Search Results (369)

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

A novel graphene-based nanomaterial, trade registered Hastalex^®, has been synthesised and investigated for its application as a 3D scaffold in surgical implantation. Hastalex is developed through the covalent bonding of amine-group-functionalised graphene oxide to the base chemical, poly(carbonate-urea)urethane. The material is under development for medical application including tendon, heart valve, and pelvic implant for prolapse surgery. For successful clinical translation, long-term rheological and chemical stability must be demonstrated and until now no systematic multi-year evaluation has been reported for graphene-poly(carbonate-urea)urethane nanocomposites. The material was synthesised in accordance with the patented formulation and evaluated at 0, 6, 12, and 24 months post-synthesis. Physicochemical properties were assessed using attenuated total reflectance Fourier-transform infrared spectroscopy, scanning electron microscope, contact angle measurements, thermogravimetric analysis, and mechanical analysis with tensile tests. Flow behaviour of Hastalex was evaluated using a rheometer to determine viscosity, shear stress response and impact of temperature changes and ageing on these factors. Hastalex exhibited non-Newtonian, shear-thinning behaviour consistent across all timepoints. Viscosity was found to increase progressively with ageing, attributed not to chemical degradation, but likely due to gradual solvent evaporation and densification of the polymer matrix during storage under ambient conditions. Rheological measurements across increasing temperature regimes revealed a heat-sensitive decrease in viscosity, followed by a reversal of changes beyond ~80 °C—likely due to enhanced solvent evaporation and chain reorganisation. This comprehensive material characterisation supports Hastalex as a promising candidate for bioengineering applications. Full article

The entropy of a Schwarzschild black hole is commonly derived using thermodynamic relations whose physical interpretation is not always transparent, in particular with respect to the localization of temperature and entropy. In this paper, we present a derivation of the Bekenstein–Hawking entropy based exclusively on the principles of phenomenological thermodynamics, formulated entirely in regions where spacetime is effectively flat. The analysis considers a reversible evaporation process in which the black hole is surrounded by a tunable thermal radiation bath whose temperature is kept arbitrarily close to the Hawking temperature. In this limit, entropy production can be made negligible. By integrating the entropy flux through a distant reference surface over the evaporation process, the standard entropy formula is obtained without invoking assumptions about the localization of the black hole entropy or about microscopic degrees of freedom. The derivation is mathematically simple but conceptually instructive. The approach is intended to be accessible to readers familiar with classical thermodynamics and general relativity at an advanced undergraduate or graduate level. Full article

This work presents a case study detailing an end-to-end workflow for reconstructing a damaged plastic component when no original design data are available. The approach integrates microscopic inspection of fracture surfaces, selective enhancement of 3D scan data, CAD-based modification of geometrically and functionally critical features, and continuous fibre-reinforced additive manufacturing. The component examined functions as a structural mounting element in an automotive lighting module, where it maintains correct alignment and provides mechanical support in service. The study concentrates on the cost-effective replacement of unique parts produced in very small batches. The results indicate that this fracture-analysis-informed reverse engineering strategy offers a practical solution for reproducing low-volume, custom, or replacement components in situations where standard manufacturing methods are not economically viable. The reconstructed part matched the geometry necessary for installation in the original assembly and successfully passed initial functional checks; however, this study did not include quantitative measurements of mechanical performance. Full article

Cervical Intervertebral Disc Degeneration (CIVDD) involves significant microenvironmental physical stiffening, forcing nucleus pulposus cells (NPCs) into a rigid phenotype via F-actin over-assembly. It remains unclear if cyclic tensile strain (CTS) can reverse this physical stiffening, particularly in severe degeneration. This study stratified 18 patients into Mild, Moderate, and Severe cohorts based on MRI. Primary NPCs were subjected to physiological 5% CTS (1 Hz, 24 h). Atomic Force Microscopy (AFM) and immunofluorescence were utilized to evaluate Young’s modulus and cytoskeletal remodeling. Results demonstrated that baseline cellular stiffness increased significantly with degeneration severity. Following CTS, all groups exhibited universal de-stiffening and F-actin depolymerization. Crucially, a “Degeneration Paradox” emerged: the Severe group displayed the highest relative elastic modulus recovery rate, significantly surpassing the Mild group. This microscopic recovery correlated inversely with preoperative disc height loss and range of motion. We conclude that severely degenerated cells are not metabolically quiescent but “physically locked” by a rigid cytoskeleton. Physiological CTS restores compliance via mechanical unloading, confirming that severe cells retain superior relative mechanoplasticity and may benefit from mechanotherapy-based “unlocking” strategies. Full article

