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Abstract Background While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear. Methods Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8+ T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy. Results We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR−661 and miR−671−5p to promote the expression of CD39, which further facilitated CD8+ T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8+ T cell exhaustion and increased the response to anti-PD−1 therapy. Conclusions Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8+ T cell exhaustion and immune resistance in GC.

Abstract Glyphosate, widely used to manage weeds in cassava crops, simultaneously inhibits cassava growth, necessitating the development of herbicide-tolerant cassava varieties. In this study, screened 262 cassava varieties, identifying the glyphosate-resistant (GR) variety ZM8701 and the glyphosate-sensitive (GS) variety SC9. Transcriptomic analysis via Illumina sequencing revealed differentially expressed genes associated with resistance, including Cytochrome P450, GST, GT, ABC transporters, and others such as MIOX1, LHCA1, PPH, HSP26, HSP83A, and UGT73C5. Notably, the EMB3004 gene, involved in the biosynthesis of aromatic amino acids, was significantly upregulated in resistant varieties, suggesting a key role in countering glyphosate’s inhibition of the shikimic acid pathway. These genes are pivotal in enhancing cell wall biosynthesis, optimizing photosynthesis, and improving detoxification processes. This research elucidated the molecular mechanisms underlying cassava’s resistance to glyphosate, thereby laying the groundwork for breeding programs aimed at developing herbicide-resistant varieties. Graphical Abstract

Background Cervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic agents, but their efficacy when combined with neoadjuvant chemotherapy (NACT) has not been fully tested, and how they alter the tumor microenvironment has not been comprehensively elucidated.Methods In this study, we conducted single-cell RNA sequencing using 46,950 cells from nine human cervical cancer tissues representing sequential different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and identified the crucial factors involved in combination therapy. Cell–cell communication analysis was performed between tumor and immune cells. In addition, THP-1-derived and primary monocyte-derived macrophages were cocultured with cervical cancer cells and phagocytosis was detected by flow cytometry. The antitumor activity of blocking CD74 was validated in vivo using a CD74 humanized subcutaneous tumor model.Results Pathway enrichment analysis indicated that NACT activated cytokine and complement-related immune responses. Cell–cell communication analysis revealed that after NACT therapy, interaction strength between T cells and cancer cells decreased, but intensified between macrophages and cancer cells. We verified that macrophages were necessary for the PD-1 blockade to exert antitumor effects in vitro. Additionally, CD74-positive macrophages frequently interacted with the most immunoreactive epithelial subgroup 3 (Epi3) cancer subgroup during combination NACT. We found that CD74 upregulation limited phagocytosis and stimulated M2 polarization, whereas CD74 blockade enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vitro and in vivo.Conclusions Our study reveals the dynamic cell–cell interaction network in the cervical cancer microenvironment influenced by combining NACT and PD-1 blockade. Furthermore, blocking tumor-associated macrophage-derived CD74 could augment neoadjuvant therapeutic efficacy.

