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Abstract Advanced pancreatic ductal adenocarcinomas (PDACs) respond poorly to all therapies, including the first-line treatment, chemotherapy, the latest immunotherapies, and KRAS-targeting therapies. Despite an enormous effort to improve therapeutic efficacy in late-stage PDAC patients, effective treatment modalities remain an unmet medical challenge. To change the status quo, we explored the key signaling networks underlying the universally poor response of PDAC to therapy. Here, we report a previously unknown chemo-induced symbiotic signaling circuit that adaptively confers chemoresistance in patients and mice with advanced PDAC. By integrating single-cell transcriptomic data from PDAC mouse models and clinical pathological information from PDAC patients, we identified Yap1 in cancer cells and Cox2 in stromal fibroblasts as two key nodes in this signaling circuit. Co-targeting Yap1 in cancer cells and Cox2 in stroma sensitized PDAC to Gemcitabine treatment and dramatically prolonged survival of mice bearing late-stage PDAC, whereas simultaneously inhibiting Yap1 and Cox2 only in cancer cells was ineffective. Mechanistically, chemotherapy triggers non-canonical Yap1 activation by nemo-like kinase in 14-3-3ζ-overexpressing PDAC cells and increases secretion of CXCL2/5, which bind to CXCR2 on fibroblasts to induce Cox2 and PGE2 expression, which reciprocally facilitate PDAC cell survival. Finally, analyses of PDAC patient data revealed that patients who received Statins, which inhibit Yap1 signaling, and Cox2 inhibitors (including Aspirin) while receiving Gemcitabine displayed markedly prolonged survival compared to others. The robust anti-tumor efficacy of Statins and Aspirin, which co-target the chemo-induced adaptive circuit in the tumor cells and stroma, signifies a unique therapeutic strategy for PDAC.

Abstract Detecting EGFR mutations in plasma using droplet digital PCR (ddPCR) assay offers a promising diagnostic tool for lung cancer patients. The performance of plasma-based ddPCR assay relative to traditional EGFR mutation testing in tissue biopsies among Asian patients with suspected lung cancer remains underexplored. Consecutive patients admitted for diagnostic workup for suspected lung cancer were recruited. Peripheral blood samples were collected on the same day of tissue biopsies. Tissue samples were subjected to EGFR mutation analysis via real-time PCR, whereas plasma samples were processed for ddPCR assay to evaluate for EGFR mutation status. The tissue re-biopsy rate was 43.8% while 0.7% of patients failed blood taking. Despite repeat biopsy, 15.2% of patients could not achieve histological diagnosis. Of the 202 patients newly diagnosed with lung cancer, EGFR mutations were detected in 13.4% of plasma samples, compared to 44.3% in tissue samples. Plasma ddPCR for EGFR mutations detection were barely detectable in stages I and II non-small cell lung cancer (NSCLC), but the sensitivity was 25.0%, 56.3%, and 75.0% in stages III, IVA, and IVB NSCLC, respectively. Plasma EGFR mutations were highly specific among all stages of lung cancer. Concordance rates of plasma ddPCR assay also rose with more advanced stages, recorded at 41.9% for stages I and II, 71.9% for stage III, 86.3% for stage IV. In stage IV lung cancer, the false negative rate for the plasma ddPCR assay was 34.4%, whereas that for the tissue testing was 19.2% due to insufficient tissue samples. Plasma-based EGFR genotyping using ddPCR is a non-invasive method that offers early diagnosis and serves as a valuable adjunct to tissue-based testing for patients with advanced-stage lung cancer. However, its usefulness is limited in the context of early-stage lung cancer, indicating a need for further research to improve its accuracy in these patients.

Abstract Complex non-local behavior makes designing high efficiency and multifunctional metasurfaces a significant challenge. While using libraries of meta-atoms provide a simple and fast implementation methodology, pillar to pillar interaction often imposes performance limitations. On the other extreme, inverse design based on topology optimization leverages non-local coupling to achieve high efficiency, but leads to complex and difficult to fabricate structures. In this paper, we demonstrate numerically and experimentally a shape optimization method that enables high efficiency metasurfaces while providing direct control of the structure complexity through a Fourier decomposition of the surface gradient. The proposed method provides a path towards manufacturability of inverse-designed high efficiency metasurfaces.

Abstract The Equilibrium Optimiser (EO) has been demonstrated to be one of the metaheuristic algorithms that can effectively solve global optimisation problems. Balancing the paradox between exploration and exploitation operations while enhancing the ability to jump out of the local optimum are two key points to be addressed in EO research. To alleviate these limitations, an EO variant named adaptive elite‐guided Equilibrium Optimiser (AEEO) is introduced. Specifically, the adaptive elite‐guided search mechanism enhances the balance between exploration and exploitation. The modified mutualism phase reinforces the information interaction among particles and local optima avoidance. The cooperation of these two mechanisms boosts the overall performance of the basic EO. The AEEO is subjected to competitive experiments with state‐of‐the‐art algorithms and modified algorithms on 23 classical benchmark functions and IEE CEC 2017 function test suite. Experimental results demonstrate that AEEO outperforms several well‐performing EO variants, DE variants, PSO variants, SSA variants, and GWO variants in terms of convergence speed and accuracy. In addition, the AEEO algorithm is used for the edge server (ES) placement problem in mobile edge computing (MEC) environments. The experimental results show that the author’s approach outperforms the representative approaches compared in terms of access latency and deployment cost.

Abstract Type 2 diabetes (T2DM) patients are at high risk for non-alcoholic fatty liver disease (NAFLD). Studies show SVD3 and dietary inflammatory index (DII) are associated with NAFLD. It’s unknown if they interact in T2DM patients with NAFLD. We collected data from 110 hospitalized T2DM patients, measured physiological and biochemical indicators, conducted dietary surveys, and converted data into DII and NFS, FIB-4, and BARD indices. We used logistic regression, mediation effect analysis, and moderation effect analysis to explore the relationship between DII and SVD3 with NAFLD and liver fibrosis in T2DM patients. DII was not significant in either NAFLD incidence in T2DM patients or liver fibrosis in NAFLD patients. SVD3 was positively correlated with NAFLD incidence in T2DM patients, but this correlation became insignificant as DII increased towards pro-inflammation. SVD3 is positively correlated with NAFLD incidence in T2DM patients, but this correlation becomes less significant as DII increases towards pro-inflammation.