Background: Tailored axillary surgery (TAS) and axillary reverse mapping (ARM)-guided axillary lymph node dissection (ALND) have been developed to avoid arm lymphedema without increasing a risk of axillary recurrence. However, the oncological feasibility of TAS and ARM-guided ALND remains a crucial consideration. Methods: This article reviewed the oncological feasibility of TAS and ARM-guided ALND based on the current literature. Results: For ALND performed after TAS, additional involved nodes were found in 70% of upfront surgery patients and 60% of neoadjuvant chemotherapy (NAC) patients. ARM nodes were also involved in up to 64.7% of patients after ALND. However, it is not necessary to preserve all ARM nodes and lymphatics because multiple ARM lymphatic pathways exist. Selective preservation of ARM nodes closest to the axillary vein significantly reduced the incidence of involved ARM nodes (from 64.7% to 15.7%). Conclusions: TAS and ARM-guided ALND remain much less radical than ALND. However, residual nodal disease after TAS or ARM-guided ALND does not always develop axillary recurrence. Postoperative irradiation is effective in achieving local control in patients with low-volume (microscopic) residual nodal disease after TAS or ARM-guided ALND. We await the long-term results of prospective randomized clinical trials comparing TAS and ARM-guided ALND with conventional ALND. Full article

Background: The modernization of Traditional Chinese Medicine (TCM) is hindered by a “structure-blind” bottleneck: establishing molecular mechanisms for complex formulations with uncharacterized chemical constituents. Conventional computational screening fails in these scenarios due to a heavy reliance on pre-determined structures. We developed NovelHTI, an inductive graph-based framework designed to reverse-engineer protein targets directly from standardized clinical symptom profiles. Methods: NovelHTI implements a “Phenotype-to-Target” paradigm by integrating heterogeneous graph neural networks with systemic pathway constraints. Unlike traditional transductive models, NovelHTI leverages multi-view feature fusion of symptom semantics and biological pathways to enable de novo prediction for unseen herbs. The framework was evaluated across 698 herbs and 7854 targets, benchmarking against advanced GNNs (HAN) and non-graph classifiers (XGBoost) under strict cold-start and knowledge erosion simulations. Results: NovelHTI maintains high precision (>$84\%$) and balanced performance (F1-score $>77\%$), outperforming baselines by over 33% (ROC-AUC) in realistic imbalanced screening, where traditional models typically fail (AUC ≈ 0.51). Robustness analysis confirmed stable performance (>$0.83$ AUC) despite 30% structural data incompleteness. Notably, retrospective validation successfully “rediscovered” emerging mechanisms (e.g., the Artemisinin-GPX4 ferroptosis axis) elucidated in 2021–2024 literature, which were entirely latent in the training data. Conclusions: NovelHTI provides a robust computational prioritization filter that effectively bridges macroscopic phenotypes and microscopic pharmacology. By enabling mechanism-driven target de-risking, this framework optimizes resource allocation for downstream experimental validation and accelerates TCM-based drug discovery. Full article

The paper develops a coarse-grained framework for computing mean extinction times in multi-metastable systems modeled as one-step continuous-time Markov chains with an absorbing state. At the microscopic level, backward equations on finite corridors are solved to obtain closed-form series for committors, mean first-passage times, and intrawell (basin) waiting times. A renewal–reward construction then yields effective interwell transition rates written as a success probability divided by a mean cycle duration, providing an interpretable effective rate constant. These rates define a reduced Markov chain on the wells together with extinction; mean extinction times follow from a linear system, and the associated fundamental matrix quantifies pre-extinction residence times in each coarse state. This framework makes explicit how multiple escape pathways and intrawell dwell times contribute to extinction statistics in finite systems. The method is illustrated on a double-well landscape with an extinction state, using a reversible potential-to-rates mapping for the numerical example. Comparisons of alternative intrawell models and validation against exact one-step computations demonstrate accuracy at finite system sizes, including regimes where diffusion approximations are unreliable. The resulting formulas require only local rate data, remain numerically stable under strong bias, and extend directly to multiple wells and flexible boundary conditions. Full article

We develop a dual-time topological framework for the mathematical description of non-equilibrium systems, aimed at reconciling time-reversible microscopic dynamics with irreversible macroscopic behavior. The formulation introduces two independent but coupled temporal parameters: a reversible time associated with microscopic or generative dynamics, and an irreversible time governing dissipation, entropy production, and macroscopic evolution. Physical states are defined on a dual-time manifold, allowing reversible and irreversible processes to be treated within a unified geometric setting. Temporal evolution is described using independent temporal connections and their associated curvature. We show that nonvanishing temporal curvature induces path dependence in temporal evolution, providing a geometric origin for memory effects, non-Markovian dynamics, and aging phenomena. Temporal asymmetry emerges dynamically through symmetry breaking between the temporal sectors and through projection from the bi-temporal domain onto a single observable time parameter. The relationship between the dual-time formalism and conventional single-time non-equilibrium models is analyzed. Standard evolution equations are recovered in integrable or decoupling limits, demonstrating that the proposed framework constitutes a genuine generalization compatible with established approaches. By encoding irreversibility in the geometry and topology of temporal evolution, this work provides a mathematically consistent geometric framework for analyzing the emergence of the arrow of time in non-equilibrium theoretical physics. Unlike conventional approaches in which irreversibility and memory are encoded phenomenologically at the level of effective equations, the present framework reformulates non-Markovian dynamics and temporal asymmetry in terms of the geometry and topology of coupled temporal evolution. In particular, a representation theorem is established showing that a broad class of convolution-type non-Markovian equations arises as projections of local dual-time dynamics. Full article