BackgroundYinChen WuLing Powder (YCWLP) has been recommended by consensus for the treatment of non-alcoholic steatohepatitis (NASH); nevertheless, its specific pharmacological mechanisms remain to be elucidated. This study aims to dissect the mechanisms underlying the therapeutic effects of YCWLP on NASH using a hybrid approach that encompasses network pharmacology, molecular docking, and in vitro experimental validation.MethodsWe compiled the chemical constituents of YCWLP from the Traditional Chinese Medicine System Pharmacological Database and Analysis Platform (TCMSP), while potential targets were predicted using the SwissTargetPrediction database. To identify NASH-related candidate targets, comprehensive retrieval was carried out using five authoritative databases. Protein-Protein Interaction (PPI) networks of direct targets of YCWLP in NASH treatment were then constructed using the String database, and functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, were conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Core targets were discerned using the Molecular Complex Detection (MCODE) and cytoHubba algorithms. Subsequently, molecular docking of key compounds to core targets was conducted using AutoDock software. Moreover, we established a free fatty acid-induced HepG2 cell model to simulate NASH in vitro, with YCWLP medicated serum intervention employed to corroborate the network pharmacology-derived hypotheses. Furthermore, a combination of enzyme-linked immunosorbent assay (ELISA), and Western blotting analyses was employed to investigate the lipid, hepatic enzyme, SHP2/PI3K/NLRP3 signaling pathway and associated cytokine levels.ResultsThe network pharmacology analysis furnished a list of 54 compounds from YCWLP and 167 intersecting targets associated with NASH. Through analytic integration with multiple algorithms, PTPN11 (also known as SHP2) emerged as a core target of YCWLP in mitigating NASH. The in vitro experiments validated that 10% YCWLP medicated serum could remarkably attenuate levels of total cholesterol (TC, 1.25 vs. 3.32) and triglyceride (TG, 0.23 vs. 0.57) while ameliorating alanine aminotransferase (ALT, 7.79 vs. 14.78) and aspartate aminotransferase (AST, 4.64 vs. 8.68) leakage in NASH-afflicted cells. In addition, YCWLP significantly enhanced the phosphorylation of SHP2 (0.55 vs. 0.20) and downregulated the expression of molecules within the SHP2/PI3K/NLRP3 signaling axis, including p-PI3K (0.42 vs. 1.02), NLRP3 (0.47 vs. 0.93), along with downstream effectors-cleaved Caspase-1 (0.21 vs. 0.49), GSDMD-NT (0.24 vs. 0.71), mature interleukin-1β (IL-1β, 0.17 vs. 0.48), pro-IL-1β (0.49 vs. 0.89), mature interleukin-18 (IL-18, 0.15 vs. 0.36), and pro-IL-18 (0.48 vs. 0.95).ConclusionOur research reveals that YCWLP exerts therapeutic effects against NASH by inhibiting lipid accumulation and inflammation, which involves the attenuation of pyroptosis via the SHP2/PI3K/NLRP3 pathway.

Abstract Background Craniotomy aneurysm clipping is one of the main treatments for intracranial aneurysm (IA). Endotracheal intubation and intraoperative operation may induce dramatic hemodynamic fluctuations and increase the risk of aneurysm rupture. Intraoperative high-dose opioid use is the main measure to reduce the intraoperative stress response, but it increases the incidence of complications such as postoperative vomiting and delayed awakening. Transcutaneous electrical acupoint stimulation (TEAS) stimulates β-endorphin expression levels and reduces opioid requirements. In this study, we aimed to assess the effects of TEAS on remifentanil dosage and oxidative stress (OS) in craniotomy aneurysm clipping. Method Forty-two patients with craniotomy aneurysm clipping were randomized into two groups: the TEAS group (T group) and the sham TEAS group (S group). “Hegu” (LI4), “Neiguan” (PC6) and “Zusanli” points (ST36) were selected, and a “HANS” percutaneous acupoint electrical stimulator was used for intervention 30 min before anesthesia induction until the end of the operation. The primary outcome was intraoperative remifentanil dosage. The secondary outcomes were intraoperative propofol dosage, mean arterial pressure (MAP) and heart rate (HR) 5 min before the TEAS intervention (T0), 5 min before head holder pinning (T1), immediately after pinning (T2), 5 min before craniotomy (T3), immediately after craniotomy (T4), at craniotomy (T5), and at the end of surgery (T6), as well as serum β-endorphin levels at T1, T2 and T6 and neuron-specific enolase (NSE), S100β, superoxide dismutase (SOD) and malondialdehyde (MDA) levels at T1, T2 and 24 h after surgery (T7). Results The dosage of remifentanil in the T group was reduced compared to that in the S group (P