Abstract Background and purpose We aimed to investigate the association between critical perfusion delay and poor outcome among recanalized stroke patients with anterior large-vessel occlusion, and to use pretreatment hypoperfusion biomarkers on CT to predict futile recanalization even after successful thrombectomy. Methods An ischemic region with time-to-maximum (Tmax) > 12s–10s was defined as critical hypoperfusion, Tmax > 8s as moderate hypoperfusion, and hypoperfusion intensity ratio (HIR, volumetric ratio of Tmax > 10s / Tmax > 6s) represented for severity of critical hypoperfusion and rCBF 10s and > 12s (P = 0.032 and 0.008, respectively), a larger volume of ischemic core (P = 0.011) and a higher HIR (P = 0.002) than those patients achieving good outcomes. In the univariable analysis, a lower HIR (OR, 0.008; 95%CI, 0.001–0.254, P = 0.006) was associated with favorable outcome. The volume size of Tmax > 12s was significantly and positively correlated with the size of ischemic core. A HIR value higher than 0.491 might predict a futile recanalization and poor outcome (AUC = 0.701). Conclusions The critical hypoperfusion biomarkers on CTP could be useful in triaging endovascular treatment and identifying stroke patients at risk of futile recanalization.

Colorectal cancer is a heterogeneous disease of the intestinal epithelium characterized by the accumulation of genetic mutations and the dysregulation of immune responses. The occurrence of colorectal cancer is the result of a combination of environmental, genetic and other factors. Among environmental factors, dietary factors are closely related to the occurrence of colorectal cancer. Dietary factors play an important role in regulating the intestinal microbiota. In addition, the composition and metabolism of the intestinal microbiome are important contributors to the development of colorectal cancer. Specific intestinal microorganisms such as Fusobacterium nucleatum have been shown to be closely correlated with the occurrence of colorectal cancer. Regulating gut microbiota has emerged as a potential means of preventing and treating colorectal cancer. In order to provide a theoretical reference for the clinical treatment of colorectal cancer, this article reviews the intervening effects of probiotics, next-generation probiotics and their metabolites on colorectal cancer, with a focus on the current status of research on the biological effects of various metabolic secretion products of probiotics, including cell-free supernatants, extracellular polysaccharides, short-chain fatty acids, bacteriocins, bacterial enzymes, bile acids and tryptophan metabolites on colorectal cancer.

Abstract This paper investigates the application of Fourier image enhancement combined with Convolutional Neural Networks (CNNs) for detecting cracks in concrete structures. Fourier enhancement is used to preprocess crack images, improving their clarity and reducing noise, which in turn enhances the performance of the CNN in accurately classifying cracks. The results demonstrate that this combination improves the classification accuracy, with the enhanced images achieving a higher accuracy compared to non-enhanced images. Additionally, the study examines the effects of this preprocessing on CNN training time. However, accuracy varies depending on the dataset used, with one dataset reaching a maximum accuracy of 95% after enhancement. These findings highlight the potential of using frequency-domain image enhancement techniques in conjunction with deep learning models for structural health monitoring.

Nitrile rubber latex was prepared by conventional emulsion polymerization combined with low-temperature batch polymerization process, the latex was hydrogenated with self-made ruthenium catalyst, and the influence of catalyst amount and hydrogen pressure on the hydrogenation effect of nitrile rubber latex was systematically studied. The results showed that the average particle size of the prepared nitrile rubber latex was 69.13 nm, and the particle size of the latex remained basically unchanged and the latex remained stable before and after hydrogenation. The higher the hydrogen pressure was, the better the catalytic hydrogenation effect was. When the mass fraction of catalyst was 0.017 5%, degree of hydrogenation of the product was more than 99% and no gel was obtained.

Rhizosphere microbial communities are believed to be vital in the adaption of dominant plants to strong waterlogging stress in the water-level-fluctuation zone (WLFZ). However, limited knowledge is available on their patterns in the WLFZ under distinct waterlogging stresses. Here, rhizosphere and non-rhizosphere bacterial and fungal communities derived from two typical dominant plants (Rumex acetosa L. and Oxybasis glauca) in the WLFZ of Three Gorges Reservoir, China were analysed through high-throughput sequencing. A total of 63 phyla, 173 classes, 259 orders, 287 families and 518 genera of bacteria, as well as 15 phyla, 50 classes, 124 orders, 265 families and 652 genera of fungi were detected in soils with different waterlogging stress intensities. The most dominant bacterial and fungal phyla in each sample are Proteobacteria and Ascomycota, respectively. Bacteria and fungi in soil may increase their microbial ɑ diversity under the intensity of waterlogging stress to cope with this stress. LEfSe analysis showed that the impact of waterlogging stress on fungal community structure in soil is more prominent than that on bacteria. Key fungal biomarkers can be found in each soil sample, but in many samples, key bacterial biomarkers cannot be found. The metabolic pathways related to aerobic respiration type I and de novo biosynthesis of adenosine ribonucleotides dominate in the microbial community. Redundancy analysis revealed that the structure of rhizosphere microbial communities in different plants is significantly influenced by environmental factors. This study provides a theoretical basis for understanding the relationship between plants and their second genome (rhizosphere microorganisms) in extreme habitats, such as the WLFZ of large reservoirs.

