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Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.

Sepsis is a life-threatening condition manifested by concurrent inflammation and immunosuppression. Ubiquitin-specific peptidase 9, X-linked (USP9x), is a USP domain-containing deubiquitinase which is required in T-cell development. In the present study, we investigate whether USP9x plays a role in hepatic CD8 + T-cell dysfunction in septic mice. We find that CD8 + T cells are decreased in the blood of septic patients with liver injury compared with those without liver injury, the CD4/CD8 ratio is increased, and the levels of cytolytic factors, granzyme B and perforin are downregulated. The number of hepatic CD8 + T cells and USP9x expression are both increased 24 h after cecal ligation and puncture-induced sepsis in a mouse model, a pattern similar to liver injury. The mechanism involves promotion of CD8 + T-cell dysfunction by USP9x associated with suppression of cell cytolytic activity via autophagy inhibition, which is reversed by the USP9x inhibitor WP1130. In the in vivo studies, autophagy is significantly increased in hepatic CD8 + T cells of septic mice with conditional knockout of mammalian target of rapamycin. This study shows that USP9x has the potential to be used as a therapeutic target in septic liver injury.

Excessive non-grain production of farmland (NGPF) seriously affects food security and hinders progress toward Sustainable Development Goal 2 (Zero Hunger). Understanding the spatial distribution and influencing factors of NGPF is essential for food and agricultural management. However, previous studies on NGPF identification have mainly relied on high-cost methods (e.g., visual interpretation). Furthermore, common machine learning techniques have difficulty in accurately identifying NGPF based solely on spectral information, as NGPF is not merely a natural phenomenon. Accurately identifying the distribution of NGPF at a grid scale and elucidating its influencing factors have emerged as critical scientific challenges in current literature. Therefore, the aims of this study are to develop a grid-scale method that integrates multisource remote sensing data and spatial factors to enhance the precision of NGPF identification and provide a more comprehensive understanding of its influencing factors. To overcome these challenges, we combined multisource remote sensing images, natural/anthropogenic spatial factors, and the maximum entropy model to reveal the spatial distribution of NGPF and its influencing factors at the grid scale. This combination can reveal more detailed spatial information on NGPF and quantify the integrated influences of multiple spatial factors from a microscale perspective. In this case study of Foshan, China, the area under the receiver operating characteristic curve is 0.786, with results differing by only 1.74% from the statistical yearbook results, demonstrating the reliability of the method. Additionally, the total error of our NGPF identification result is lower than that of using only natural/anthropogenic information. Our method enhances the spatial resolution of NGPF identification and effectively detects small and fragmented farmlands. We identified elevation, farming radius, and population density as dominant factors affecting the spatial distribution of NGPF. These results offer targeted strategies to mitigate excessive NGPF. The advantage of our method lies in its independence from negative samples. This feature enhances its applicability to other cases, particularly in regions lacking high-resolution grain crop-related data. [ABSTRACT FROM AUTHOR]

This study aims to determine the effects of Tuina on a rat KOA model, focusing on the role of chondrocyte apoptosis and autophagy mechanisms. Methods: KOA was induced in rats by intra-articular injection of L-cysteine-activated papain into the right knee. Thirty-six male Sprague Dawley (SD) rats were randomly divided into blank, model control, Tuina, and positive drug groups. Paw withdrawal threshold tests, knee joint swelling, and passive range of motion assessed knee behavior. Cartilage tissue cytology, cytokine contents, and the mRNA and protein expression of PI3K/AKT/mTOR signaling pathway components were analyzed using HE and TUNEL staining, ELISA, RT-qPCR, and Western blotting, respectively. In addition, we used machine learning methods to conduct a secondary analysis of the dataset from the in vivo experiments in rats to verify the findings. Results: Tuina significantly relieved pain and joint swelling, and improved range of motion. Staining showed reduced articular cartilage destruction and apoptosis. Tuina reduced the serum levels of IL-1β, IL-17, MMP-3, and MMP-13. Tuina downregulated Bax, ULK1, Beclin-1, LC3-II/I and upregulated PI3K, AKT, mTOR, and BCL-2 in cartilage tissue. The machine learning results indicated an 83.33% accuracy for the prediction model, remaining stable through both uni- and multivariate analyses. Tuina yielded the best comprehensive efficacy on KOA as well as better rat behavior and PI3K/AKT/mTOR signaling pathway improvement effect than positive drugs, while its cytokine-reducing ability was comparable to that of positive drugs. Conclusion: Tuina can alleviate cartilage tissue injury in KOA, relieve inflammation, and reduce chondrocyte apoptosis and autophagy, the underlying mechanisms of which may be associated with activation of the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

The resilience-based systemic safety analysis paradigm offers a scientific and practical approach to managing the operational safety of modern highway tunnels. To gain a deeper understanding of resilience, the authors review advancements in resilience research across various engineering disciplines globally and distill two key insights: (1) resilience is a comprehensive capability that emphasizes performance throughout the entire process, and (2) it comprises distinct attributes, namely robustness, redundancy, resource adequacy, and rapid response. Recognizing the limitations of traditional risk analysis methods in the context of highway tunnel operations, the study underscores the necessity and value of incorporating resilience into safety management frameworks. Operational resilience in highway tunnels is defined as "the ability to prevent, resist, adapt to, and recover from actual or potential disruptions that may hinder the normal operation and traffic flow of highway tunnels". Furthermore, the concepts of full-stage performance, dynamic evolution, and objective quantification are analyzed, leading to the development of a preliminary conceptual framework. To enhance tunnel operational resilience, a strategy is proposed based on four functions: perception, response, learning, and prediction, along with preliminary measures to enhance resilience. In particular, in addressing fire risk, intelligent technologies and systems are highlighted, including advanced fire detection, fire prediction tools, and flexible entry blocking mechanisms for tunnels. Future research on highway tunnel operational resilience is expected to deepen, providing practical guidance and promoting the scientific and systematic development of tunnel safety management. The ultimate goal is to create a safer, more efficient, and sustainable tunnel operation system through the establishment of a comprehensive theoretical framework. [ABSTRACT FROM AUTHOR]

In order to effectively solve the double water hazard problem of the roof and floor aquifer in the coalfield of the north of the Yellow River, we takes the treatment of water disaster in Shandong Energy Qiuji Coal Mine as an example, which based on the analysis of mine hydrogeology and water disaster characteristics, determines the concept of water control in advance, regional coordination, grouting where water leakage occurs and safety promotion. We put forward the technology of limestone water disaster control with “roof and floor injection and curtain grouting”. The “plum blossom” and “upper and lower strata penetration” drilling methods are used to effectively explore karst fissures and concealed water channel in aquifers, and through the real-time observation technology of equidistant directional drilling and hydrogeology borehole to ensure the precise grouting. By the end of 2018, 19 main holes and 95 branch holes were constructed in the grouting project, which accumulated 64 183.74 meters, 329 035 tons of cement and 24 845 tons of coal ash. The results showed that the water pressure of limestone decreased obviously after grouting and gushing water volume was less than 10 cubic meters per hour, which achieved the safety exposing and pilot production in coalface. It is pointed out that the key technology of directional grouting in the north of the Yellow River coalfield can effectively seal karst fissure and concealed water channel in aquifers and achieve high quality precision grouting for karst fissure and water channel of aquifers. This technology provides safety guarantee for the two hundred million tons of coal of the lower coal group, and also provides reference for the prevention and control of similar water disasters in the north of the Yellow River coalfield of China.resources

Background and Aims The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. Methods The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. Results Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase–DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. Conclusions ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation. [ABSTRACT FROM AUTHOR]