Search Results (635)

Background: The glucocorticoid receptor NR3C1 exhibits antiepileptic properties, but the mechanisms governing its stability during epileptogenesis remain elusive. This study investigated whether the E3 ubiquitin ligase TRIM8 regulates neuronal hyperexcitability and epileptic activity by modulating NR3C1. Methods: We established an in vivo epilepsy model via intrahippocampal kainic acid (KA) injection and an in vitro epileptiform model using Mg²⁺-free artificial cerebrospinal fluid in primary hippocampal neurons. The roles of TRIM8 and NR3C1 were assessed using in vivo and in vitro gain- and loss-of-function approaches, alongside co-immunoprecipitation, Western blotting, immunofluorescence and whole-cell patch-clamp recording. Results: TRIM8 is significantly upregulated in hippocampal and temporal lobe neurons in epileptic mice. TRIM8 was markedly upregulated in the hippocampal neurons of epileptic mice, inversely correlating with NR3C1 levels. Mechanistically, TRIM8 interacted with NR3C1, promoting its polyubiquitination and proteasomal degradation. This TRIM8-mediated NR3C1 reduction enhanced the phosphorylation of AMPA receptor (AMPAR) subunits GluR1 (Ser831) and GluR2 (Ser880) without affecting total receptor expression. In vitro, TRIM8 overexpression exacerbated calcium dysregulation, neuronal injury, and AMPAR phosphorylation; crucially, concurrent NR3C1 overexpression rescued these effects. In vivo, knockdown of TRIM8 significantly reduced seizure frequency, prolonged the latency to the first Stage III seizure, shortened average seizure duration, and decreased total seizure burden in KA-induced epileptic mice. Electrophysiologically, TRIM8 overexpression significantly increased the frequency of spontaneous action potentials and amplitudes of spontaneous excitatory postsynaptic currents under Mg²⁺-free conditions. Furthermore, in vivo knockdown of TRIM8 attenuated KA-induced seizure severity, restored NR3C1 protein stability, and suppressed aberrant AMPAR phosphorylation in the hippocampus. Triple immunofluorescence staining showed that KA-induced epilepsy increased TRIM8 but decreased NR3C1 immunoreactivity in NeuN⁺ hippocampal neurons, and TRIM8 knockdown reversed these changes. Conclusions: TRIM8 acts as a critical driver of epileptiform activity by targeting NR3C1 for degradation, thereby disinhibiting AMPAR phosphorylation and enhancing network hyperexcitability. The TRIM8-NR3C1-AMPAR axis emerges as a previously unrecognized molecular pathway in epileptogenesis, highlighting its potential as a promising therapeutic target for epilepsy. Full article

Background/Objectives: Glucocorticoids, including dexamethasone (DEX), are known to demonstrate anti-inflammatory activity, suppress steroidogenesis, and mitigate the adverse effects of chemotherapy. They are therefore widely employed for managing solid malignancies. Emerging evidence indicates that DEX modulates both systemic and local renin–angiotensin system (RAS) activity, including genomic signaling via the glucocorticoid receptor (GR). Methods: DEX-dependent transcriptional responses for the angiotensin receptor genes (AGTR1, AGTR2, MAS1, and LNPEP) were evaluated in ovarian (SKOV3, KURAMOCHI) and prostate (DU-145, PC3) cancer cell lines. The cells were cultured under different serum conditions to determine the influence of nutrient availability on tumor progression. Results: DEX demonstrated distinct mechanisms of action between the ovarian and prostate cancer models. It was found to promote cancer cell survival through tissue-specific modulation of metabolic activity, clonogenic capacity, cell cycle distribution, and apoptotic responses. These effects were accompanied by condition-dependent alterations in angiotensin receptor gene expression. Hence, DEX may mediate the remodeling of local RAS signaling, which may be significant in overall survival and disease-free survival. The findings also indicate a previously-unreported NR3C1–LNPEP correlation, which was consistently observed across in vitro systems and patient datasets, in both ovarian- and prostate-derived cancer models. Conclusions: DEX appears to exert context-dependent regulation of RAS-associated gene networks in ovarian and prostate cancer, suggesting a role in tumor adaptive responses and potentially in therapeutic contexts. Full article