Abstract As frontline cells, the precise recruitment of neutrophils is crucial for resolving inflammation and maintaining the homeostasis of the organism. Increasing evidence suggests the pivotal role of neutrophil chemotaxis in cancer progression and metastasis. Here, we collected clinical data and peripheral blood samples from patients with tumours to examine the alterations in the neutrophil quantity and chemotactic function using the Cell Chemotaxis Analysis Platform (CCAP). Transcriptome sequencing data of pan-cancer were obtained from The Cancer Genome Atlas (TCGA). Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, we selected a total of 29 genes from 155 neutrophil- and chemotaxis-related genes to construct the ChemoScore model. Meanwhile, nomogram-based comprehensive model was established for clinical application. Furthermore, immunofluorescence (IF) staining was employed to assess the relationship between the neutrophils infiltrating and the survival outcomes of tumours. In this observational study, the chemotactic function of neutrophils was notably diminished in patients. The establishment and validation of ChemoScore suggested neutrophil chemotaxis to be a risk factor in most tumours, whereby higher scores were associated with poorer survival outcomes and were correlated with various immune cells and malignant biological processes. Moreover, IF staining of tumour tissue substantiated the adverse correlation between neutrophil infiltration and the survival of patients with lung adenocarcinoma (P = 0.0002) and colon adenocarcinoma (P = 0.0472). Taken together, patients with tumours demonstrated a decrease in chemotactic function. ChemoScore potentially prognosticates the survival of patients with tumours. Neutrophil chemotaxis provides novel directions and theoretical foundations for anti-tumour treatment.

Abstract Background Recent studies have established a correlation between ADAMTSL2 (ADAMTS-like 2) and the development of various cancers. This study aims to conduct a comprehensive pan-cancer analysis in 37 cancer types and investigate its potential role in colon and rectal adenocarcinoma (COADREAD). Method Pan-cancer and mutation data were sourced from The Cancer Genome Atlas (TCGA) database and analyzed using Sangerbox analysis platform. We explored the expression patterns and prognostic implications of ADAMTSL2, and investigated its relationships with tumor heterogeneity, stemness, immune checkpoint genes, immune cell infiltration, RNA modifications, and mutational profiles across different cancers. Additionally, with Ethics Committee approval, we conducted immunohistochemical (IHC) analysis on 120 COADEAD samples to evaluate ADAMTSL2 expression and its association with clinicopathological parameters. Results ADAMTSL2 expression was positively correlated with the hazard ratio of OS, DSS, DFI and PFI for ESCA and COADREAD. A negative correlation was observed between ADAMTSL2 expression and NEO levels in COAD. Gene alterations in ADAMTSL2 were observed, with a mutation frequency of 5.0% in COAD. There is a significant correlation between ADAMTSL2 expression and immune cell infiltration in a variety of cancers. The expression level of ADAMTSL2 protein was associated with T stage, N stage, M stage (p

Abstract Achieving near-zero-wear remains a major challenge in mechanical engineering and material science. Current ultra-low wear materials are typically developed based on the self-consumption strategy. Here, we demonstrate a new self-repairing approach to achieve near-zero-wear. We find that the WB4-βB/WC tribo-pair has a low wear rate of 10−8 mm3 N−1 m−1 in low vacuum conditions, under a maximum Hertzian contact stress of 2.23 GPa over 1 × 105 friction cycles. Additionally, we observe an abnormal wear phenomenon after 5 × 104 friction cycles, characterized by an increase in the dimensions of the tribo-pair. This near-zero-wear mechanism is attributed to the synergistic action of the super-hard WB4-βB substrate and the self-repairing tribo-oxide layer. This research provides a new approach for advancing wear-resistant materials and enhancing material longevity.

Background/purpose: Oral submucous fibrosis (OSF) is a condition characterized by inflammation and excessive collagen deposition, which has been identified as a potentially malignant disorder. Recently, several microRNAs (miRNAs) have been shown to be implicated in various disorders associated with fibrosis. However, how these miRNAs modulate OSF development is poorly understood. Therefore, the study aimed to identify the specific miRNAs that contribute to the progression of OSF and to investigate their molecular mechanisms in promoting fibrosis. Materials and methods: The expression and clinical significance of potential pro-fibrosis miRNA in the OSF cohort and primary buccal mucosal fibroblasts were confirmed through RNA sequencing and qRT–PCR. Luciferase reporter activity assay, miRNA mimic or inhibitor, and short-hairpin RNA silencing were used to elucidate the molecular mechanism of miRNA. Transwell migration, collagen contraction, and reactive oxygen species (ROS) generation detection were used to investigate the effects of this mechanism on the myofibroblast phenotype and cellular pro-fibrosis capacity. Results: This study demonstrated that miR-190a was overexpressed in fibrotic buccal mucosal fibroblasts (fBMFs). Transfecting fBMFs with miR-190a inhibitor resulted in reduced cell migration, collagen gel contraction, ROS generation, and expression of fibrotic markers. Furthermore, miR-190a exerted this pro-fibrosis property by direct binding to its target, Krüppel-like factor 15 (KLF15). The results also indicated that the aberrant upregulation of miR-190a, in turn, downregulated the expression of KLF15, which resulted in the activation of myofibroblast. Conclusion: Our findings demonstrated that miR-190a was involved in myofibroblast activation, suggesting that targeting the miR-190a/KLF15 axis may be a feasible approach in the therapy of OSF.

Objective(s): Hepatic ischemia-reperfusion (HIR) is a severe process in pathophysiology that occurs clinically in hepatectomy, and hepatic transplantations. The present study aimed to investigate the effect of PKC θ deletion against HIR injury and elucidate its mechanism in pathophysiology.Materials and Methods: HIR injury was induced in wild-type and PKC θ deletion mice treated with or without heme. The ALT and AST levels were determined to evaluate liver function. HIR injury was observed via histological examination. Oxidative stress and inflammatory response markers, and their signaling pathways were detected.Results: The study found that PKC θ knockout decreased serum AST and ALT levels when compared to the WT mice. Furthermore, heme treatment significantly reduced the ALT and AST levels of the PKC θ deletion mice compared with the untreated PKC θ deletion mice. PKC θ deletion markedly elevated superoxide dismutase activity in the liver tissue, reduced malondialdehyde content in the tissue, and the serum TNF-α and IL-6 levels compared with the WT mice. Heme treatment was observed to elevate the activity of SOD and reduced MDA content and serum of TNF-α and IL 6 in the PKC θ deletion animals. Meanwhile, heme treatment increased HO-1 and Nrf 2 protein expression, and reduced the levels of TLR4, phosphorylated NF-κB, and IKB-α.Conclusion: These findings suggested that PKC θ deletion ameliorates HIR, and heme treatment further improves HIR, which is related to regulation of PKC θ deletion on Nrf 2/HO-1 and TLR4/NF-κB/IKB α pathway.

