Search Results (3,161)

Background: Transmissible gastroenteritis virus (TGEV) is a highly pathogenic porcine coronavirus that causes severe gastrointestinal damage in piglets. However, how TGEV affects host iron homeostasis, oxidative stress, and the ferroptosis process remains unclear. This study aimed to investigate the effects of TGEV infection on cellular iron metabolism, oxidative damage, and lipid peroxidation-mediated ferroptosis, as well as to evaluate the potential therapeutic role of retinoic acid (RA). Methods: Using an intestinal epithelial cell model of TGEV infection, we assessed key regulators of iron handling, oxidative stress, lipid peroxidation, and ferroptosis. The expression of ferroportin (FPN) and ferritin (FTH/L) and the activity of the p62–NRF2–GPX4/HO-1 antioxidant axis were analyzed, and the effects of exogenous RA treatment on these endpoints were examined. Results: TGEV infection disrupted cellular iron homeostasis by downregulating the expression of ferroportin (FPN) and ferritin (FTH/L), leading to the accumulation of intracellular free iron, which in turn induced the generation of a large amount of reactive oxygen species (ROS) and ultimately triggered ferroptosis in intestinal epithelial cells. Additionally, TGEV infection significantly inhibited the p62-NRF2-GPX4/HO-1 antioxidant signaling pathway, further exacerbating the ferroptosis process. Conclusions: This study reveals that ferroptosis is a key pathological mechanism in TGEV-induced intestinal injury and demonstrates that RA exerts a therapeutic effect by regulating iron metabolism and activating the p62-NRF2-GPX4/HO-1 signaling pathway. These findings provide new theoretical insights for potential intervention strategies targeting virus infection-associated ferroptosis and intestinal damage. Full article

This study evaluated the potential protective effect of a synthesized self-antibacterial nano-hydroxyapatite (nano-HA) toothpaste against erosive changes in the enamel surface induced by a cola-based soft drink, based on a qualitative scanning electron microscopy (SEM) study, in comparison with conventional fluoride toothpaste. Thirty extracted human premolars were sectioned to obtain enamel specimens and randomly assigned into a control group and experimental groups in which fluoride or synthesized nano-HA toothpaste was applied either before or after cola exposure (n = 5 per group). Enamel surface morphology was qualitatively assessed using SEM, and surface roughness (Ra) was estimated using a semi-quantitative approach based on SEM image analysis using ImageJ software. Antibacterial activity was evaluated using the agar diffusion method to explore the potential additional benefits of the synthesized self-antibacterial nano-HA formulation. SEM observations showed that, after cola exposure, specimens treated with nano-HA exhibited less surface erosion than fluoride-treated groups. Post-treatment with nano-HA results in a denser and more uniform surface layer with fewer structural defects. Similarly, enamel treated with nano-HA after cola exposure showed a statistically significant reduction in surface roughness compared with the fluoride group (p < 0.05). These findings suggest that nano-HA provides greater protective effects against acid-induced enamel surface erosion. Furthermore, nano-HA indicated potential antibacterial activity against S. aureus and E. coli. Overall, nano-HA toothpaste provided enhanced protection against acid-induced enamel erosion with additional antibacterial effects. Full article

Initial excavation-induced damage may alter water-driven weakening and failure in bedded shale, yet direct experimental evidence from comparable loading–hydration routes remains limited. In this study, uniaxial compression tests with acoustic emission (AE) monitoring were conducted on bedded shale from the Longmaxi Formation in the Sichuan Basin, China, under two routes, i.e., direct saturation (DS) and pre-damage followed by saturation (PDRS), across seven bedding orientations from 0° to 90°. Pre-damage was introduced by loading–unloading to 0.6 of the orientation-dependent peak strength, producing measurable defects and reducing P-wave velocity by an average of 1.23% while preserving the overall anisotropic pattern of wave propagation. Compared with DS, PDRS caused clear mechanical deterioration, with mean reductions of 37.63% in peak strength and 31.14% in elastic modulus. Both routes retained pronounced bedding-angle dependence, although the locations of minimum strength and stiffness differed between them. AE activity in the PDRS group generally initiated earlier and accumulated more persistently before peak stress. RA–AF analysis showed that tensile-like cracking dominated across all bedding orientations in PDRS, whereas the DS group exhibited stronger orientation-dependent variation in cracking mode. The b-value range was also narrower in PDRS than in DS, indicating reduced dispersion of event-size statistics among orientations. Macroscopically, failure evolved from more distributed multi-crack and mixed-mode patterns in DS to more localized dominant-fracture failure with reduced branching in PDRS. Overall, the results suggest that pre-damage before saturation changes the subsequent weakening and fracture development of bedded shale during reloading. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune cell associations and continuous joint damage. Personalized clinical assessment and treatment options for RA remain hindered by a precision gap due to an inability to precisely match current global treatment strategies to individual molecular and spatial disease profiles. Recent advances in spatial transcriptomics and proteomics offer unprecedented opportunities to map molecular heterogeneity and spatial heterogeneity within RA tissues by identifying immune microenvironments activated during the disease, thus enabling precise therapeutic targeting. These techniques address the precision gap in RA by identifying distinct pathogenic subpopulations and cellular niches, providing insights into the biomolecules that possess significant therapeutic responses and are involved in disease progression. This review synthesizes recent findings demonstrating how spatial omics technologies, including spatial transcriptomics and proteomics, together with artificial intelligence, are transforming precision rheumatology. Full article