Rapid detection of foodborne pathogenic and spoilage microorganisms is critical for ensuring food safety and quality in liquid matrices. While Raman tweezers spectroscopy (RTS) enables label-free single-cell analysis, its application in high-throughput inline inspection faces a fundamental bottleneck: high flow rates required for efficiency induce severe motion blur and low signal-to-noise ratios (SNR), which blind automated control systems and destabilize optical trapping. To overcome this, we present a Spatiotemporal Video-Enhanced Raman Tweezers (SVERT) system integrating a deceleration-optimized microfluidic chip with a deep learning-based visual feedback loop. We propose a Local–Global Unified Denoising Network (LGU-Net) tailored to recover high-fidelity bacterial structures from low-SNR video streams, achieving a deterministic processing latency of ~0.49 ms. Experimental results demonstrate that SVERT improves the optical trapping success rate from 21.27% ± 2% to 91.47% ± 1.8% compared to raw video input, enabling a four-fold increase in spectral acquisition efficiency. Leveraging the acquired high-quality dataset, we achieved a classification accuracy of 96.74% across four bacterial species of relevance to food safety and quality. Crucially, we validated the system’s practical robustness by successfully isolating and tracking trace E. coli in an unpurified commercial beverage. This capability to effectively mitigate natural background interference demonstrates the system’s promising potential to be expanded for broader applications in liquid food safety screening. Full article

Phosphoric acid-doped polybenzimidazole membranes are a leading fluorine-free electrolyte platform for high-temperature proton exchange membrane fuel cells, enabling proton transport under anhydrous conditions. However, recent evidence shows that conductivity, mechanical stability, and acid retention are intrinsically coupled, preventing independent optimization of these properties. This review establishes a unified framework in which membrane performance is governed by a multidimensional design space defined by acid doping level, activation energy (E_a), hydrogen-bond network topology, and mechanical confinement. Conductivity is shown to scale with both carrier density and hopping energetics, while mechanical stability decays with increasing ADL due to acid-induced plasticization, described through a semi-empirical relationship. Analysis across molecular architectures, including molecular weight control, crosslinking, backbone modification, topological design, and free-volume engineering, demonstrates that performance emerges from a balance between transport efficiency and structural stability. Device-level benchmarking further reveals that similar conductivity values can correspond to orders-of-magnitude differences in voltage decay rate, confirming that durability is governed primarily by mechanical confinement and acid mobility rather than σ alone. A multivariate stability corridor is identified, within which phosphoric acid-doped polybenzimidazole membranes achieve σ ≈ 0.14–0.20 S·cm⁻¹ while maintaining low degradation rates under realistic high temperature proton exchange membrane conditions. Based on this framework, quantitative design rules are derived linking acid doping level, activation, topology, and mechanical properties. This work shifts membrane design from conductivity-driven optimization toward predictive structure–property–durability engineering, providing a basis for the development of next-generation HT-PEM fuel cells with sustained long-term performance. Full article

Objectives: This study aimed to identify core genes associated with mitochondria-related transcriptomic signatures and evaluate their potential as computational biomarkers, immune characteristics, regulatory mechanisms, and potential therapeutic relevance. Methods: Obesity-related transcriptome datasets were obtained from the GEO database. Differentially expressed genes (DEGs) were intersected with mitochondria-related genes (MRGs) to identify obesity-related MRGs. Functional enrichment, protein–protein interaction (PPI) analysis, CytoHubba, LASSO and random forest algorithms were used to screen core genes. External validation, ROC analysis, immune infiltration analysis, regulatory network construction, candidate drug prediction, and molecular docking were further performed. Results: A total of 527 DEGs and 15 differentially expressed MRGs were identified. Enrichment analysis suggested that these mitochondria-related genes were mainly associated with disrupted mitochondrial energy metabolism, lipid metabolic remodeling, and altered substrate utilization. ECHDC2, FASN, NAT8L, and AASS were identified as core MRGs; these genes are respectively associated with mitochondrial metabolic regulation, de novo fatty acid synthesis, N-acetylaspartate-related mitochondrial metabolism, and lysine degradation. These genes were significantly downregulated in obesity and showed good diagnostic performance. Immune infiltration analysis revealed alterations in the immune microenvironment, and the core genes were negatively correlated with multiple immune cell types. Molecular docking showed that Genistein had the lowest predicted binding free energy with NAT8L (−8.89 kcal/mol), suggesting relatively favorable binding among the tested ligand–target pairs. Conclusions: ECHDC2, FASN, NAT8L, and AASS may serve as candidate computational biomarkers, among which FASN represents a known lipid metabolism-related gene, supporting the biological plausibility of the workflow. Full article