Abstract The evolution process of regional space between coastal and interior areas is a direct manifestation of the theory of regional economic development imbalance. Previous research has neglected the impacts of population, and economic factor flows on the balance of regional development between coastal and interior areas. By constructing global coastal-interior regional population-economic panel data and a threshold effect model, this study explored regional development imbalance on the largest scale between global coastal and interior areas. The results indicated that the global population is unevenly distributed across coastal and interior areas. Global coastal areas (accounting for 18.43% of the world’s landmass) are occupied by ~52.8% of the global population; meanwhile, ~23% of the global population is concentrated in the ‘near region’ subtropical zone extending from 10° to 30° north and south in latitude. The economic pattern between global coastal and interior areas has become more balanced, and the per capita GDP gap between the two sub-regions has decreased from 2.08 times to 1.78 times during the study period (2000 to 2018). Nevertheless, the evolutionary process of population factors lags behind that of economic factors. Apart from Africa, the development gap of intercontinental coastal and interior areas has been converging to varying degrees. Adjusting regional per capita income levels and population-economic density can promote balanced development between coastal and interior areas both globally and across continents. These findings may contribute to the implementation of effective policies for spatial balance and sustainable development in coastal and interior areas across multiple spatial scales. This study extends the theoretical research on uneven regional growth and provides a foundation for further research to achieve the goals of the UN 2030 Agenda for Sustainable Development.

Abstract Background This study assessed the global trends and burden of severe chest injury, including rib fractures, lung contusions, and heart injuries from 1990 to 2019. Herein, we predicted the burden patterns and temporal trends of severe chest injuries to provide epidemiological evidence globally and in China. Methods In our analysis, the age-standardized incidence rate (ASIR), prevalence rate (ASPR), and years lived with disability rate (ASYR) of severe chest injury were analyzed by gender, age, sociodemographic index, and geographical region between 1990 and 2019 using data from the Global Burden of Disease study 2019. Trends were depicted by calculating the estimated annual percentage changes (EAPCs). The impact of age, period, and cohort factors was assessed using an Age-Period-Cohort model. Autoregressive integrated moving average (ARIMA) model was employed to predict severe chest injury trends from 2020 to 2050. Results In 2019, the global number of severe chest injury cases reached 7.95 million, with the highest incidence rate observed in Central Europe (209.61). Afghanistan had the highest ASIRs at 277.52, while North Korea had the lowest ASIRs at 41.02. From 1990 to 2019, the Syrian Arab Republic saw significant increases in ASIR, ASPR, and ASYR, with EAPCs of 10.4%, 9.31%, and 10.3%, respectively. Burundi experienced a decrease in ASIR with an EAPC of − 6.85% (95% confidence interval [CI] − 11.11, − 2.37), while Liberia’s ASPR and ASYR declined with EAPCs of − 3.22% (95% CI − 4.73, − 1.69) and − 5.67% (95% CI − 8.00, − 3.28), respectively. Falls and road injuries remained the most common causes. The relative risk of severe chest injury by age, period, and cohort demonstrated a complex effect globally and in China. The ARIMA model forecasted a steady increase in global numbers from 2020 to 2050, while in China, it forecasted an increase in incidence, a decrease in ASIR and ASYR, and an increase in ASPR. Conclusions This study provides a groundbreaking analysis of global severe chest injury, shedding light on its measures and impact. These findings highlight the need for timely, specialized care and addressing regional disparities to mitigate the severe chest injury burden.

Abstract In this paper, a flexural Mikaelian lens in thin plate is designed by using conformation transformation. The propagation characteristics of flexural waves in the lens are investigated through rays trajectory equation, simulation analyses, and experimental tests, confirming the self-focusing properties of the Mikaelian lens. Additionally, the study explores the Talbot effect for flexural waves, revealing through simulation studies that the Talbot effect within the Mikaelian lens exhibits nearly diffraction-free properties. Building on the non-diffractive nature of the Talbot effect within the Mikaelian lens, we explore the potential for encoding flexural waves using active interference sources. The simulation and experiment results demonstrate the good performance of the designed active encoding system. This work opens up new avenues for the encoding of flexural waves, presenting promising implications for applications in communication such as structural health monitoring, wireless communication in solid media and data transmission in robotics and other areas related to flexural wave technology.

Abstract The crosstalk and balance regulation of Wnt-Notch have been known to be essential for cell fate decision and tissue regeneration, however, how this balance is maintained and how the Wnt-Notch pathways are connected with cell cycle regulation is still not clear. By analyzing the molecular alterations in mouse model with accelerated aging phenotypes due to loss of p21 function in a Werner syndrome background, we observed that Wnt3 and β-Catenin were down-regulated, while Notch1 and Hes1 were up-regulated. This disruption in Wnt-Notch signaling was accompanied by the loss of intestinal stem cell compartment, increase in Bmi1 positive cells, loss of Olfm4/Lgr5 positive cells, and reduced secretory Paneth cells and goblet cells in the intestinal crypts of p21TKO mice. BrdU incorporation, cleaved caspase 3, and Tunel assay results revealed the fast turnover of intestinal epithelia, which may result in abnormal stem cell mobilization and exhaustion of the stem cell reservoir in the intestinal crypts. We further identified shift of DREAM complex towards MMB complex due to the loss of p21 as the cause for faster turnover of intestinal epithelia. Importantly, we identified the E2F1 as the transcriptional regulator for Notch1, which linked the p21-DREAM/MMB/Rb-E2F1 pathway with Wnt-Notch pathway. The overexpression of p21 rescued the DREAM pathway, as well as the imbalance of Wnt-Notch pathway. In summary, our data identify p21 as an important factor in maintaining sequential mobilization, proliferation, and homeostasis of intestinal stem cells.