Cuproptosis-related key genes play a significant role in the pathological processes of acute myocardial infarction (AMI). However, a complete understanding of the molecular mechanisms behind this participation remains elusive. This study was designed to identify genes and immune cells critical to AMI pathogenesis. Based on the GSE48060 dataset (31 AMI patients and 21 healthy persons, GPL570-55999), we identified genes associated with dysregulated cuproptosis and the activation of immune responses between normal subjects and patients with a first myocardial attack. Two molecular clusters associated with cuproptosis were defined in patients with AMI. Immune infiltration analysis showed that there was significant immunity heterogeneity among different clusters. Multiple immune responses were closely associated with Cluster2-specific differentially expressed genes (DEGs). The generalized linear model machine model presented the best discriminative performance with relatively lower residual and root mean square error, and a higher area under the curve (AUC = 0.870). A final two-gene-based generalized linear model was constructed, exhibiting satisfactory performance in two external validation datasets (AUC = 0.719, GSE66360 and AUC = 0.856, GSE123342). Column graph, calibration curve, and decision curve analyses also proved the accuracy of AMI prediction. We also constructed a mouse C57BL/6 model of AMI (3 h, 48 h, and 1 week) and used qRT-PCR and immunofluorescence to detect the expression changes of CBLB and ZNF302. In this study, we present a systematic analysis of the complex relationship between cuproptosis and a first AMI attack, and provide new insights into the diagnosis and treatment of AMI.

Introduction: Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we aimed to elucidate the cellular molecular protective mechanism of Cel against diabetes-induced inflammation and endothelial dysfunction.Methods: Type 2 diabetes (T2DM) was induced by db/db mice, and osmotic pumps containing Cel (100 μg/kg/day) were implanted intraperitoneally and were calibrated to release the drug for 28 days. In addition, human umbilical vein endothelial cells (HUVECs) were cultured in normal or high glucose and palmitic acid-containing (HG + PA) media in the presence or absence of Cel for 48 h.Results: Cel significantly ameliorated the hyperglycemia-induced abnormalities in nuclear factor (erythroid-derived 2)-like protein 2 (Nrf2) pathway activity and alleviated HG + PA-induced oxidative damage. However, the protective effect of Cel was almost completely abolished in HUVECs transfected with short hairpin (sh)RNA targeting Nrf2, but not by nonsense shRNA. Furthermore, HG + PA reduced the phosphorylation of AMP-activated protein kinase (AMPK), the autophagic degradation of p62/Kelch-like ECH-associated protein 1 (Keap1), and the nuclear localization of Nrf2. However, these catabolic pathways were inhibited by Cel treatment in HUVECs. In addition, compound C (AMPK inhibitors) and AAV9-sh-Nrf2 reduced Cel-induced Nrf2 activation and angiogenesis in db/db mice.Discussion: Taking these findings together, the endothelial protective effect of Cel in the presence of HG + PA may be at least in part attributed to its effects to reduce reactive oxygen species (ROS) and inflammation through p62/Keap1-mediated Nrf2 activation.

Purpose: The integrator subunit (INTS) family, a group exclusive to metazoans, participates in various biologic processes. However, their roles in hepatocellular carcinoma (HCC) remain largely unexplored. Methods: Public databases were utilized to investigate the transcriptional and protein expression, and clinical relevance of the INTS family in HCC. Meanwhile, the effects of INTS13 knockdown and overexpression on cell proliferation and apoptosis were studied using HCC cell lines. Results: The mRNA expression of most INTSs were higher in tumor than normal tissues. Higher expression of INTS1/2/3/4/7/8/9/11/12/13 were correlated with poorer overall survival (OS) in Kaplan-Meier Survival Analysis. Multivariate analysis revealed higher level of INTS13 was an independent prognostic factor for shorter OS. Furthermore, genetic alteration of INTS3/6/7/8/9/10 were found in HCC patients and was associated with shorter disease-free survival and progression-free survival. INTS1/2/3/5/7/11/13/14 were associated with activation of tumor-induced immune response and immune infiltration in HCC. Knockdown of INTS13 inhibited cell proliferation and induced apoptosis in HCC cell lines, while overexpression of INTS13 had the opposite effect. Conclusion: Our results indicate that INTS13 is an independent prognostic biomarker in HCC. Furthermore, INTS13 enhances cell proliferation and decreases cell apoptosis in HCC cell lines leading to a poorer OS in HCC patients.

