Search Results (210)

Osteoarthritis (OA) is characterized by chronic inflammation, and progressive cartilage degradation. Poricoic acid A (PAA), a triterpenoid compound derived from Poria cocos, exhibits anti-inflammatory and anti-fibrotic activities, but its therapeutic potential in OA remains unknown. Here, we investigated the protective effects and mechanisms of PAA in IL-1β-stimulated chondrocytes and a destabilization of a medial meniscus (DMM) mouse model. PAA significantly restored cartilage matrix synthesis, reduced inflammatory catabolism, and alleviated cartilage degeneration in vivo. RNA-seq identified PI3K/AKT signaling as a major pathway regulated by PAA. Mechanistically, PAA stabilized PTEN protein, suppressed PI3K/AKT phosphorylation, and reversed IL-1β-induced cartilage catabolism. PTEN inhibition abolished the beneficial effects of PAA. These findings identify PAA as a promising therapeutic candidate for OA and reveal PTEN-PI3K-AKT as its major regulatory axis. Full article

Background: Anastomotic leaks (ALs) remain a critical complication after rectal cancer surgery. Emerging evidence suggests that local immune dysregulation may play a key role in anastomotic healing. We investigated the immune microenvironment of histologically normal, tumor-adjacent rectal mucosa—a tumor-conditioned field—as a potential substrate for AL predisposition. Methods: IMMUNOREACT 4 is a sub-analysis of the IMMUNOREACT project (clinicaltrials.gov NCT04915326 and NCT04915326), a multicenter translational study evaluating immune features of histologically normal, tumor-adjacent rectal mucosa of patients undergoing colorectal anastomosis. A prospective cohort (n = 121) was analyzed using flow cytometry, in addition to a retrospective cohort (n = 262) using immunohistochemistry. Immune markers of epithelial activation and lymphocyte subsets were compared between patients with and without postoperative ALs. Exploratory predictive models combining immune and clinical variables were developed and evaluated using discrimination, calibration and decision curve analyses. Results: At flow cytometry, the CK⁺HLAabc⁺ MFI (AUC 0.66, 95% CI 0.52–0.80), CD8⁺CD38⁺ cell rate (AUC 0.65, 95% CI 0.52–0.78) and CD3⁺CTLA4⁺ cell rate (AUC 0.65, 95% CI 0.51–0.80) showed moderate predictive potential for ALs. In immunohistochemistry, CD3⁺ (AUC 0.57, 95% CI 0.54–0.60), CD8⁺ (AUC 0.57, 95% CI 0.52–0.62), CD8β⁺ (AUC 0.59, 95% CI 0.53–0.65) and Tbet⁺ (AUC 0.60, 95% CI 0.56–0.64) showed some predictive ability for ALs. The model including CD8β⁺, the BMI, neutrophile/lymphocyte ratio and tumor location had an AUC of 0.67 (95% CI 0.62–0.72). Conclusions: Immune activation within histologically normal, tumor-adjacent rectal mucosa—characterized by epithelial HLA upregulation and cytotoxic or Th1 T cell infiltration—is associated with postoperative ALs. Although predictive accuracy is limited, these findings support the concept that a tumor-conditioned immune microenvironment may predispose patients to impaired anastomotic healing. Integration of mucosal immune profiling with clinical variables represents a promising exploratory approach that warrants further prospective validation. Full article

To elucidate the modification and pre-swelling mechanisms of instant bituminous modifiers and their contribution to bituminous materials’ performance, this study investigates an instant ultra-high-performance bitumen modifier (SHVE-M). Fluorescence microscopy (FM), gel permeation chromatography (GPC), physical property tests, viscoelastic properties tests, dynamic shear rheometer (DSR), and mixture pavement performance tests were employed to systematically characterise the instant modified bitumen (SHVE-MB) and its mixture (SHVE-MBM). The results indicate that SHVE-M forms a stable “bitumen phase–polymer spherical phase” structure. ImageJ-win64 analysis revealed that SHVE-M exhibits a modifier area fraction of 46.68% and an average area fraction of 0.22‰, while SHVE-MB achieves a modifier area fraction of 17.54% and an average area fraction of 0.18‰. This morphology is supported by a large molecular size (LMS) content of 43% in SHVE-M. In terms of physical properties, the SHVE-MB (prepared via 10 min shearing) exhibited a penetration of 46.2 dmm, a softening point of 91.7 °C, and a ductility of 34.3 cm. These values are highly comparable to the conventional wet-process HVE-MB (prepared via 4 h maturation), with negligible differences of 0.5 dmm, 1.7 °C, and 1.4 cm, respectively. Quantitatively for viscoelasticity, SHVE-MB achieved a dynamic viscosity of 425,283.4 Pa·s at 60 °C and an elastic recovery rate of 92.1%, paralleling the 414,623.7 Pa·s and 93.6% of HVE-MB. Regarding mixture performance, the high-temperature dynamic stability (DS) of SHVE-MBM reached 7974 times/mm, approaching the 8256 times/mm of HVE-MBM. The water stability was excellent with a splitting tensile strength ratio (TSR) of 97.4% (vs. 98.0% for HVE-MBM). Furthermore, the low-temperature fracture toughness (K_IC) reached 39.8 N/mm^1.5, significantly outperforming SBS-MBM (27.9 N/mm^1.5) and remaining close to HVE-MBM (43.9 N/mm^1.5). These findings indicate that SHVE-MB effectively bridges the performance gap between instant and traditional high-viscosity modified bitumen, and the pre-swelling mechanism of SHVE-M is well characterized in this study. Full article