Under the vision of carbon neutrality, the global energy system urgently requires storable, transportable, and tradable zero-carbon carriers. Iron, due to its high crustal abundance, low cost, environmentally friendly reaction products, and ease of closed-loop cycling, is being reconsidered as a potential “metallic energy” alternative to fossil fuels. This paper systematically reviews the conceptual evolution, scientific lineage, and paradigm shift logic of iron-based energy within the framework of dual pathways: combustion and electrochemistry. On the combustion front, a multi-level understanding has been established—ranging from microscopic reaction mechanisms to macroscopic flame propagation, and from unit combustors to diversified thermal power systems—laying a methodological foundation for an integrated “solid fuel–thermal–power” approach. In parallel, the electrochemical pathway has developed both liquid and solid routes, integrating energy storage, pollution control, and resource recovery within a single device through multi-valent redox reversibility, thereby expanding the concept of generalized energy storage under the “battery-as-factory” paradigm. Current research is shifting its focus from single performance metrics toward synergistic optimization of efficiency, lifespan, cost, safety, and environmental impact, marking a transition in technological paradigm from “material trial-and-error” to “mechanism design.” Looking forward, to advance iron energy beyond the experimental validation stage, it is imperative to establish a cross-scale, closed-loop scientific characterization system, develop recycling strategies with low entropy and low energy consumption, and deeply integrate with renewable electricity, hydrogen, and high-temperature heat sources to form spatiotemporally transferable zero-carbon energy systems. In this way, iron may integrate into global energy trade as a “metallic energy in specific scenarios like ports/islands,” offering a scalable, hydrocarbon-independent technological option for achieving carbon neutrality. Full article

This study investigates the evolution of the structures of China’s domestic intercity tourism information flow networks, an increasingly important issue in an information-driven society. Moving beyond prior research that primarily emphasizes urban node attributes and multidimensional distances, this study applies social network analysis to develop an integrated analytical framework that incorporates endogenous structural effects, exogenous network effects, node attributes, and similarity effects. Using tourism information flows in China as an empirical proxy, the study examines the mechanisms underlying the formation and persistence of intercity relationships within the country. The results indicate that the self-organization of microscopic network structures plays a significant role in both tie formation and persistence, particularly through reciprocity, cyclicity, and convergence. Notably, the effect of cyclicity reversed during the COVID-19 pandemic and changed direction from relationship formation to persistence. In addition, cultural distance (proxied by dialect distance), geographical distance, and institutional distance significantly inhibit both the formation and persistence of intercity tourism information flows. Changes in urban node scale and node similarity also exert significant influences on network evolution. This study deepens the understanding of the spatial structural dynamics of China’s domestic intercity tourism information flows and provides a conceptual basis for future research on the evolutionary mechanisms of tourism network structures within a domestic context. Its direct significance lies in promoting sustainable urban tourism development, network resilience, and adaptive governance of urban systems. Full article

The present work focuses on the fatigue behaviour of the additively manufactured Ti6Al4V-ELI alloy, which is mainly used for biomedical applications such as implants and prosthetics. It was found that the studied material is characterised by an almost fully dense (relative density higher than 99.97%) microstructure, which consists of needle-like α-Ti lamellae with β-Ti phase on their boundaries. Fatigue tests showed that the lifespan of the Ti6Al4V-ELI alloy produced by laser powder bed fusion within the stress amplitude of 300–400 MPa lies in the range of 10⁶–10⁷ cycles. Scanning electron microscope fractographic images showed that the surface of the studied material plays the most important role in determining the material’s lifetime. The findings of this study contribute to a deeper understanding of the structure–property relationships in terms of extremely damaging fully reversible (tension-compression) fatigue measurements in additively manufactured Ti6Al4V-ELI and support the development of more reliable biomedical components, especially hip joint prostheses. Full article