Abstract Objective Cryopyrin-associated periodic syndrome (CAPS) is characterized by excessive IL-1β release resulting in systemic and organ inflammation. As an anti-IL-1 agent, canakinumab has been approved with all CAPS phenotypes in USA and European countries. However, the use of canakinumab in CAPS in Chinese patients was rarely reported. In this study, we aimed to assess the effectiveness and safety of canakinumab in Chinese patients with CAPS. Methods Patients with CAPS treated with canakinumab were included. Clinical data were collected retrospectively from medical records. Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels. Data was analyzed at canakinumab initiation, at months 1, 3, 6, 9, and 12, or the last follow-up. Results A total of 10 CAPS patients were included. 40% of patients were males, the median age at disease onset was 2.5 (2.5, 6) days and the median duration of follow-up while on canakinumab was 22.5 (8.5, 27.5) months. 80% (8/10) of CAPS patients presented with moderate-severe disease activity before the canakinumab treatment. 30% (3/10) of patients required canakinumab dose increase to control disease activity. After treatments, 60% (6/10) of CAPS patients achieved complete remission without relapse and the rest showed minimal disease activity. Clinical symptoms such as fever and rash were improved significantly in most patients (80%). Although abnormal imaging in brain MRI remained in over half of those patients, neurological manifestations were all relieved. 60% (6/10) of patients received prednisone before starting canakinumab therapy and five of them discontinued prednisone later. The most common adverse event was infection (40%). No serious adverse events occurred during the treatment of canakinumab. Conclusions Canakinumab may be effective and tolerable for Chinese CAPS patients, helping to reduce the dosage of corticosteroids. However, additional trials on large samples are required to further evaluate its efficacy and safety in China.

The traditional method of screening plants for disease resistance phenotype is both time-consuming and costly. Genomic selection offers a potential solution to improve efficiency, but accurately predicting plant disease resistance remains a challenge. In this study, we evaluated eight different machine learning (ML) methods, including random forest classification (RFC), support vector classifier (SVC), light gradient boosting machine (lightGBM), random forest classification plus kinship (RFC_K), support vector classification plus kinship (SVC_K), light gradient boosting machine plus kinship (lightGBM_K), deep neural network genomic prediction (DNNGP), and densely connected convolutional networks (DenseNet), for predicting plant disease resistance. Our results demonstrate that the three plus kinship (K) methods developed in this study achieved high prediction accuracy. Specifically, these methods achieved accuracies of up to 95% for rice blast (RB), 85% for rice black-streaked dwarf virus (RBSDV), and 85% for rice sheath blight (RSB) when trained and applied to the rice diversity panel I (RDPI). Furthermore, the plus K models performed well in predicting wheat blast (WB) and wheat stripe rust (WSR) diseases, with mean accuracies of up to 90% and 93%, respectively. To assess the generalizability of our models, we applied the trained plus K methods to predict RB disease resistance in an independent population, rice diversity panel II (RDPII). Concurrently, we evaluated the RB resistance of RDPII cultivars using spray inoculation. Comparing the predictions with the spray inoculation results, we found that the accuracy of the plus K methods reached 91%. These findings highlight the effectiveness of the plus K methods (RFC_K, SVC_K, and lightGBM_K) in accurately predicting plant disease resistance for RB, RBSDV, RSB, WB, and WSR. The methods developed in this study not only provide valuable strategies for predicting disease resistance, but also pave the way for using machine learning to streamline genome-based crop breeding.

Abstract Background Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis. Methods MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice. Results This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis. Conclusion These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases.

Abstract Hydrogels, provided that they integrate strength and toughness at desired high content of water, promise in load-bearing tissues such as articular cartilage, ligaments, tendons. Many developed strategies impart hydrogels with some mechanical properties akin to natural tissues, but compromise water content. Herein, a strategy deprotonation-complexation-reprotonation is proposed to prepare polyvinyl alcohol hydrogels with water content as high as ~80% and favorable mechanical properties, including tensile strength of 7.4 MPa, elongation of around 1350%, and fracture toughness of 12.4 kJ m−2. The key to water holding yet improved mechanical properties lies in controllable nucleation for refinement of crystalline morphology. With nearly constant water content, mechanical properties of as-prepared hydrogels are successfully tailored by tuning crystal nuclei density via deprotonation degree and their distribution uniformity via complexation temperature. This work provides a nucleation concept to design robust hydrogels with desired water content, holding implications for practical application in tissue engineering.

While numerous studies have highlighted the potential benefits of programming environment (PE) use for children's learning, the boundary conditions of children's PE acceptance within the programming education context are less clear. This study fills this gap in the literature by investigating the critical determinants of children's PE use intention and extending the boundary conditions to programming competition, computational thinking, and programming modality. A total of 1527 primary students participated in this study. Using structural equation modelling (SEM) analyses, the measurement model was validated, and the configural, metric and scalar invariance of the measurement model was established. The structural model was also confirmed, with most of the hypothesized relationships were supported. Multigroup SEM analyses were conducted to compare structural path coefficient differences across different personal moderators (i.e., gender, grade, and experience), environmental moderators (i.e., both parents' education level), and PE use-relevant moderators (i.e., programming competition, computational thinking, and programming modality). The results revealed significant path differences in six group comparisons, with most of the path differences associated with perceived self-efficacy and perceived ease of use. It should be noted that no significant path differences were identified for the gender and programming competition group comparisons. This work serves as a pioneer study of a comprehensive understanding of the determinants and moderators of children's PE use intention. The findings offer important theoretical implications through accommodating essential constructs within a PE acceptance framework and recommending effective strategies to improve primary students' PE acceptance for programming learning in primary education.

Jupiter is the biggest and fastest-rotating planet in our solar system. As a gas giant without land–sea distribution or topography, Jupiter is an ideal natural laboratory for studying atmospheric dynamics. Jupiter's atmospheric composition, atmospheric circulation, and internal structure are all topics of scientific significance. On December 4, 1973, Pioneer 10 achieved its closest approach to Jupiter, marking the first successful exploration mission to the Jovian system. Since then, Jupiter exploration has gathered more than 50 years of experience with 10 missions, including 7 flyby missions, 2 orbiting missions, Galileo and Juno, and the still en route mission Jupiter Icy moons Explorer (JUICE). This review takes a brief look-back to these 10 Jupiter missions and their science results, especially the progress on Jupiter's atmospheric composition, waves and zonal jet streams, the Great Red Spot, and polar vortices, as well as the unsolved scientific problems. China plans to launch Tianwen-4 by 2030, targeting the Jovian system. To shed some light on the scientific payloads and target design of Tianwen-4, reviewing the past Jupiter missions has certain significance.