Background: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease worldwide and lack of research on the diagnostic utility of mitochondrial regulators in NAFLD. Mitochondrial dysfunction plays a pivotal role in the development and progression of NAFLD, especially oxidative stress and acidity β-oxidative overload. Thus, we aimed to identify and validate a panel of mitochondrial gene expression biomarkers for detection of NAFLD. Methods: We selected the GSE89632 dataset and identified key mitochondrial regulators by intersecting DEGs, WGCNA modules, and MRGs. Classification of NAFLD subtypes based on these key mitochondrial regulatory factors was performed, and the pattern of immune system infiltration in different NAFLD subtypes were also investigated. RF, LASSO, and SVM-RFE were employed to identify possible diagnostic biomarkers from key mitochondrial regulatory factors and the predictive power was demonstrated through ROC curves. Finally, we validated these potential diagnostic biomarkers in human peripheral blood samples and a high-fat diet-induced NAFLD mouse model. Results: We identified 25 key regulators of mitochondria and two NAFLD subtypes with different immune infiltration patterns. Four potential diagnostic biomarkers (BCL2L11, NAGS, HDHD3, and RMND1) were screened by three machine learning methods thereby establishing the diagnostic model, which showed favorable predictive power and achieved significant clinical benefit at certain threshold probabilities. Then, through internal and external validation, we identified and confirmed that BCL2L11 was significantly downregulated in NAFLD, while the other three were significantly upregulated. Conclusion: The four MRGs, namely BCL2L11, NAGS, HDHD3, and RMND1, are novel potential biomarkers for diagnosing NAFLD. A diagnostic model constructed using the four MRGs may aid early diagnosis of NAFLD in clinics.

Globally, natural landscapes and their recreational ecosystem services (RES) are both under threat from anthropogenic activities and environmental changes. But the demand for RES increases with the development of human living standards. Therefore, mapping and assessing the supply–demand relationships of RES is crucial for landscape planning, management, and human well-being. This study aimed to study the relationships between supply and demand of RES in Shandong province, China, quantify the supply, demand, and supporting capacity of RES, analyze the degree of matching and coupling between the supply and demand of RES, and explore the effect of terrain gradient to RES. The results indicated that the average value of coupling coordination (CCD) between supply–demand of RES in Shandong province was 0.45, which is a mild balance. According to the supply–demand matching types, areas with low supply-high demand accounted for 6.62%, indicating a serious shortage matching of supply and demand. Using hotel quantity and roads as indicators of the supporting capacity of RES, the overall coordination between landscape aesthetic quality (LAQ) and regional hotel quantity shows a mild imbalance (0.38), while that with the regional road density shows a good balance (0.60). Furthermore, the scenery spots density, RES supply, RES supply–demand CCD and support capacity CCD shows an upward trend with the increase of elevation and slope, an “increased-decreased-increased” trend with the increase of terrain niche index. This study provides spatial matching of RES supply and demand in Shandong province. Optimizing land-use structures and improving natural resource allocation were proposed to boost coordination of RES supply and demand.

Gastric cancer (GC) is difficult to characterize due to its heterogeneity, and the complicated heterogeneity leads to the difficulty of precisely targeted therapy. The spatially heterogeneous composition plays a crucial role in GC onset, progression, treatment efficacy, and drug resistance. In recent years, the technological advancements in spatial omics has shifted our understanding of the tumor microenvironment (TME) from cancer-centered model to a dynamic and variant whole. In this review, we concentrated on the spatial heterogeneity within the primary lesions and between the primary and metastatic lesions of GC through the TME heterogeneity including the tertiary lymphoid structures (TLSs), the uniquely spatial organization. Meanwhile, the immune phenotype based on spatial distribution was also outlined. Furthermore, we recapitulated the clinical treatment in mediating spatial heterogeneity in GC, hoping to provide a systematic view of how spatial information could be integrated into anti-cancer immunity.