Scaffolds designed for mechanically demanding soft tissue engineering applications should integrate mechanical support, efficient mass transfer, and good cellular compatibility. This work presents a one-pot method based on “radical-free click chemistry + carbodiimide coupling” to produce a double-network (DN) PEG–alginate cryogel. The PEG network is formed by a Michael addition reaction between thiol-based crosslinker and 8-arm PEG-acrylate. The second network is covalently crosslinked through EDC/NHS-mediated coupling of carboxyl groups in alginate and adipic acid dihydrazide (AAD). The subsequent freezing and gelation of the gel precursor at sub-zero temperatures results in an ice templated cryogel with an interconnected macroporous network. These cryogels demonstrate high elasticity, compressive modulus and rapid swelling equilibrium in aqueous environments, as well as controlled degradation under physiological conditions. Compared to the classical Ca²⁺ ion crosslinking systems, the covalent linking of the alginate in the double-network cryogel shows advantages in mechanical and structural stability. In addition, it is cell-compatible and allows culture of mesenchymal stem cells (MSCs) with homogeneous infiltration. Furthermore, the double-network cryogels supports chondrogenic differentiation of MSCs upon treatment with chondrogenic media or macrophage-conditioned media for a short period of time. These results indicate that crosslinking chemistry and polymer composition can be used to modulate the balance between mechanical performance and degradation behavior, while maintaining cytocompatibility and an interconnected macroporous network, thereby providing a scaffold design strategy for applications that require coordinated mechanical support and mass transfer, such as cartilage-related tissue engineering. Full article

Background/Objectives: Chlamydia trachomatis (CT) is a prevalent sexually transmitted pathogen associated with pelvic inflammatory disease, infertility, and has been proposed as a potential contributor to carcinogenesis through chronic inflammation and tissue remodeling. The molecular mechanisms triggered by CT infection in fallopian tube cellular contexts and their relevance to ovarian cancer transcriptomes remain incompletely understood. Methods: We analyzed GSE109428, profiling primary human fallopian tube mesenchymal cells infected with CT, to identify differentially expressed genes and characterize affected pathways using g:Profiler and STRING protein–protein association networks (confidence ≥ 0.7). To provide translational context, we computed ssGSEA scores in TCGA-OV for four signatures capturing IFN/ISG, TNF/NF-κB, NOD/innate immunity, and ECM programs, and evaluated inter-signature correlations and exploratory associations with overall survival (OS) and progression-free interval (PFI). Results: CT infection induced sustained inflammatory and interferon-associated transcriptional programs, with STRING networks highlighting cytokine hubs and a densely connected ISG module. Genes downregulated at 48 h post-infection (48-hpi) showed coherent enrichment for ECM organization and adhesion pathways. In TCGA-OV (n = 307), inflammatory and innate immune signatures co-occurred across tumors, with moderate correlations between TNF/NF-κB and NOD/innate (ρ = 0.591) and IFN/ISG and NOD/innate (ρ = 0.534). Exploratory survival analyses showed no significant associations with OS or PFI in Kaplan–Meier analyses or multivariable Cox models, including clinically adjusted and tumor microenvironment-adjusted specifications. Conclusions: CT infection induces sustained inflammatory and interferon-linked programs and coordinated repression of ECM networks in fallopian tube mesenchymal cells. Analogous immune transcriptional states co-occur in ovarian tumors, though the signatures evaluated did not yield robust prognostic signals in TCGA-OV. As this is an entirely in silico study without experimental validation, these findings should be treated as hypothesis-generating; thus, further mechanistic and experimental studies are warranted to clarify how CT infection-associated pathways may intersect with female tumorigenesis. Full article