Assessing residents’ perceptions of urban ecosystem services (UESs) is crucial for incorporating it into environmental management. However, evaluations seldom consider variations in perceptions at sub-city scale. Our study demonstrates how UES perceptions varies at sub-city level through a case study in Beijing, China. We interviewed 550 residents of Beijing’s oldest and newest urban zones to obtain their perceptions of 10 UES types. We analysed participants’ responses using importance-performance analysis, optimal scale regression, and textual analysis. Results showed that residents confirmed the value of UES in both zones. However, differences existed in their perceptions of several UESs, reflecting different environmental problems between two zones. Additionally, education, gender, and age significantly affected residents’ perceptions. Residents in both zones prioritised greenery-expanding activities for improving UES performance. Based on these findings, we recommend that variances in UES perception be considered when managing urban ecosystems to improve its supply and contribute to human well-being.

In recent years, acoustic metamaterials, as a sort of novel artificial composite materials, have demonstrated the ability to surpass the limitations of traditional materials through their exceptional acoustic parameter manipulation capabilities. Thus, acoustic metamaterials have shown promising applications in numerous areas such as underwater detection, underwater target identification, acoustic imaging, navigation, and underwater communication. The advancements in metamaterial-based underwater acoustic communication were reviewed, focusing primarily on multiplex communication based on acoustic orbital angular momentum, underwater acoustic communication between specific transmitter and receiver based on beam steering of acoustic metasurface, and water-air trans-medium acoustic communication. The key technologies were summarized, and the current challenges and future prospects of metamaterial-based underwater acoustic communication were outlined.

In the scenario where multi-autonomous surface vehicles(ASVs) round up an actively escaped adversarial target, a game model of the multi-ASV cooperative hunting problem was established using differential game theory. A surround term consisting of the escape angle was introduced into the payment function which included the distance cost so that the escape probability of the target was reduced. At the same time, the hunting problem was converted into an optimization problem for solving achievable strategies, and the particle swarm optimization(PSO) algorithm was used to solve the optimal strategy that satisfied the Nash equilibrium. The simulation and lake test results show the effectiveness of the hunting algorithm based on differential game and PSO.

Utilizing multi-band and multi-carrier techniques enhances throughput and capacity in Long-Term Evolution (LTE)-Advanced and 5G New Radio (NR) mobile networks. However, these techniques introduce Passive Inter-Modulation (PIM) interference in Frequency-Division Duplexing (FDD) systems. In this paper, a novel multi-band Wiener-Hammerstein model is presented to digitally reconstruct PIM interference signals, thereby achieving effective PIM Cancellation (PIMC) in multi-band scenarios. In the model, transmitted signals are independently processed to simulate Inter-Modulation Distortions (IMDs) and Cross-Modulation Distortions (CMDs). Furthermore, the Finite Impulse Response (FIR) filter, basis function generation, and B-spline function are applied for precise PIM product estimation and generation in multi-band scenarios. Simulations involving 4 carrier components from diverse NR frequency bands at varying transmitting powers validate the feasibility of the model for multi-band PIMC, achieving up to 19 dB in PIMC performance. Compared to other models, this approach offers superior PIMC performance, exceeding them by more than 5 dB in high transmitting power scenarios. Additionally, its lower sampling rate requirement reduces the hardware complexity associated with implementing multi-band PIMC.

Abstract Background UV-B, an important environmental factor, has been shown to affect the yield and quality of rice (Oryza sativa) worldwide. However, the molecular mechanisms underlying the response to UV-B stress remain elusive in rice. Results We perform comprehensive metabolic profiling of leaves from 160 diverse rice accessions under UV-B and normal light conditions using a widely targeted metabolomics approach. Our results reveal substantial differences in metabolite accumulation between the two major rice subspecies indica and japonica, especially after UV-B treatment, implying the possible role and mechanism of metabolome changes in subspecies differentiation and the stress response. We next conduct a transcriptome analysis from four representative rice varieties under UV-B stress, revealing genes from amino acid and flavonoid pathways involved in the UV-B response. We further perform a metabolite-based genome-wide association study (mGWAS), which reveals 3307 distinct loci under UV-B stress. Identification and functional validation of candidate genes show that OsMYB44 regulates tryptamine accumulation to mediate UV-B tolerance, while OsUVR8 interacts with OsMYB110 to promote flavonoid accumulation and UV-B tolerance in a coordinated manner. Additionally, haplotype analysis suggests that natural variation of OsUVR8 groupA contributes to UV-B resistance in rice. Conclusions Our study reveals the complex biochemical and genetic foundations that govern the metabolite dynamics underlying the response, tolerance, and adaptive strategies of rice to UV-B stress. These findings provide new insights into the biochemical and genetic basis of the metabolome underlying the crop response, tolerance, and adaptation to UV-B stress.

Abstract Background High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets. Methods Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA. Results By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly. Conclusion Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.

Abstract Global warming has led to the enhancement of diurnal (daytime-nighttime) compound heat waves, which can severely affect the population’s physical health and productive life; this is particularly the case for vulnerable populations that are more susceptible to psychological and physiological harm with the future normalization of heatwave scenarios. In this study, we attributed the changes in population exposure under diurnal compound high temperatures (HTs) and extremely high temperatures (EHTs) to the influence of climatic (exposure duration) and population factors and their combined influence to determine the relationship between exposure duration and the changes in exposure of vulnerable populations. Diurnal compound HT and EHT covered a land area of 4,016,800 and 1,984,200 km2, respectively. The heat-exposed area spread step-like in all directions, centering on the 24-h high-exposure area with a strong gradient effect. The area of prolonged exposure shifted from the Yellow-Huai-Huai Plain across the geographical boundary between the south and the north to the middle and lower reaches of the Yangtze River Plain. Meanwhile, the average maximum value of vulnerable population exposure reached 186,800 and 93,100 person-h, with high values in Zhengzhou, Chongqing, Wuhan, Chengdu, Beijing, and other cities. Changes in vulnerable population exposure were dominated first by demographic factors and then by climatic factors, with the dominance of climatic factors evident in areas of prolonged exposure. Under prolonged exposure to daytime-nighttime compound EHT, changes in the exposure of child and older populations were dominated by climatic factors with a contribution rate of 87.16% and 87.43%, respectively. Therefore, suitable cooling measures should be proposed for vulnerable populations under prolonged exposure, focusing more on the physical and mental health of children and older adults exposed to compound EHT.