Groundwater used for drinking in settlements located near decommissioned uranium mining facilities may contain elevated naturally occurring radioactive materials, posing long-term public-health concerns. The purpose of this study was to evaluate the radiological quality of groundwater used for drinking in the Saumalkol settlement by applying gross alpha–beta screening and isotope-specific analysis of ²²⁶Ra and ²²⁸Ra to identify the main contributors to groundwater radioactivity and estimate the associated radiation dose from water consumption. Groundwater samples were analyzed using gross alpha–beta screening and isotope-specific determination of ²²⁶Ra and ²²⁸Ra by radiochemical separation and low-background counting, and ingestion doses were estimated using international dose coefficients. Gross alpha activity averaged 2.26 ± 0.96 Bq/L, with most samples exceeding the WHO screening value of 0.5 Bq/L, while gross beta activity averaged 0.65 ± 0.17 Bq/L. Mean activity concentrations of ²²⁶Ra and ²²⁸Ra were 0.17 ± 0.03 Bq/L and 1.47 ± 0.9 Bq/L, respectively, with significantly higher ²²⁸Ra in deep boreholes and a systematic predominance of ²²⁸Ra over ²²⁶Ra (p < 0.05), indicating a thorium-controlled geochemical signature in fractured crystalline aquifers. The estimated annual committed effective ingestion dose from radium isotopes was 0.46 mSv, exceeding the reference level of 0.1 mSv for drinking-water exposure. These findings demonstrate that groundwater radioactivity in Saumalkol is dominated by radium from the thorium series and highlight the need for sustained radionuclide-specific monitoring and targeted water management strategies in uranium-affected regions. Full article

Low-Rank Adaptation (LoRA) has become a widely adopted parameter-efficient fine-tuning (PEFT) technique for large language models (LLMs). LoRA’s benefits stem from its light weight and modular adapters. Standard LoRA applies adapters uniformly across all Transformer layers, implicitly assuming that each layer contributes equally to task adaptation. However, LLMs are found to have internal substructures that contribute in a disproportionate manner. In this work, we provide a theoretical analysis of how LoRA weight updates are influenced by a layer’s activation magnitude. We propose Act-LoRA, a simple activation-guided layer selection strategy for selective Low-Rank Adaptation. We evaluate this strategy for both encoder-only and decoder-only architectures using the GLUE benchmark. Our method achieved a 20% GPUh saving with a 1% drop in GLUE score using DeBERTaV3-Base on a single-instance GPU with 50% less LoRA parameters. It also achieved 2% GPUh savings with a less than 0.15% drop in GLUE score with the Llama-3.1-8B model in Distributed Data Parallel mode with 25% fewer LoRA parameters. Our experiments and analysis show that the compute and memory requirements of LoRA adapters increase linearly with the number of selected layers. We further compare activation-guided selection against gradient-guided importance metrics and show that activation norms yield more stable and reproducible layer rankings across seeds and datasets. Overall, our results demonstrate that activation-guided layer selection is a practical and effective way to improve the efficiency of LoRA fine-tuning, making it immediately compatible with some existing PEFT techniques and distributed training frameworks. Full article