Background/Objectives: The widespread adoption of high-fat diets has contributed to a rising incidence of metabolic disorders and associated cardiovascular diseases. This trend exacerbates myocardial ischemia–reperfusion (I/R) injury following interventional or thrombolytic therapy for acute myocardial infarction, leading to higher mortality and heart failure in affected individuals with metabolic dysregulation, for whom effective interventions are limited. Nuciferine, which possesses anti-inflammatory, antioxidant, and metabolic regulatory properties, has shown potential in improving post-I/R cardiac function, yet its mechanism remains unclear. Methods: This study utilized an ex vivo mouse heart model perfused with high-glucose/high-fatty acid solutions to establish a metabolic stress condition mimicking key aspects of the diabetic milieu and to evaluate the underlying mechanisms of nuciferine. Complementarily, a model of lipotoxicity combined with hypoxia/reoxygenation (H/R) injury was established in human cardiomyocyte cells (AC16). Results: Nuciferine significantly improved post-I/R functional recovery and attenuated succinate accumulation, an effect comparable to the succinate dehydrogenase (SDH) inhibitor dimethyl malonate (DMM). Mechanistically, nuciferine bound to an SDH subunit, inhibiting its activity and subsequent reactive oxygen species (ROS) production via mitochondrial reverse electron transport (RET). It also activated Sirt1-dependent pathways, mitigating apoptosis and mitochondrial dysfunction in AC16 cardiomyocytes. The Sirtuin 1 (Sirt1) inhibitor selisistat (EX527) abolished nuciferine’s protection, while DMM mirrored its efficacy, underscoring nuciferine’s dual role in inhibiting SDH-mediated RET and activating Sirt1 in alleviating I/R injury under metabolic stress conditions. Conclusions: These findings suggest that nuciferine confers cardioprotection by simultaneously attenuating RET-related oxidative stress and activating Sirt1. Full article

One of the main obstacles to producing natural rubber-modified asphalt is the difficulty of mixing Technical Specification Natural Rubber (TSNR) or its compounds with asphalt, leading to long mixing times and high costs. This study aims to evaluate the use of 60/70 penetration asphalt as a plasticizer to accelerate the mixing process and improve the rheological properties of modified asphalt using Technical Specification Natural Rubber (TSNR). The production process for technical specification natural rubber-modified asphalt involves two stages: the production of the technical specification natural rubber compound (CTSNR) and the production of CTSNR-based modified asphalt (CTSNRMA). The CTSNR production process begins with mastication of technical specification natural rubber (TSNR), followed by the addition of activators (zinc oxide, stearic acid), accelerators (Mercaptobenzothiazole sulfenamide (MBTS)), antioxidants (2,2,4-Trimethyl-1,2-dihydroquinoline (TMQ)), and 60/70 penetration asphalt as a plasticizer (at concentrations of 30%, 40%, and 50%). After homogeneous mixing for 30–60 min, the CTSNR is diluted 5–10 mm for the next mixing stage with hot asphalt at 160–170 °C. The best results of this study showed that CTSNR-modified asphalt with 4% rubber content and 50% plasticizer (CTSNRM-450) successfully reduced the mixing time to 16 min, making it more efficient than the traditional method, which takes up to 180 min. The addition of asphalt plasticizer decreased penetration to 35.6 dmm and increased the softening point to 55.4 °C. The CTSNRMA-440 formula, with 4% rubber content and 40% plasticizer, produced the best results in terms of storage stability, meeting the ASTM D5892 standard with a softening-point difference of 0.95 °C, which is well below the threshold of 2.2 °C. The CTSNRMA-440 sample achieved a Performance Grade (PG) of 76, suitable for hot-climate conditions, with a significant reduction in mixing time, greater stability, and increased resistance to high temperatures. Full article

