditions—a classification gap of 73.3 percentage points. Methods: In simulation trials, we evaluated the Advanced Falling Object Detection System (AFODS—where “falling object” denotes the low-profile human form at road level, distinguishing the prone pedestrian from the upright postures addressed by conventional ADAS) on a composite dataset of 3200 annotated fall events and 12,000 negative samples (training/validation), with 320 independent controlled simulation trials used for performance evaluation, spanning real-world, forensic-reconstruction, and Total Human Body Model for Safety (THUMS)-validated synthetic scenarios. No physical prototype has been evaluated; all performance data are derived from simulation, and 37.5% of positive samples are synthetically generated. These simulation conditions represent a first feasibility demonstration pending real-world hardware validation. This paper introduces three original contributions absent from prior work: a three-stage quantitative injury-risk model, a formal ISO 26262 Hazard Analysis and Risk Assessment (HARA), and a medicolegal SHAP interpretability framework. The injury-risk model translated detection latency via impact velocity to Head Injury Criterion (HIC) and estimated fatal injury probability (AIS ≥ 5); these model outputs should be interpreted as exploratory estimates pending ATD validation. Reporting follows principles consistent with the TRIPOD statement. Results: Under clear daytime conditions, AFODS demonstrated a TPR of 98.2% (95% CI: 97.4–98.8%) in simulation, decreasing to 95.6% under night dry-road conditions and 89.4% under night rain. The system achieved an AUC of 0.981 and a mean end-to-end latency of 46.5 ms, representing a 76.8 percentage-point improvement in simulation over the monocular RGB baseline (p < 0.001). The injury-risk model projects a reduction in estimated fatal head injury probability from 66.2% (Monte Carlo mean) (no detection, 50 km/h full-speed impact) to 0.7% under AFODS worst-case night/rain conditions, and to ≈0% under clear daytime simulation conditions. Conclusions: A 73.3 percentage-point classification gap places pedestrians lying on the road outside the effective detection envelope of current ADAS, compounded by the systematic exclusion of non-upright postures from regulatory test protocols and benchmark datasets. AFODS supports proof-of-concept feasibility under simulation conditions. Three translational steps are required: prototype validation on real-world hardware using instrumented Anthropomorphic Test Devices (ATDs); prone-posture biomechanical injury modelling using HIC and BrIC criteria; and regulatory extension of pedestrian AEB test standards to non-upright scenarios. Full article

Ganoderma lucidum spores protein (GLSP) holds significant potential for providing antioxidant peptides. We employed in silico enzymatic hydrolysis to generate small peptide fragments by specific proteins. Through fast computer screening and molecular docking with Keap1 receptor, we identified two potential antioxidant peptides, KAF (Lys-Ala-Phe) and NDSF (Asn-Asp-Ser-Phe), from 1171 candidates after efficient hydrolysis by pepsin and proteinase K. Molecular docking result showed both of them could bind onto the Leu557, Ala 510 and Val512 of bioactive pockets of Keap1 through hydrogen bonds and NDSF had lower docking energy (−85.6073 kcal/mol). The in vitro antioxidant validation indicated both of them could eliminate DPPH and ABTS radicals dramatically, and NDSF had a stronger scavenging capacity on DPPH (IC₅₀ = 35.1 μg/mL) and ABTS (IC₅₀ = 55.9 μg/mL), respectively. Quantitative chemical analysis further revealed that the key antioxidant active sites of NDSF were located at O18 of Ser amino side chain, and N9 of Lys terminal amino residue for KAF. Furthermore, in the cellular experiments, NDSF and KAF effectively increased the activities of antioxidant enzymes such as SOD, CAT, and GPx, while also reducing the level of MDA. Together, these findings highlight the potential of Ganoderma lucidum spore proteins as a source for the rapid identification of antioxidant peptides. The two selected peptides, therefore, s hold promising prospects for applications in functional foods and health products. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