The interaction between small organic molecules and coal macerals plays a critical role in regulating fluid retention and transport in coal-related energy and environmental systems. However, the microscopic mechanisms governing adsorption selectivity and interfacial dynamics on different maceral surfaces remain insufficiently understood. In this study, molecular dynamics simulations were employed to investigate the adsorption and desorption behaviors of toluene (TOL) and tetrahydrofuran-2-ol (FUR) on inertinite (INE) and vitrinite (VIT) surfaces at the molecular level. Time-dependent variations in adsorption number, residence time, molecular mobility, interaction energies, and hydrogen-bond characteristics were systematically analyzed. The results reveal strong maceral- and molecule-dependent adsorption preferences. TOL exhibits the most stable adsorption on the INE surface, characterized by rapid surface accumulation, minimal desorption, and a long residence time of 0.43547 ns, which is mainly driven by strong van der Waals interactions and aromatic stacking effects. In contrast, TOL adsorption on VIT is highly dynamic, with frequent desorption events and a markedly reduced residence time of 0.1077 ns. FUR shows relatively weaker and more reversible adsorption on INE, accompanied by enhanced molecular mobility and a shorter residence time of 0.31354 ns. Notably, FUR demonstrates stronger surface retention on VIT, with an extended residence time of 0.34439 ns, which can be attributed to increased electrostatic contributions and intermittent hydrogen bonding. Hydrogen-bond analysis indicates that FUR forms longer-lived hydrogen bonds with VIT (22.05 ps) than with INE (17.86 ps), providing additional stabilization at the interface. These findings elucidate the distinct adsorption mechanisms of aromatic and polar molecules on heterogeneous coal macerals and offer molecular-scale insights into organic matter–coal interfacial processes relevant to energy extraction and subsurface transport. Full article

Background: Scattering of the sclera limits optical coherence tomography (OCT) imaging of deeper targets including lesions, malignancies, and other surgical targets. While existing applications of fluorescein dye are currently focused on fluorescence properties for tissue labeling, the absorption characteristics of the dye also hold potential for scleral tissue clearing. Methods: Fluorescein is investigated here to gauge the potential impact of its optical clearing on intrasurgical OCT guidance. Fluorescein was applied topically to ex vivo porcine and human eye models. OCT imaging was conducted over time to assess the increases in imaging depth due to fluorescein clearing. High-speed microscope-integrated OCT was used during pilot trabeculectomy surgery on cleared eye models to assess clearing applications in a surgical context. Results: The OCT depth of imaging increased with fluorescein concentration and application time. The effect saturates at a near-20% concentration with 50 min of application time, with a maximum signal increase of +15 dB. Reversal of the effect was observed following 10 min of rinsing. Conclusions: High-concentration fluorescein dye has novel applications as an optical clearing agent, increasing the OCT imaging depth through highly scattering biological tissue. These properties can be leveraged for improved image guidance in surgical contexts. Full article

Background/Objectives: This 7-day rat tracheocutaneous fistula study considered the not-studied issues of tracheocutaneous fistula course, wound healing, and fistula in the NO-system relations. Therefore, we focused on fistulas’ severe course, tracheocutaneous fistula → air leak → compensatory diaphragmatic/abdominal “heaving”, NO-system failed relations, and therapy resolution. Stable gastric pentadecapeptide BPC 157 was proposed. Methods: Tracheocutaneous fistula rats received daily medication (/kg), alone or combined, BPC 157 therapy (10 µg, 10 ng, in drinking water or intraperitoneally) along with a triple NO-agent approach (L-NAME 5 mg, L-arginine 100 mg, and L-NAME+L-arginine, intraperitoneally). Results: Tracheocutaneous fistulas occurred as specific and NO-system-related as follows: NO system: blockade (L-NAME-aggravation) over-activity (L-arginine-amelioration) or immobilization (L-NAME+L-arginine oppose each other’s effects). Controls presented severe clinical signs of respiratory distress, failed healing, skin and tracheal defects, a not-healed and open, macro/microscopically, and fistulous tract that was well-formed and wide, tracheal shrinking below the fistula, and clinically, open-mouth breathing, “heaving abdomen”, cyanosis (bluish snout, ears, extremities), abundant secretion through the fistula, and weight loss. Fistula tissue NO level decreased, and the malondialdehyde (MDA) level increased. The BPC 157 therapy (both application routes) resulted in rapid recovery. Healing of defects (skin and trachea) and fistula closure, macro/microscopically, corresponded with clinical findings, avoiding observable clinical signs of dyspnea, reducing weight loss, and avoiding any sign of “heaving abdomen”. BPC 157-treated rats displayed regular breathing movements without observable signs of respiratory distress. Finally, when combined, BPC 157 therapy upgrades L-arginine amelioration, abolishes L-NAME-induced worsening, and restores full healing after NO immobilization (L-NAME+L-arginine). BPC 157 counteracted increase in NO level and counteracted increase in MDA level. Conclusions: Thus, first, acting systemically, BPC 157 reverses tracheocutaneous fistula course in rats. It acts through the NO system. Full article