Digital transformation is increasingly central to the development of transport systems, yet current research offers limited guidance on how digital maturity levels shape operational risk. Existing digital maturity models primarily support benchmarking and planning, but rarely integrate structured risk assessment. This study addresses this gap by proposing a framework that links digital maturity with the systematic identification and prioritisation of digital transformation risks. A Digital Maturity-Based Risk Assessment Framework (DMRisk-TS) is developed, classifying risks into three categories. Probability and severity are evaluated using fuzzy logic, while contextual modifiers account for the maturity gap and system coverage. The approach is demonstrated using a real tram transport system and the DMM-TRAM model. The analysis shows that risk profiles differ markedly across maturity levels. Low-maturity environments generate operational risks related to insufficient or non-integrated information. Transitioning between levels introduces implementation and data-integration risks. At high maturity levels, new systemic risks emerge, including error propagation, cyber vulnerabilities, and over-reliance on automated processes. DMRisk-TS offers a meaningful basis for understanding and managing risks in transport systems. The framework supports the prioritisation of mitigation actions, informs decisions on advancing maturity, and highlights that higher digitisation creates new classes of systemic risk. Full article

To ensure all-day detection performance, unmanned aerial vehicles (UAVs) usually need both visible and infrared images for dual-modality fusion object detection. However, misalignment between the RGB-IR image pairs and complexity of fusion models constrain the fusion detection performance. Specifically, typical alignment methods choose only one modality as a reference modality, leading to excessive dependence on the chosen modality quality. Furthermore, current multimodal fusion detection methods still struggle to strike a balance between high accuracy and low computational complexity, thus making the deployment of these models on resource-constrained UAV platforms a challenge. In order to solve the above problems, this paper proposes a dual-modality UAV image target detection method named Mutual-Spectrum Perception Deformable Fusion Mamba (MSDF-Mamba). First, we designed a Mutual Spectral Deformable Alignment (MSDA) module. This module employs a bidirectional cross-attention mechanism to enable one modality to actively extract the semantic information of the other, generating fusion features rich in cross-modal context as shared references. These fusion features are then used to predict spatial offsets, with deformable convolutions achieving feature alignment. Based on the MSDA module, a Selective Scan Fusion (SSF) module is carefully designed to project the aligned features onto a unified hidden state space. With this method, we achieve full interaction and enhanced fusion of intermodal features with low computational complexity. Experiment results demonstrate that our method outperforms existing state-of-the-art cross-modality detection methods on the mAP metric, achieving a relative improvement of 3.1% compared to baseline models such as DMM, while still maintaining high computational efficiency. Full article

Background: Osteoarthritis (OA) is a chronic degenerative whole joint disease characterized by cartilage breakdown and inflammation. Galectin-3 (Gal-3), a β-galactoside-binding lectin secreted into the extracellular space, binds to glycosylated components of the extracellular matrix (ECM), modulating cell–matrix interactions and inflammation. This study aims to evaluate the anti-inflammatory effects of Hylach^®, a hyaluronic acid (HA) derivative conjugated with lactose-based residues that bind Gal-3, on in vitro inflamed primary human chondrocytes. Methods: Chondrocyte viability, after both Hylach^® and HA treatments at different concentrations was assessed using the MTT assay. Two-dimensional and 3D cell cultures exposed to the conditioned medium (CM) of activated U937 monocytes and subsequently treated with Hylach or HA, were analyzed for the expression of IL-1β, IL-6, TNF-α, and Gal-3 at different time points (4, 10, and 24 h). Results: HA and Hylach^® did not affect cell viability at any of the tested concentrations. Both molecules reduced the overexpression of Gal-3 and pro-inflammatory molecules in 2D inflamed cell cultures, at both gene and protein levels. Notably, IL-1β, IL-6 and Gal-3 showed a more pronounced inhibitory effect at 4 h, with Hylach demonstrating a stronger reduction compared to native HA. Moreover, in inflamed 3D chondrocyte cultures, Hylach^® but not HA, significantly reduced IL-1β, TNF-α and Gal-3 gene expression. Conclusions: Hylach^® exerts an early and more potent anti-inflammatory effect in inflamed 2D and 3D chondrocyte cultures when compared to HA. These findings suggest that targeting Gal-3 through selective HA derivatives may represent a promising strategy for modulating both inflammation and matrix remodelling in OA. Full article