Abstract Cuproptosis is characterized by lipoylated protein aggregation and loss of iron–sulfur (Fe–S) proteins, which are crucial for a wide range of important cellular functions, including DNA replication and damage repair. Sirt2 and sirt4 are lipoamidases that remove the lipoyl moiety from lipoylated proteins using nicotinamide adenine dinucleotide (NAD+) as a cofactor. However, to date, it is not clear whether nicotinamide mononucleotide (NMN), a precursor of NAD+, affects cellular sensitivity to cuproptosis. Therefore, in the current study, cuproptosis was induced by the copper (Cu) ionophore elesclomol (Es) in HeLa cells. It was also found that Es/Cu treatment increased cellular DNA damage level. On the other hand, NMN treatment partially rescued cuproptosis in a dose-dependent manner, as well as reduced cellular DNA damage level. In addition, NMN upregulated the expression of Fe-S protein POLD1, without affecting the aggregation of lipoylated proteins. Mechanistic study revealed that NMN increased the expression of sirt2 and cellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) level. Overexpression of sirt2 and sirt4 did not change the aggregation of lipoylated proteins, however, sirt2, but not sirt4, increased cellular NADPH levels and partially rescued cuproptosis. Inhibition of NAD+ kinase (NADK), which is responsible for generating NADPH, abolished the rescuing function of NMN and sirt2 for Es/Cu induced cell death. Taken together, our results suggested that DNA damage is a characteristic feature of cuproptosis. NMN can partially rescue cuproptosis by upregulating sirt2, increase intracellular NADPH content and maintain the level of Fe-S proteins, independent of the lipoamidase activity of sirt2.

Abstract Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC–MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.

Abstract Background There is growing evidence for a relationship between gut microbiota and hepatic encephalopathy (HE). However, the causal nature of the relationship between gut microbiota and HE has not been thoroughly investigated. Method This study utilized the large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and HE risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for HE. The inverse variance weighted (IVW) method was used as the primary MR analysis. Sensitive analyses were performed to validate the robustness of the results. Results The IVW method revealed that the genus Bifidobacterium (OR = 0.363, 95% CI: 0.139-0.943, P = 0.037), the family Bifidobacteriaceae (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039), and the order Bifidobacteriales (OR = 0.359, 95% CI: 0.133-0.950, P = 0.039) were negatively associated with HE. However, no causal relationship was observed among them after the Bonferroni correction test. Neither heterogeneity nor horizontal pleiotropy was found in the sensitivity analysis. Conclusion Our MR study demonstrated a potential causal association between Bifidobacterium, Bifidobacteriaceae, and Bifidobacteriales and HE. This finding may provide new therapeutic targets for patients at risk of HE in the future.

Abstract The unconstrained partitioned-block frequency-domain adaptive filter (PBFDAF) offers superior computational efficiency over its constrained counterpart. However, the correlation matrix governing the natural modes of the unconstrained PBFDAF is not full rank. Consequently, the mean coefficient behavior of the algorithm depends on the initialization of adaptive coefficients and the Wiener solution is non-unique. To address the above problems, a new theoretical model for the deficient-length unconstrained PBFDAF is proposed by constructing a modified filter weight vector within a system identification framework. Specifically, we analyze the transient and steady-state convergence behavior. Our analysis reveals that modified weight vector is independent of its initialization in the steady state. The deficient-length unconstrained PBFDAF converges to a unique Wiener solution, which does not match the true impulse response of the unknown plant. However, the unconstrained PBFDAF can recover more coefficients of the parameter vector of the unknown system than the constrained PBFDAF in certain cases. Also, the modified filter coefficient yields better mean square deviation (MSD) performance than previously assumed. The presented alternative performance analysis provides new insight into convergence properties of the deficient-length unconstrained PBFDAF. Simulations validate the analysis based on the proposed theoretical model.

Abstract Little is known about the prognostic value of left atrial strain by four-dimensional speckle-tracking echocardiography in end-stage renal disease patients with preserved left ventricular ejection fraction. This prospective study collected clinical and echocardiographic data from 80 stable dialysis patients (mean age 57 ± 10 years; 62.5% men). All patients underwent the dedicated four-dimensional speckle-tracking echocardiography to measure LASr (peak longitudinal strain of reservoir function), LAScd (peak longitudinal strain of conduit function), LASct (peak longitudinal strain of contractile function), LASr_c (peak circumferential strain of reservoir function), LAScd_c (peak circumferential strain of conduit function) and LASct_c (peak circumferential strain of contractile function). These patients were enrolled from August 2021 to August 2023 and followed-up for 19 months (interquartile-range 15 to 20 months). The primary outcome was a composite of all-cause mortality or major adverse cardiovascular events (MACEs). The study patients were classified into event (developed mortality or MACEs) and event-free group according to the primary outcome. Multivariate Cox regression analysis was used to investigate risk factors for all-cause mortality or MACEs. The event group had lower LASr (16.4% vs. 21.2%, P = 0.0003), LASct (8.2% vs. 11.2%, P = 0.01), LASr_c (25.2% vs. 35.0%, P = 0.0004) and LASct_c (14.9% vs. 20.9%, P = 0.001) than the event-free group. Using optimal cut-off value determined by ROC curve, the less LASr (LASr