Lysine and methionine are commonly regarded as the first limiting amino acids for lactating dairy cows, yet production responses to rumen-protected lysine (RPLys), rumen-protected methionine (RPMet), and methionine analogues vary across studies due to differences in basal diets, lactation stage, product formulation, and amino acid bioavailability. This meta-analysis synthesized evidence from 42 studies conducted in Holstein dairy cows to evaluate the effects of RPLys, RPMet, their combined supplementation, and methionine analogues on milk yield, milk fat, milk protein, milk lactose, and feed conversion-related traits. Random-effects meta-analysis showed that RPLys primarily increased milk yield, RPMet increased milk yield and milk fat percentage, combined supplementation improved milk yield, and methionine analogues increased milk yield and selected milk components. Exploratory analyses of supplementation level and Lys:Met ratio were considered hypothesis-generating only due to study-level aggregation and variation in product bioavailability. Overall, these findings support precision amino acid supplementation rather than universal strategies, and highlight the need for standardized reporting of basal diet amino acid supply and product-specific bioavailability to optimize lactation performance. Full article

Perishable products are usually priced in real-time to volatile market environments, thereby optimizing inventory control, minimizing resource wastage, and maximizing corporate profitability. Based on the public dataset from the 2023 Higher Education Press Cup National College Students Mathematical Modeling Competition, this paper addresses the challenge of multi-product joint pricing for perishable fresh produce and proposes an attention-augmented proximal policy optimization algorithm (termed ATT-PPO), which embeds an attention mechanism into the proximal policy optimization (PPO) framework. The integrated attention mechanism confers three core advantages to the model: first, it dynamically captures inter-product interdependencies, enabling an accurate reflection of cross-price elasticity and demand correlations; second, it reduces feature redundancy and computational overhead in multi-product collaborative pricing strategies; third, it enhances both the interpretability and computational efficiency of the model. Experimental results demonstrate that in the scenario of multi-product pricing, the ATT-PPO algorithm achieves competitive performance compared to PPO, DDPG (Deep Deterministic Policy Gradient), SAC (Soft Actor-Critic), and TD3 (Twin Delayed Deep Deterministic Policy Gradient), with the key advantage lying in its ability to provide interpretable attention weights that reveal dynamic cross-product dependencies in pricing decisions. This study not only expands the applicability of DRL (Deep Reinforcement Learning) to practical economic problems in the fresh produce sector but also provides valuable theoretical insights that can be generalized to other short-lifecycle product domains, including fashion apparel and consumer electronics. Full article

Venous Thrombosis is a frequent and clinically significant complication in lymphoma patients, resulting in increased morbidity, mortality and therapeutic challenges. The pathophysiological mechanisms underlying lymphoma-associated thrombosis are multifactorial, involving patients’ clinical characteristics, tumour biology, systemic inflammation, endothelial dysfunction and therapy-induced prothrombotic changes. Traditional predictive tools for cancer-associated thrombosis (CAT) have shown suboptimal application in lymphoma patients due to disease-specific heterogeneity. The ThroLy score was developed as a lymphoma-specific model incorporating parameters such as extranodal involvement, mediastinal disease, performance status, a prior venous thromboembolic event, and specific laboratory values. While it shows improved predictive value compared with general CAT models, its accuracy remains limited, particularly across different lymphoma subtypes and treatment regimens. Research in the field has therefore focused on evaluating emerging biomarkers—D-dimer, microparticles and inflammatory cytokines—as risk assessment tools. Integrative approaches that combine clinical variables with such biomarkers may yield a more dynamic and individualised risk-prediction model to guide thromboprophylactic strategies. The present review summarises current knowledge on thrombotic risk assessment across lymphoma subtypes and highlights the potential role of novel biomarkers in developing a more precise approach to thrombosis prevention and management. Importantly, it provides a comprehensive overview of currently available literature, highlighting the need for personalised thrombosis risk stratification strategies in lymphoma. Full article

Monitor-roof designs are widely used in buildings to enhance natural ventilation while protecting interior spaces from rain penetration. However, the ventilation performance of rain-shield monitor roofs can be significantly influenced by their geometric configuration and the interaction between wind-driven and buoyancy-driven airflow. In this study, computational fluid dynamics (CFD) simulations were conducted to investigate the ventilation performance of rain-shield monitor roofs under hybrid natural ventilation conditions. The effects of key geometric parameters, including the outlet height (Lz) and lateral spacing (Ly), were examined under different approaching wind conditions. The results indicate that ventilation performance is governed by the combined influence of wind-driven and buoyancy-driven mechanisms. Among the investigated configurations, an intermediate outlet height of approximately Lz ≈ 0.6 m generally provides favorable ventilation performance, while a lateral spacing Ly in the range of 0.6–0.8 m maintains effective airflow passage without excessive flow resistance. The findings provide quantitative guidance for the design of rain-shield monitor-roof ventilation systems in buildings operating under hybrid natural ventilation conditions. Full article