There is cumulative evidence that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can offer cardiovascular protection extending beyond glucose-lowering and weight reduction, but the underlying mechanisms contributing to these effects remain incompletely understood. Modulation of platelet function might contribute to the aforementioned benefits. In the current literature review article, we synthesized available preclinical and clinical data evaluating the effects of GLP-1 RAs on platelet activation and function. Preclinical data indicate that GLP-1 RAs might decrease platelet activation via both GLP-1 receptor-dependent and -independent mechanisms with the involvement of cyclic adenosine monophosphate signaling, increase in nitric oxide bioavailability, and suppression of thromboxane-mediated pathways, particularly under inflammatory or shear-stress conditions. Additionally, clinical studies, despite being limited and heterogeneous, support a reduction in platelet activation markers, even independently of glycemic control or weight loss. However, most of them are characterized by small sample sizes and significant heterogeneity among them. In summary, existing evidence suggests that GLP-1 RAs exhibit potential antiplatelet effects that could contribute to their cardioprotective profile. Larger, well-designed clinical studies are crucial to better understand the clinical importance of platelet modulation by GLP-1 RAs and their potential implications for cardiovascular risk reduction. Full article

Background: Despite the widespread implementation of treat-to-target strategies and modern disease-modifying antirheumatic drugs, a substantial proportion of patients with rheumatoid arthritis (RA) continue to report unmet needs (UNs), defined as a mismatch between patient expectations and symptom burden on the one hand and outcomes achieved with current care on the other. Patient–physician discordance in global assessments may reflect multidimensional influences, including pain mechanisms, psychosocial factors, functional impairment, and communication gaps, extending beyond inflammatory disease activity. Methods: In this cross-sectional study, 133 patients with RA and 57 healthy controls were included. UNs were operationalized as the signed difference between patient global assessment and physician global assessment (ΔPGA–PhGA). Clinical variables, patient-reported outcomes, and Short Form-36 (SF-36) domains were incorporated into two regularized partial correlation network models estimated using the extended Bayesian information criterion graphical least absolute shrinkage and selection operator (EBICglasso). Node centrality indices (strength, signed strength, betweenness, and closeness) were calculated. Network stability was evaluated using 2000 bootstrap resamples and correlation stability (CS) coefficients. Results: In the clinical network, pain intensity demonstrated the highest strength centrality and the strongest direct association with UNs. In contrast, Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) showed no direct association with UNs after accounting for shared variance. In the SF-36-based quality-of-life network, UNs exhibited inverse associations, particularly with perceived health change and role–emotional functioning. Stability analyses indicated acceptable to good robustness (clinical network: CS = 0.59 for edge weights and 0.44 for strength; SF-36 network: CS = 0.59), supporting the reliability of the estimated network structures. Conclusions: UNs in RA are not solely determined by inflammatory disease activity but are embedded within interconnected clinical and psychosocial domains. Pain occupies a structurally central position in the clinical network, whereas perceived health change and emotional role limitations characterize the quality-of-life context of UNs. These findings underscore the importance of multidimensional and patient-centered assessment strategies in RA management. Full article

Background/Aim: This study aimed to evaluate the changes in hematological indices following methotrexate (MTX) initiation and assess their correlation with and predictive value for treatment responses in rheumatoid arthritis (RA) patients. Methods: A retrospective study was conducted on 299 DMARD-naïve RA patients who received MTX monotherapy for 12 weeks. Univariate and multivariate logistic regression identified predictors of remission and low disease activity. Correlation analyses assessed relationships between hematological and disease activity changes. Receiver operating characteristic (ROC) curve analysis evaluated the discriminatory ability of hematological parameters. Results: After 12 weeks of MTX, significant decreases were observed in white blood cell (p = 0.025), neutrophil (p = 0.026), hemoglobin (p = 0.001), and platelet counts (p < 0.001), alongside an increase in red cell distribution width (RDW) (p < 0.001). Multivariate analysis identified only baseline DAS28-CRP (OR: 9826.7, p < 0.001) and CRP (OR: 0.45, p = 0.005) as independent predictors for remission, and baseline swollen joint count, DAS28-CRP, and CRP for LDA. Hematological parameters were not independent predictors. ROC analysis revealed neither baseline values nor changes in hematological indices had satisfactory discriminatory power for remission or LDA. Conclusions: Hematological parameter changes do not serve as robust independent predictors for early treatment response. Clinical disease activity indices remain superior for prognostication in DMARD-naïve patients starting MTX. Full article