Caveolin-1 is a scaffolding protein of caveolae, flask-shaped membrane microdomains involved in diverse cellular processes. Caveolae are primarily localized to the plasma membrane, the trans-Golgi network, and mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). Most enzymes involved in cholesterol biosynthesis reside in the ER, and although caveolin-1 avidly binds cholesterol, its role in cholesterol trafficking remains unclear. Acyl-coenzyme A:cholesterol acyltransferases (ACAT1 and ACAT2) convert free cholesterol into cholesteryl esters for storage, with ACAT1 serving as the predominant isoenzyme in most cell types. ACAT1 is an ER-resident protein, with a fraction associated with specialized ER subdomains, including the MAM. Here, we report that a subset of caveolin-1 molecules appears to be associated with a fraction of ACAT1 in ER subdomains. Using immunoprecipitation under detergent conditions, immunoadsorption of MAM-enriched membranes under detergent-free conditions, and electron microscopy, we provide evidence consistent with an association between a subset of caveolin-1 molecules and ACAT1. Functionally, in mouse embryonic fibroblasts, we show that genetic ablation of caveolin-1 significantly increases the esterification of low-density lipoprotein-derived cholesterol, suggesting that caveolin-1 may attenuate ACAT1 activity. Collectively, these findings indicate that caveolin-1 may modulate cholesterol esterification and contribute to the regulation of cholesterol distribution among cellular membranes. Full article

Background: Plasticizers, including phthalate esters and phthalate-free alternatives, are widely detected environmental chemicals. Although increasing evidence suggests that plasticizers may disrupt gastrointestinal homeostasis, their potential molecular links with inflammatory gastrointestinal disorders (IGDs) remain unclear. Methods: This study aimed to systematically identify potential molecular targets and pathways linking representative plasticizers with IGDs. An integrative network toxicology framework was applied to investigate four plasticizers, including dimethyl phthalate (DMP), diethyl phthalate (DEP), dioctyl phthalate/di(2-ethylhexyl) phthalate (DOP/DEHP), and acetyl tributyl citrate (ATBC), in relation to Crohn’s disease (CD), ulcerative colitis (UC), esophagitis, and gastritis. Plasticizer- and disease-related targets were collected from public databases, followed by overlapping target screening, protein–protein interaction network analysis, functional enrichment analysis, GEO-based transcriptomic validation, molecular docking, molecular dynamics simulation, and single-cell RNA-seq analysis. Results: Disease-specific candidate targets were identified, including CXCL8 and FN1 for CD, IL1B for UC, MAPK3, FASN, FN1, PPARG, CXCL8, FOS, and HIF1A for esophagitis, and MMP9, TNF, TLR4, IL6, CCR2, IFNG, and PTGS2 for gastritis. Cross-disease analysis further identified plasticizer-associated signature targets, including MMP7 for DMP, HMOX1 and NOS2 for DEP, and LTF and CCL11 for ATBC. Enrichment analysis indicated that these targets were mainly involved in inflammatory, chemokine, MAPK-related, and xenobiotic response pathways. Molecular docking and dynamics simulations suggested stable interactions between selected plasticizers and candidate targets, while single-cell analysis revealed their cell-type-specific expression patterns in epithelial, immune, and stromal compartments. Conclusions: This study provides an exploratory network toxicology framework for identifying potential molecular associations between plasticizer exposure and IGDs. The findings highlight disease-specific and plasticizer-associated candidate targets that may guide future experimental validation and environmental risk assessment. Full article