LY104 (previously designated as B7) is a selective phosphodiesterase 4 inhibitor with promising activity against chronic obstructive pulmonary disease. We previously reported its single-dose pharmacokinetics and tissue distribution in rats. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of LY104 and its major metabolite M1 in rat plasma following ICH M10 guidelines. The method showed excellent linearity over 20–1200 ng/mL for both analytes, with retention times of 2.85 min (LY104) and 3.22 min (M1). Using this method, we extended our previous work in several directions. Re-analysis of previously published single-dose pharmacokinetic and tissue distribution data revealed no significant sex differences for LY104. Newly generated multiple-dose studies (1 mg/kg daily for 7 days) demonstrated no accumulation of LY104 or M1. The pharmacokinetic profile of M1 was quantified for the first time. Comprehensive in vitro investigations included plasma and liver microsomal stability, plasma protein binding, and excretion studies. This systematic preclinical pharmacokinetic characterization of LY104 and M1, incorporating re-analysis of existing data with sex stratification, newly generated multiple-dose and metabolite data, excretion studies, and comprehensive in vitro investigations, provides useful information to support further drug development and clinical trial design. Full article

The global dissemination of carbapenem resistance is predominantly facilitated by plasmid-mediated carbapenemase genes, notably blaOXA-48-like genes. A comprehensive understanding of their evolutionary relationships and structural conservation is essential for monitoring their spread and informing therapeutic strategies. This study aimed to investigate the phylogenetic relationships and structural conservation of blaOXA-48-like carbapenemase genes in multiple Gram-negative bacterial species. We analysed blaOXA-48-like carbapenemase sequences obtained from a hospital in Pakistan and compared them with globally reported variants retrieved from GenBank. Carbapenemase gene sequences (blaOXA-48-like, blaNDM, and blaVIM) were analyzed using maximum-likelihood phylogenetics (MEGA11, Tamura–Nei model, 1000 bootstrap replicates). Comparative global sequences were retrieved from GenBank. Structural modeling of blaOXA-48-like genes was performed using SWISS-MODEL Workspace with the template PDB 3HBR, followed by validation using GMQE, QMEANDisCo, and Ramachandran plot analyses. Phylogenetic analysis revealed a tight clustering of blaOXA-48-like genes across A. baumannii, K. pneumoniae, and E. meningoseptica, showing high similarity to globally distributed plasmid-associated sequences. Structural modeling demonstrated strong conservation of the enzyme, with preserved catalytic residues (Ser70, Lys73, Ser118, Trp157, and Tyr211) and minimal structural deviation (RMSD < 0.3 Å). blaOXA-48-like carbapenemases exhibit strong phylogenetic conservation and structural stability across species and regions, consistent with the horizontal dissemination of blaOXA-48-like genes across bacterial hosts. These findings indicate that blaOXA-48-like carbapenemases have high evolutionary stability. Full article

The treatment of intracellular bacterial infections such as Chlamydia remains a significant clinical challenge due to rising antibiotic resistance and persistent, immunopathology-driven tissue damage. Macrophages are essential for host defense; they can originate from both tissue-resident precursors and circulating monocytes. During infection, macrophages at infected sites are largely derived from monocytes that migrate and differentiate there, where they phagocytose pathogens and orchestrate immune responses. The chemokine receptor CCR2 is a key regulator of this process, yet its role beyond monocyte trafficking is not fully understood. Previous studies have shown that CCR2 deficiency impairs monocyte mobilization and exacerbates disease during Chlamydia infection, shifting immune responses away from protective Th1 immunity toward pathological Th2 and Th17 polarization. Here, we investigate how CCR2 regulates macrophage function to balance protective Th1 versus pathological Th2/Th17 immunity during Chlamydia respiratory infection. Our results show that CCR2 deficiency reduces pulmonary infiltration of Ly6C^hi and Ly6C^low monocytes and shifts macrophage differentiation away from an M1-like toward an M2-like phenotype. Mechanistically, CCR2 deficiency compromises macrophage endocytosis and survival, elevates ROS production, and activates the NLRP3 inflammasome, leading to Caspase-3/GSDME-mediated pyroptosis with increased IL-1β and IL-18, while suppressing the Caspase-1/GSDMD pathway. These findings were recapitulated in vitro using C. muridarum-stimulated Ccr2-deficient bone marrow-derived macrophages (BMDMs), which also showed impaired migration, reduced M1-like polarization, diminished endocytosis, and enhanced ROS/NLRP3/pyroptosis. Furthermore, co-culture of these BMDMs with CD4⁺ T cells revealed that Th1 differentiation was inhibited, whereas Th2 and Th17 responses were promoted. Collectively, CCR2 orchestrates monocyte–macrophage function by driving M1-like polarization and inhibiting NLRP3/Caspase-3/GSDME pyroptosis to rebalance Th1/Th2/Th17 immunity, thereby enhancing bacterial clearance while mitigating immunopathological tissue damage during Chlamydia infection. Full article