Abstract Homotypic cell-in-cell structures (hoCICs) are associated with tumor proliferation, invasion, and metastasis and is considered a promising prognostic marker in various cancers. However, the role of hoCICs in non-small cell lung cancer (NSCLC) remains unclear. Tumor tissue sections were obtained from 411 NSCLC patients. We analyzed the relationship between clinicopathological variables and the number of hoCICs. LASSO and multivariate Cox regression analysis were employed to identify prognostic factors for NSCLC. The impact of hoCICs on overall survival (OS) and disease-free survival (DFS) was assessed using the Kaplan–Meier curves and log-rank test. Prognostic models for OS and DFS were developed and validated using the C-index, time-dependent area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curves and decision curve analysis (DCA). Among the cohort, 56% of patients had hoCICs while 44% did not. Notably, hoCICs were primarily found at the tumor invasion front. Male gender, smoking, squamous cell carcinoma, low differentiation, tumor size ≥ 3 cm, advanced TNM stage, lymph node metastasis, pleural invasion, vascular invasion, necrosis, P53 mutation, and high expression of Ki-67 were identified as relative risk factors for hoCICs. Furthermore, hoCICs was found to be a significant prognostic factor for both OS and DFS, with higher frequencies of hoCICs correlating with poorer outcomes. We constructed nomograms for predicting 1-, 3-, and 5-year OS and DFS based on hoCICs, and the calibration curves showed good agreement between the predicted and actual outcomes. The results of the C-index, time-dependent AUC, NRI, IDI, and DCA analyses demonstrated that incorporating hoCICs into the prognostic model significantly enhanced its predictive power and clinical applicability. HoCICs indicated independent perdictive value for OS and DFS in patients with NSCLC. Furthermore, the frequent localization of hoCICs at the tumor invasion front suggested a strong association between hoCICs and tumor invasion as well as metastasis.

Abstract Background Stroke is a globally dangerous disease capable of causing irreversible neuronal damage with limited therapeutic options. Meldonium, an inhibitor of carnitine-dependent metabolism, is considered an anti-ischemic drug. However, the mechanisms through which meldonium improves ischemic injury and its potential to protect neurons remain largely unknown. Methods A rat model with middle cerebral artery occlusion (MCAO) was used to investigate meldonium’s neuroprotective efficacy in vivo. Infarct volume, neurological deficit score, histopathology, neuronal apoptosis, motor function, morphological alteration and antioxidant capacity were explored via 2,3,5-Triphenyltetrazolium chloride staining, Longa scoring method, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay, rotarod test, transmission electron microscopy and Oxidative stress index related kit. A primary rat hippocampal neuron model subjected to oxygen–glucose deprivation reperfusion was used to study meldonium’s protective ability in vitro. Neuronal viability, mitochondrial membrane potential, mitochondrial morphology, respiratory function, ATP production, and its potential mechanism were assayed by MTT cell proliferation and cytotoxicity assay kit, cell-permeant MitoTracker® probes, mitochondrial stress, real-time ATP rate and western blotting. Results Meldonium markedly reduced the infarct size, improved neurological function and motor ability, and inhibited neuronal apoptosis in vivo. Meldonium enhanced the morphology, antioxidant capacity, and ATP production of mitochondria and inhibited the opening of the mitochondrial permeability transition pore in the cerebral cortex and hippocampus during cerebral ischemia–reperfusion injury (CIRI) in rats. Additionally, meldonium improved the damaged fusion process and respiratory function of neuronal mitochondria in vitro. Further investigation revealed that meldonium activated the Akt/GSK-3β signaling pathway to inhibit mitochondria-dependent neuronal apoptosis. Conclusion Our study demonstrated that meldonium shows a neuroprotective function during CIRI by preserving the mitochondrial function, thus prevented neurons from apoptosis.

The deformation control of surrounding rock in gob−side roadway with thick and hard roof poses a significant challenge to the safety and efficiency of coal mining. To address this issue, a novel approach combining directional and non-directional blasting techniques, known as combined blasting, was proposed. This study focuses on the experimental investigation of the proposed method in the 122108 working face in Caojiatan Coal Mine as the engineering background. The initial phase of the study involves physical model experiments to reveal the underlying mechanisms of combined blasting for protecting gob-side roadway with thick and hard roof. The results demonstrate that this approach effectively accelerates the collapse of thick and hard roofs, enhances the fragmentation and expansion coefficient of gangue, facilitates the filling of the goaf with gangue, and provides support to the overlying strata, thus reducing the subsidence of the overlying strata above the goaf. Additionally, the method involves cutting the main roof into shorter beams to decrease the stress and disrupt stress transmission pathways. Subsequent numerical simulations were conducted to corroborate the findings of the physical model experiments, thus validating the accuracy of the experimental results. Furthermore, field engineering experiments were performed, affirming the efficacy of the combined blasting method in mitigating the deformation of surrounding rock and achieving the desired protection of the gob-side roadway.

Osteoarthritis (OA) is an aging-associated disease characterized by joint stiffness pain and destroyed articular cartilage. Traditional treatments for OA are limited to alleviating various OA symptoms. There is a lack of drugs available in clinical practice that can truly repair cartilage damage. Here, we developed the chondroitin sulfate analog CS-semi5, semi-synthesized from chondroitin sulfate A. In vivo, CS-semi5 alleviated inflammation, provided analgesic effects, and protected cartilage in the modified Hulth OA rat model and papain-induced OA rat model. A bioinformatics analysis was performed on samples from OA patients and an exosome analysis on papain-induced OA rats, revealing miR-122-5p as the key regulator associated with CS-semi5 in OA treatment. Binding prediction revealed that miR-122-5p acted on the 3′-untranslated region of p38 mitogen-activated protein kinase, which was related to MMP13 regulation. Subsequent in vitro experiments revealed that CS-semi5 effectively reduced cartilage degeneration and maintained matrix homeostasis by inhibiting matrix breakdown through the miR-122-5p/p38/MMP13 axis, which was further validated in the articular cartilage of OA rats. This is the first study to investigate the semi-synthesized chondroitin sulfate CS-semi5, revealing its cartilage-protecting, anti-inflammatory, and analgesic properties that show promising therapeutic effects in OA via the miR-122-5p/p38/MMP13 pathway.