Increasing emphasis is being placed on evaluating pain and mobility outcomes of osteoarthritis (OA) in both clinical and preclinical studies. In rodent models of post-traumatic OA (PTOA), particularly those utilizing destabilization of the medial meniscus (DMM), behavioral assays are becoming more prominent as researchers seek to bridge the translational gap between structural joint pathology and human disability. However, substantial variability exists in how behavior, mobility, and pain are assessed, potentially limiting reproducibility and cross-study comparisons. This review evaluates the current literature on behavioral and pain-related outcomes in rodent DMM models, with the aim of cataloging observed phenotypes, identifying methodological inconsistencies, and proposing recommendations for standardization. We compiled data on a range of behavioral assays, including mechanical and thermal sensitivity, cage monitoring, gait analysis, weight distribution, balance, and joint compression, to construct a temporal framework of post-injury changes in behavior. Across studies, behavioral changes were observed as early as one day post-injury and persisted up to 30 weeks, with notable variability depending on age, sex, and testing protocols. Young male mice (≤12 weeks old) were the most extensively studied. The findings highlight clear trends in pain sensitivity and functional decline but also underscore the need for harmonized methodologies and reporting standards. By providing a comprehensive synthesis of behavioral outcomes post-DMM, this review aims to support more informed study design and interpretation, offering a foundation for greater consistency and translational relevance in future rodent DMM research. Full article

Ferroptosis is a novel iron-sensitive subtype of regulated cell death (RCD), persisting under extreme lipid peroxidation and iron/redox imbalances. Unlike apoptosis, necroptosis, and pyroptosis, ferroptosis is a signaling-driven process mediated through iron metabolism imbalance, polyunsaturated fatty acid (PUFA) exceeding oxidation, and defects in its protective systems like Xc-/GSH/GPx4. Specifically, this review establishes that iron-driven ferroptosis is a central underlying pathomechanistic factor in a broad range of human diseases. Significantly, whether its modulation is therapeutic, it is entirely conditional on the specific disease context. Thus, its induction can provide a promising antidote for destructive cancer cells when conjoined with immuno-therapies to boost anticancer immunity. Conversely, iron-mediated ferroptosis suppression is a key factor in countering destructive changes in a whole range of degenerative and acute injuries. Current therapeutic approaches include iron chelators, lipid oxidation inhibitors, GPx4 activators, natural and active compounds, and novel drug delivery systems. However, against all odds and despite its intense therapeutic promise, its translation into a practical medicinal strategy faces many difficulties. Thus, a therapeutic agent specifically focused on its modulation is still lacking. The availability of selective biologic markers is a concern. The challenges in the direct pathologic identification of ferroptosis in a complex in vivo systemic scenario remain. Current avenues for its future development are pathogen infections, the discovery of novel regulating factors, and novel approaches to personalized medicine centered on its organ-level in vivo signatures. Full article

Endometriosis (ENDO) and poor ovarian response (POR) represent challenging conditions in assisted reproduction. Both, associated with altered follicular fluid (FF) composition, specifically impact on granulosa cell (GC) function in an incompletely understood way. GCs from male factor (MF, n = 30), ENDO (n = 38), and POR (n = 27) patients were cultured in media supplemented with FF from each group (FF-MF, FF-ENDO, FF-POR). Proliferation, morphology, and secretory activity (cortisol, estradiol, progesterone, IL-6) were assessed. GC proliferation depended primarily on FF origin, being highest with FF-ENDO, intermediate with FF-POR, and lowest with FF-MF. Morphological analysis revealed enrichment of muscle-like and fibroblast-like morphologies under FF-ENDO and FF-POR, suggestive of dysregulated luteinization and extracellular matrix remodeling. Secretory activity reflected a complex interplay between GC origin and FF type: IL-6 was strongly induced by FF-MF and FF-POR but consistently suppressed by FF-ENDO; cortisol and estradiol were generally consumed, while progesterone synthesis was largely confined to MF-GCs, with only variable induction in ENDO-GCs exposed to FF-POR. These findings indicate that pathological FF milieus reprogram GC behavior in distinct ways, with potential consequences for luteal function and oocyte competence. Identifying the molecular mediators of these alterations may guide tailored strategies to improve ART outcomes in ENDO and POR patients. Full article