Forest disturbances significantly affect the terrestrial carbon cycle, yet high-resolution detection, driver attribution, and carbon loss quantification remain challenging in cloudy and complex terrains. Here, we investigated the Northeast China and Southwest Hengduan Mountains forest regions from 2021 to 2024. We developed a Bayesian Model Averaging (BMA) framework integrating multi-source remote sensing (Sentinel-1/2, Landsat 8/9) and multi-algorithm ensembles (LandTrendr, CCDC, 1D-CNN) to extract 10 m disturbance features. Automated driver attribution and carbon loss quantification were achieved utilizing the Fire Information for Resource Management System (FIRMS), Dynamic World, and GEDI L4B LiDAR data. Validation yielded overall spatial accuracies of 91.15% in the Northeast and 89.62% in the Hengduan Mountains, with corresponding ensemble F1-Scores of 0.92 in both regions. Results indicated the disturbed area in the Northeast (1084.58 ha) significantly exceeded the Hengduan region (133.48 ha). Natural degradation dominated both regions (Northeast: 72.25%; Hengduan: 88.43%), though the Northeast experienced more wildfires and anthropogenic activities. Topographically, Northeast disturbances clustered on low-lying, gentle landscapes, whereas Hengduan events occurred on steep, high-altitude terrains. Due to denser per-pixel carbon storage, the Hengduan area exhibited higher carbon emission costs per unit area. Ultimately, this framework provides a quantitative technical foundation supporting high-resolution forest conservation and spatial evaluations for carbon neutrality commitments. Full article

Background/Objectives: Chronic pain is a significant clinical challenge, in part due to the absence of reliable objective biomarkers for its evaluation and treatment. Growing evidence indicates that immune cells, including natural killer (NK) cells, are involved in the regulation of pain processes. NK cells are innate cytotoxic lymphocytes whose functional status may mirror underlying pathological pain states. In this study, we investigated μ-opioid receptor (MOR) expression and functional alterations of NK cells in a murine model of neuropathic pain induced by chronic constriction injury (CCI). Methods: Mice were divided into three groups: Sham (sciatic nerve exposure without ligation), CCI 14-day, and CCI 21-day groups. At the respective time points, animals were sacrificed and spleens were collected for analysis. Splenocytes were isolated by mechanical dissociation followed by centrifugation and erythrocyte lysis. Lymphocytes were analyzed by flow cytometry to evaluate MOR expression in NK cells and their degranulation activity (CD107a assay). Cells were incubated with fluorochrome-conjugated antibodies against NK cell markers (NK1.1, CD3, Ly49A, Ly49C/I) in combination with anti-MOR and anti-Interferon γ antibody (IFN-γ). Immunofluorescence and confocal microscopy analyses were performed to assess MOR localization and granzyme localization, supporting CD107a-mediated degranulation. Results: Flow cytometry analysis revealed a significant reduction in surface MOR expression on total NK cells from CCI mice compared with sham controls at 14 and 21 days post-injury, a finding corroborated by immunofluorescence evidence of MOR cellular internalization. Functionally, CCI induced a marked decrease in CD107a expression and impaired IFN-γ production both under basal conditions and following PMA/ionomycin stimulation, indicating a hyporesponsive state of NK cells. Consistently, confocal microscopy revealed extracellular release of Granzyme A following CCI, suggesting dysregulated degranulation. Conclusions: Neuropathic pain is associated with a remodeling of NK cell phenotype and effector functions, characterized by impaired cytotoxic activity and cytokine production, along with modulation of inhibitory receptor expression. Notably, MOR-reduced surface expression in NK cells emerges as a potential biomarker of neuropathic pain. Further studies are needed to elucidate the molecular mechanisms regulating MOR expression and its relationship with NK cell hyporesponsiveness and degranulation in chronic pain conditions. Full article