Unmanned aerial vehicle (UAV)-assisted millimeter-wave (mmWave) and terahertz (THz) communications are promising enablers of ultra-reliable and low-latency communication in next-generation wireless networks. However, the initial access and beam alignment process remains challenging because highly directional beams must be rapidly aligned in a three-dimensional environment. In this paper, we investigate a risk-aware beam alignment framework for UAV-assisted mmWave/THz systems, where user equipment scans a 3D spherical region to detect UAV base stations. The objective is to jointly minimize the expected cell-search latency and its variance while satisfying detection-failure and link-quality constraints. To solve this non-convex optimization problem efficiently, we employ the Lévy Self-Renewable Flow Direction Algorithm (LSRFDA), which combines Lévy-flight exploration with self-renewal to improve convergence robustness. A unified propagation model is adopted to cover both mmWave and THz regimes by incorporating free-space spreading loss and frequency-dependent molecular absorption. Extensive Monte Carlo simulations compare the proposed approach with Particle Swarm Optimization, Random Search, Reinforcement Learning, and PPO-Lagrangian methods. The results show that LSRFDA achieves lower latency, lower latency variation, more reliable detection, and lower energy consumption across a wide range of UAV densities and coverage radii. These outcomes highlight the effectiveness of risk-aware geometric optimization for fast and dependable initial access in UAV-assisted 5G mmWave and 6G THz networks. Full article

This study proposes a novel hardware-impairment-aware convolutional neural network (CNN)-based hybrid precoding scheme for cell-free massive multiple input multiple output (MIMO) systems operating in the terahertz (THz) band under practical constraints of imperfect channel state information (CSI) and transceiver hardware non-idealities. In a realistic THz simulation environment incorporating molecular absorption, phase noise, channel aging, and power consumption models, the proposed CNN precoder demonstrates significant performance improvements over conventional Zero-Forcing (ZF), Kalman, and Minimum Mean Square Error (MMSE) schemes. Quantitative results show that the CNN achieves spectral efficiency gains of 10.67% over Kalman, 14.67% over MMSE, and 70% over ZF for an eight-user scenario. In addition, the CNN-based precoder provides an SNR gain of 0.8 dB over MMSE and 2 dB over ZF. Complexity analysis indicates that the CNN approach is 17% less complex than ZF, 44% less complex than Kalman, and 60% less complex than MMSE. Further analysis of individual impairment effects reveals that the CNN effectively mitigates the compounded degradation caused by hardware distortions and CSI imperfections, exhibiting only a 25% performance loss compared to an ideal hardware baseline. These results establish the proposed data-driven precoder as a robust, computationally efficient, and high-performance solution for reliable and energy-sustainable ultra-high-throughput THz communication networks. Full article

Developing hydrogel dressings that simultaneously achieve robust wet tissue adhesion, mechanical stability, antibacterial activity, and oxidative stress regulation remains challenging. In this study, a dual-network poly (thioctic acid)/ammonium glycyrrhizinate (PTA/AG) hydrogel was developed through thermally induced ring-opening polymerization (ROP) of TA and sodium thioctate (TA-Na) to form a primary network, followed by the formation of an AG-driven secondary network during cooling. TA-Na improved the aqueous processability of TA, while the AG secondary network reinforced the stability of the PTA primary network. The resulting hydrogel exhibited a crossover strain of 454% and a wet adhesion strength of up to 16.37 kPa on porcine skin. In addition, the hydrogel showed strong antibacterial activity against S. aureus (>99%), high cytocompatibility (>95% cell viability), and effective free-radical-scavenging activity (>77% scavenging of both DPPH and ABTS radicals). Notably, the hydrogel exhibited effective intracellular antioxidant activity, reducing ROS levels to near those of the control group and increasing SOD activity by approximately 13-fold and the GSH/GSSG ratio by 97.83% relative to the H₂O₂ group. Overall, the PTA/AG hydrogel is a promising candidate for multifunctional wound dressing applications. Full article

Cell-free massive multiple-input multiple-output (CF-mMIMO) systems have emerged as a promising architecture for beyond-5G wireless networks because they can provide user-centric coverage, improved spectral efficiency, and reduced cell-boundary limitations. However, dynamic downlink power allocation remains challenging due to user mobility, time-varying channel conditions, interference coupling, and the need to maintain Quality of Service (QoS) under practical transmit-power constraints. This paper proposes a Deep Hybrid Intelligent (DHI) framework for dynamic downlink power allocation in CF-mMIMO systems. The proposed framework integrates Soft Actor–Critic (SAC) reinforcement learning with three power-control strategies: DHI-Max-Min, DHI-Max-Product, and DHI-Max-Sum-Rate. The SAC agent learns adaptive power-allocation policies from the network state, while L-BFGS-B refinement is applied to the Max-Product and Max-Sum-Rate strategies to improve the power-allocation decisions under bounded transmit power. The framework is evaluated using a CF-mMIMO scenario with 64 access points and 32 pieces of user equipment distributed over a 1000 × 1000 m² area. The simulation results show that DHI-Max-Sum-Rate achieves the highest sum spectral efficiency, while DHI-Max-Min provides the strongest QoS-oriented performance with a QoS satisfaction rate of 93.75%. In addition, DHI-Max-Product and DHI-Max-Sum-Rate achieve mean computational times of 0.0690 s and 0.0696 s, respectively, compared with 0.63 s for the DDPG benchmark. These results demonstrate that the proposed DHI framework provides an adaptive and computationally efficient solution for QoS-aware downlink power allocation in dynamic CF-mMIMO networks. Full article