Sea surface temperature (SST) gradients modulate surface wind variability at the mesoscale O(100 km), with relevant impacts on surface fluxes, rainfall, cloudiness and storms. The dependence of the SST-wind coupling mechanisms on physical environmental conditions has been proven using global ERA5 reanalysis data, regional observations and models. However, recent literature calls for the need of an observational confirmation to overcome the limitations of numerical simulations in representing such turbulent processes. Here, we employ O(10 km) MetOp A observations of surface wind and SST to verify the dependence of the downward momentum mixing (DMM) mechanism on large-scale wind U and atmospheric stability. We propose a simple empirical model describing how the coupling intensity varies as a function of U, where we account for the role of the characteristic SST length scale LSST and the boundary layer height h in determining the balance between the advective and response timescales, and therefore the decoupling of the atmospheric response from the SST forcing due to advection. Fitting such a model to the observations, we retrieve a scaling with U that depends on the atmospheric stability, in agreement with the literature. The physical interpretation from ERA5 is confirmed, albeit relevant discrepancies emerge in stable regimes and specific regional contexts. This suggests that global numerical models are not able to properly reproduce the coupling in certain conditions, which might have important implications for air–sea fluxes. Full article

Lorenz-type systems are dissipative dynamical systems that are described by three nonlinear equations with derivatives of the first order and are capable of exhibiting chaotic behavior. The generalization of Lorenz-type equations by using general fractional derivatives (GFDs) and periodical kicks is proposed. GFDs allow us to use the general form of memory functions as operator kernels to describe nonlinear dynamics with memory. The exact analytical solutions of Lorenz-type equations with GFDs are derived in the general case for the wide class of nonlinearity and memory functions. Using the exact solutions, we obtain discrete maps with memory (DMMs) that describe kicked GF Lorenz-type systems with general forms of memory and nonlinearity. The proposed maps describe the exact solution of nonlinear equations with GFDs at discrete time points as the function of all past discrete moments of time. The proposed multi-dimensional DMMs are derived from kicked GF Lorenz-type equations with GFDs without any approximations. The proposed results and the method to derive multi-dimensional DMMs are derived for arbitrary dimensions. The importance and unusualness of the proposed results lies in the fact that obtained solutions for equations of the Lorenz-type system are exact analytical solutions. Full article

This paper presents the experimental implementation and validation of the two-chamber method presented in Part I for the high-precision determination of the temperature coefficient of resistance (TCR) of current shunts. The two-chamber approach enables improved thermal isolation and independent temperature control of the reference and test shunts, which significantly reduces the measurement uncertainty. In this part, the complete experimental setup is described, including the thermoelectric temperature control, the current generation and the data acquisition system with synchronized high-resolution digital multimeters (DMMs). The experimental measurements were carried out for different resistance ratios ranging from 0.1 to 10. The results confirm the theoretical predictions and the uncertainty analysis from Part I. The influences of the stability of the current source, the temperature uniformity and the synchronization accuracy on the measurement results are evaluated. The two-chamber method shows high repeatability, ease of use and suitability for laboratory and interlaboratory tests, and thus represents a robust alternative to classical TCR determination methods. Full article

Osteoarthritis (OA) is a degenerative joint disorder characterized by progressive articular cartilage degradation, leading to pain, stiffness, and impaired mobility. This study investigated the anti-osteoarthritic effects of Lindera obtusiloba (LO) leaf extract in primary cultured chondrocytes and a mouse model of destabilization of the medial meniscus (DMM)-induced OA. Mouse primary chondrocytes were treated with IL-1β and various concentrations of LO leaf extract (50–150 μg/mL), and analyzed by RT-PCR, Western blotting, and ELISA. For the in vivo experiments, male C57BL/6 mice underwent DMM surgery and were administered LO leaf extract (50–200 mg/kg/day) for eight weeks, followed by micro-CT, histological, and immunohistochemical analyses. LO leaf extract exhibited no cytotoxicity in chondrocytes. In interleukin-1β-induced inflammatory chondrocytes, LO leaf extract significantly suppressed the expression of OA-associated catabolic factors, including cyclooxygenase-2 (Cox-2), matrix metalloproteinases (MMP3 and MMP13), and phosphorylated nuclear factor-kappa B (NF-κB). It also reduced the production of destructive mediators, such as prostaglandin E₂ (PGE₂) and collagenase, in a dose-dependent manner. In vivo, LO leaf extract-treated mice demonstrated significant reductions in articular cartilage degradation, subchondral bone sclerosis, and the expression of catabolic and inflammatory mediators. Additionally, LO leaf extract administration significantly decreased systemic pro-inflammatory cytokine levels in DMM-induced mice. Collectively, these findings indicate that LO leaf extract attenuates OA progression by suppressing both local and systemic inflammatory responses, supporting its potential as a natural therapeutic agent for the prevention and treatment of OA. Full article