Gastrointestinal acute graft-versus-host disease (GI aGvHD) remains a leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Current diagnostic methods rely on invasive procedures with limited sensitivity. While circulating biomarkers have been proposed, little is known about the local transcriptomic landscape within inflamed GI tissue. We performed integrated profiling of mRNA and microRNA expression in colonoscopically resected GI biopsies from n = 8 HSCT patients, including n = 3 with histologically confirmed GI aGvHD and n = 5 without. Using NanoString nCounter technology, we quantified 770 immune-related mRNAs and 799 mature human microRNAs. Differential expression analysis, pathway enrichment, cell type deconvolution, and machine learning–based biomarker prioritisation were conducted to define disease-specific molecular signatures. GI aGvHD was marked by upregulation of inflammatory genes (e.g., IL1B, IL17RA, HLA-DRA) and immune-regulatory microRNAs (e.g., miR-155-3p, miR-223-3p), alongside downregulation of epithelial and anti-inflammatory markers (ST6GAL1, THBS1, miR-1915-3p, miR-145-5p). Enrichment analyses revealed activation of IL2/STAT5, JAK/STAT3, TCR signalling, and antigen presentation pathways. Machine learning identified LCN2, CXCL13, and miR-1269b as top-ranked biomarker candidates. Cell deconvolution showed increased M0 macrophage and decreased dendritic cell signatures in aGvHD tissue. This is the first study to integrate mRNA and microRNA profiling in GI tissue using NanoString technology to characterise the immune and epithelial transcriptomic landscape of aGvHD. Our findings reveal dysregulated immune pathways, altered myeloid cell populations, and novel biomarker candidates, offering tissue-specific insights into disease pathogenesis and potential diagnostic targets. Larger validation studies and functional assays are warranted to confirm clinical utility. Full article

Background: Abnormal activation of the NRF2-cGAS-STING-NF-κB pathway can trigger an inflammatory cascade in rheumatoid arthritis (RA). Curcumin (CUR), a polyphenolic compound extracted from turmeric, possesses anti-inflammatory activity, but whether it can modulate this pathway to ameliorate RA remains unclear. This study aims to elucidate whether CUR inhibits the inflammatory response in synovial fibroblasts (MH7A) by suppressing the NRF2-cGAS-STING-NF-κB signaling cascade. Methods: An RA inflammatory model was constructed by stimulating MH7A cells with 20 ng/mL tumor necrosis factor (TNF). Groups included a control group, a model group, a methotrexate positive control group [MTX(methotrexate), 10 μmol/L], and curcumin treatment groups at varying concentrations (10–100 μmol/L). Cell viability was assessed using the CCK-8(Cell Counting Kit-8) assay. Cell migration and invasion capabilities were evaluated via scratch wound healing and Transwell assays, respectively. Apoptosis was detected by flow cytometry. mRNA and protein expression levels of NRF2(Nuclear factor erythroid 2-related factor 2), cGAS(cyclic GMP-AMP synthase), STING(stimulator of interferon genes), and NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells) were measured using qRT-PCR and Western blot, respectively. Protein localization was determined by immunofluorescence. Results: Compared to the model group (TNF-induced), the cell migration rate in the curcumin (CUR) groups was significantly decreased (p < 0.001), with a particularly marked reduction observed at a concentration of 50 μmol/L. Furthermore, as the concentration of curcumin increased, cell invasion capacity showed a significant dose-dependent decline. The apoptosis rate also significantly decreased with increasing curcumin concentrations, demonstrating a clear concentration-dependent effect. Mechanistically, curcumin treatment significantly upregulated the expression of NRF2 and inhibited the activation of its downstream cGAS-STING-NF-κB signaling pathway. Specifically, both mRNA and protein expression levels of NRF2 were markedly elevated (p < 0.001), while the mRNA and protein levels of cGAS, STING, and NF-κB were all significantly reduced (p < 0.001). Conclusions: Curcumin (CUR) can effectively inhibit the inflammatory response of synovial fibroblasts by activating the expression of NRF2 and subsequently suppressing the cGAS-STING-NF-κB signaling pathway. This study provides a new molecular mechanism target for curcumin in the treatment of RA and offers a theoretical basis for the intervention of autoimmune diseases with natural products. Full article

Background/Objectives: The coexistence of chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2D) poses significant clinical challenges due to overlapping mechanisms of systemic inflammation, oxidative stress, hypoxia, and metabolic dysregulation. Patients with both conditions face higher risks of exacerbations, prolonged hospitalizations, cardiovascular events, and reduced quality of life. This review aims to summarize current evidence on the pathophysiological interplay between COPD and T2D and to evaluate the impact of lifestyle and pharmacologic interventions. Methods: A narrative review of the literature was conducted to evaluate the pathophysiological links between COPD and T2D, assess the effects of pharmacologic and lifestyle interventions, and highlight key gaps and priorities for future research, with an emphasis on integrated, evidence-based management for this high-risk population. Results: Lifestyle interventions, including smoking cessation and structured physical activity, remain foundational to management. Emerging evidence indicates that antidiabetic therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter-2 inhibitors (SGLT-2is), may confer additional pulmonary, metabolic, and cardiovascular benefits. These agents modulate systemic inflammation, oxidative stress, endothelial function, and insulin sensitivity, potentially reducing COPD exacerbations, improving lung function, and enhancing survival. Safety concerns, including glucocorticoid-induced hyperglycaemia and hypoxia-related metabolic complications, underscore the need for careful monitoring and individualized therapy COPD patients. Conclusions: Optimal care requires a multidisciplinary, patient-centred approach integrating pulmonology, endocrinology, primary care, nutrition, and rehabilitation, alongside shared decision-making and patient education. Despite promising findings, critical knowledge gaps remain. Large, well-designed randomized controlled trials and standardized definitions are needed to guide personalized therapeutic strategies. Full article