Abstract Cervical cancer (CC) is a gynecological neoplasm with the highest incidence rate, primarily attributed to the persistent infection of high-risk Human papillomavirus (HPV). Despite extensive research, the pathogenesis of CC remains unclear. N6-methyladenosine (m6A) methylation, the most prevalent form of epigenetic modification in RNA, is intricately linked to cell proliferation, metastasis, metabolism, and therapeutic resistance within the tumor microenvironment (TME) of CC. The involvement of the writer, reader, and eraser in m6A modification impacts the advancement of tumors through the regulation of RNA stability, nuclear export, translation efficiency, and RNA degradation. Here, we discuss the biogenesis of m6A, the atypical expressions of m6A regulators, the mechanisms of molecular interactions, and their functions in CC. Furthermore, we elucidate m6A modification of non-coding RNA. In the context of precision medicine, and with the advancements of genomics, proteomics, and high-throughput sequencing technologies, we summarize the application of m6A in the clinical diagnosis and treatment of CC. Additionally, new perspectives on detection methods, immune regulation, and nano-drug development are presented, which lay the foundation for further research of m6A and provide new ideas for the clinical treatment of CC.

Abstract The direct current (DC)‐link voltage control of the flywheel energy storage system plays an important role in realizing high‐quality grid connection. With the traditional proportional‐integral control, the DC‐link voltage cannot track its reference value quickly and smoothly when the flywheel energy storage system switches from the charging stage to other working stages. Therefore, a DC‐link voltage control strategy for the flywheel energy storage system based on active disturbance rejection control is proposed in this paper to deal with this issue. The DC‐link voltage and its differential value are considered as the state variables in this strategy. The internal and external disturbances, such as load power, switching loss, and parameter uncertainty, are regarded as an expanded state. By inputting the voltage error and the observed disturbance into the nonlinear state feedback control law, the rapidity and anti‐interference of the DC‐link voltage control are ensured under different States of Charge of the flywheel energy storage system. Then, the coefficient freezing method is used to analyze the effects of the disturbance observation bandwidth by nonlinear gain and pole position changes. The DC‐link voltage can track the reference value over a wider frequency range of disturbances. By configuring the appropriate observer structure parameters, the disturbance observation bandwidth under the nonlinear function gain variation is always higher than the expected bandwidth. The effectiveness of the proposed control strategy is verified by simulation results at last.

ObjectivesThis study aimed to analyze the predictive value of umbilical cord blood Interleukin-6 (UCB IL-6) for the severity-graded BPD and to establish machine learning (ML) predictive models in a Chinese population based on the 2019 NRN evidence-based guidelines.MethodsIn this retrospective analysis, we included infants born with gestational age

Up to now, there are no relevant studies on prognostic factors of cervical mucinous adenocarcinoma. Therefore, we explored the prognostic factors for cervical mucinous adenocarcinoma, and established and validated the prognostic model using the SEER database. We selected the independent factors through univariate and multivariate analyses. LASSO regression analysis was conducted to identify potential risk factors. In conjunction with LASSO and multivariate analysis, the nomogram incorporated three variables, including age, tumour size, and AJCC stage for OS. The c-index was 0.794 and 0.831 in development and validated cohorts, indicating that this prediction model showed adequate discriminative ability in the development cohort. Besides, calibration curves showed good concordance for the development cohort, as well as the validation cohort. We constructed a first-of-its-kind nomogram to predict cervical mucinous adenocarcinomas OS and it showed better performance than AJCC and FIGO stages. Patients with cervical mucinous adenocarcinoma might benefit from using this model to develop tailored treatments.IMPACT STATEMENT What is already known on this subject? Cervical cancer has a variety of pathological types. The biological behaviour of each type is different, and the prognosis is quite different. What do the results of this study add? We analysed and explored the relevant factors affecting the prognosis of cervical mucinous adenocarcinoma. What are the implications of these findings for clinical practice and/or further research? Through the analysis of the SEER dataset, the prognostic factors affecting cervical mucinous adenocarcinoma were identified, and the first predictive model was created to predict the prognosis to help doctors develop individualised treatment plans and follow-up plans.

Highlights The environmental risks of hydrochar on soils need to be clarified before mass engineering application. The influence of soil microbes needs to be investigated to illustrate the impact of hydrochar on greenhouse gas emissions. More research needs to be conducted to reveal the economic benefits of hydrochar and the coupling with anaerobic digestion.

Highlights Novel formable porous functional biochar (LaFe/MB) was prepared for P removal. La/Fe oxide provides abundant sorption sites for P and almost no La/Fe leaching. LaFe/MB presented high compressive strength with high sorption capacity for P.