Cell culture is foundational to biomedical advancements, yet its widespread clinical and practical distribution is severely constrained by the high infrastructural costs of cryogenic logistics and the physical stressors of liquid-phase transit. Herein, we propose a proof-of-concept cryogen-free cell transportation strategy leveraging a rapid reversible thermoresponsive collagen (RRTC) hydrogel regulated by simulated body fluid (SBF). Operating via temperature-driven physical network assembly and disassembly rather than chemical crosslinking or chemical modifications, the RRTC system undergoes a rapid sol-to-gel transition within 60 s at 37 °C for efficient cell encapsulation, and completely reverses to a free-flowing sol state within 60 s at 4 °C to facilitate enzyme-free, non-destructive cell retrieval. Using L929 fibroblasts as a standardized benchmarking cell model, the biophysical protection of the matrix was systematically evaluated under both static simulated transit (48 h and 120 h) and real-world trans-city courier transportation (an approximate 50 h round trip via SF Express) within a passively temperature-shield configuration. The SBF-regulated 3D physical confinement successfully shielded cells from manual handling, multi-axis shipping vibrations, and environmental thermal fluctuations. Post-transport evaluations demonstrated that the encapsulated cells maintained a high viability above 90% and a stable recovery yield of approximately 78%, while exhibiting robust subsequent 2D re-adhesion and sustained re-culture capacity. This thermoresponsive matrix provides a potential matrix for short-term cryogen-free cell transportation and post-transport recovery, while further studies using additional cell types, longer transportation periods, and functional assays are required to evaluate its broader applicability. Full article

Background: Immune checkpoint inhibitor–tyrosine kinase inhibitor combinations represent a standard first-line option for metastatic renal cell carcinoma (mRCC). However, patients enrolled in pivotal trials often differ from those treated in routine practice. We report real-world outcomes of pembrolizumab plus axitinib within the Campania Oncology Network. Methods: We conducted a multicenter retrospective study including consecutive treatment-naïve mRCC patients who received first-line pembrolizumab plus axitinib between January 2021 and November 2023 across eight regional centers. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate (ORR) and safety. Results: A total of 117 patients were included. IMDC risk was favorable in 19.6%, intermediate/poor in 65%, and unknown in 15.4%. Median age was 59 years, and 53.8% had ECOG performance status ≥ 1. Clear-cell histology accounted for 87.2% of cases; brain metastases were present in 36%. After a median follow-up of 12.8 months, median PFS was 15.1 months (95% CI 9.6–NR), and median OS was not reached. ORR was 27.3%, with a disease control rate of 79.5%; patients with non-clear-cell histology showed an ORR of 41.7%. Disease progression was the main cause of treatment discontinuation (49%), while adverse events (AEs) led to discontinuation in 6% of cases. Grade ≥3 AEs occurred in 14% of patients. Most toxicities were grade 1–2, including diarrhea (23.9%), asthenia (18%), hypothyroidism (12.8%), and hypertension (9.4%). Grade 1–2 AEs were significantly more frequent in females compared with males (57.6% vs. 35.7%, p = 0.05). Conclusions: In this consecutive regional cohort, pembrolizumab plus axitinib showed clinically relevant disease control, although ORR was lower than in pivotal trials. Performance status emerged as a key prognostic factor. Real-world data from oncology networks may support personalized first-line treatment decisions in mRCC. Full article