The increasing reliance of Internet of Things (IoT) applications on low-power wide-area network technologies, particularly Long Range Wide Area Network (LoRaWAN), has amplified the need for security monitoring approaches that go beyond attack-specific signatures and generic traffic anomalies. Existing solutions are often tailored to individual threat scenarios or rely on statistical indicators, which limits their ability to systematically capture protocol-level misuse in an interpretable manner. This paper addresses this gap by proposing a protocol-aware validation methodology based on a Digital Twin abstraction of LoRaWAN communication behavior. The Over-The-Air Activation (OTAA) procedure is modeled as a finite-state machine that encodes expected message sequences, timing constraints, and specification-driven state transitions. Observed network events are continuously evaluated against this formal state model, enabling the identification of protocol-level deviations indicative of anomalous or non-conformant behavior. Illustrative examples include replay behavior, timing inconsistencies, and integrity-related anomalies, although the framework is not limited to predefined attack categories. The results demonstrate that state machine-based Digital Twin provides a structured and extensible foundation for protocol-aware security validation and Security Operation Center (SOC)-oriented telemetry enrichment. In this sense, the presented approach represents a concrete step toward protocol-aware intrusion detection for LoRaWAN networks by establishing a state-synchronized semantic validation layer upon which higher-level detection mechanisms can be built. Full article

Atherosclerosis (AS), a chronic cardiovascular disease, originates from endothelial dysfunction, a process closely linked to cellular energy metabolism. While rosmarinic acid (RA) exhibits protective cardiovascular effects, its precise mechanism against AS remains undefined. This study demonstrates that RA alleviates AS in ApoE^−/− mice, as evidenced by reduced aortic plaques, enhanced CD31 expression, and improved serum NO and ET-levels. Integrating network pharmacology and experimental validation, we identified Aldo-keto reductase family 1 member B1 (AKR1B1) as a direct functional target of RA. Mechanistically, RA downregulated AKR1B1, thereby activating the SIRT3/PFKFB3 axis. In Ox-LDL-induced HUVECs, RA enhanced viability, reduced ROS, and boosted energy metabolism, indicated by elevated ECAR, OCR, and levels of G-6-P, F-6-P, and ATP. Crucially, RA rescued endothelial injury induced by AKR1B1 overexpression via this pathway. Our findings establish that RA protects against AS by directly targeting AKR1B1 to restore endothelial energy homeostasis through the AKR1B1/SIRT3/PFKFB3 signaling axis, offering a novel therapeutic strategy. Full article

Natural compounds are increasingly recognized as valuable sources of pharmacologically active agents for cancer therapy. Among them, plant-derived triterpenoids attract attention due to their structural diversity and broad biological activity. Roburic acid (RA), a tetracyclic triterpenoid, has previously been shown to exert antiproliferative effects in colorectal cancer (CRC) cells with limited cytotoxicity. In the present study, we investigated the cellular mechanisms underlying RA activity in CRC cells, focusing on cell cycle regulation, mitochondrial function, apoptosis, oxidative stress, and DNA integrity. RA treatment markedly suppressed CRC cell proliferation, resulting in G₀/G₁ cell cycle arrest and downregulation of key proliferation markers. Mitochondrial analysis revealed an early reduction in mitochondrial membrane potential (MMP) following RA exposure, indicating mitochondrial dysfunction. Importantly, these effects occurred in the absence of intracellular reactive oxygen species (ROS) generation and without induction of DNA strand breaks, demonstrating a non-pro-oxidant and non-genotoxic profile of RA. Apoptotic features were observed mainly at higher concentrations and after prolonged exposure and were strongly dependent on cell line and assay type. Overall, RA limits CRC cell growth predominantly through cytostatic mechanisms, including cell cycle arrest and mitochondrial modulation, while apoptosis is a secondary, context-dependent response. The lack of oxidative stress and genotoxicity distinguishes RA from many conventional cytotoxic agents and supports its further investigation as a non-genotoxic anticancer compound. Full article