Postoperative cognitive dysfunction (POCD) is a common postsurgical complication in elderly individuals, significantly impacting the quality of life of patients; however, there is currently no effective clinical treatment for POCD. Recent studies have shown that Icariin (ICA) has antiaging effects and improves cognitive function, but its effect in POCD has not been studied. In this study, we investigated the influence of ICA on cognitive function and the TLR4/NF-κB signaling pathway in a POCD rat model. We found that ICA reduced surgery-induced memory impairment, decreased hippocampal inflammatory responses, ameliorated neuronal injury in the hippocampus and inhibited microglial activation. In addition, we also observed that ICA inhibited activation of the TLR4/NF-κB signaling pathway. In summary, our research suggest that ICA can ameliorate surgery-induced memory impairment and that the improvements resulting from administration of ICA may be associated with inhibition of hippocampal neuroinflammation. Our research findings also provide insight into potential therapeutic targets and methods for POCD.

Background: Depression has a significant effect on cardiovascular disease (CVD), but uncertainties persist regarding which modifiable risk factors mediate the causal effects. We aim to determine whether depression is causally linked to CVD and which modifiable risk factors play potential mediating roles. Methods: We used a two-sample Mendelian randomization (MR) approach and NHANES 2007–2018 data to estimate the effects of depression on various CVD cases and investigated 28 potential mediators of the association between depression and CVD. Results: The results of our MR analysis indicated that genetically determined depression was associated with increased risk of several CVD, including coronary heart disease (odds ratio (OR) = 1.14; 95% confidence interval (CI): 1.05,1.22), myocardial infarction (OR = 1.19; 95% CI, 1.09,1.31), atrial fibrillation (OR = 1.14; 95% CI, 1.06,1.22), and stroke (OR = 1.13; 95% CI, 1.05,1.22). However, there was no causal association between depression and heart failure. Four out of 28 cardiometabolic risk factors, including hyperlipidemia, hypertension, diabetes, and prescription opioid use, were identified as mediators of the association between depression and various CVDs. Observational association analyses from NHANES data yielded consistent results. Conclusion: Our findings demonstrated that depression has a causal detrimental effect on various CVDs. Four causal mediators (hyperlipidemia, hypertension, diabetes, and prescription opioid use) were screened to explain the causal effect. Implementing targeted management strategies for these risk factors may be warranted to mitigate the public health burden of CVD among individuals with depression.

Highlights Aged hydrochar undergoes surface oxidation, mineral complexation, and leaching. Ash content and SSA play the essential role in enhancing Cd sorption and site heterogeneity. Aging degree and sorption behavior differ markedly between pyrochar and hydrochar.

Abstract The objective of the microgrid secondary control system (MSCS) is to regulate frequency and voltage and allocate active and reactive power among distributed generations in the microgrid. Sequential denial‐of‐service (DoS) attacks have a lasting impact that reduce the vulnerability of the MSCS. A vulnerability assessment method is proposed for when the microgrid experiences DoS attacks. The sequence model of attack actions and N–1 contingency actions are proposed to find the traversal expression. With the traversal method, vulnerable factors of the microgrid can be interpreted by the proposed comprehensive vulnerability metric, which provides an intuitive and easy way to understand the vulnerability of the MSCS. The metric is composed of four basic indicators concerning not only final states of the microgrid when a DoS attack ends, but also the dynamic process of the microgrid. To test the proposed metric, two mitigation methods with the purpose of mitigating the impact on the physical system caused by DoS attacks are proposed: the self‐adaptive coefficient method and the fault‐tolerance method. Finally, a 33‐node microgrid platform with eight distributed generations has been built to test the proposed vulnerability assessment method. From the analysis results, nodes with a high cyber‐degree are vulnerable and the fault‐tolerance method can provide a better mitigation result with an average metric of 9.41 compared with the self‐adaptive coefficient method with a metric of 9.03.

Ferroptosis is a novel cell death modality discovered in recent years that is different from apoptosis and necrosis. It is usually associated with changes in the regulatory signaling in multiple organelles and depends on iron. It is caused by an imbalance between the generation and degradation of intracellular lipid reactive oxygen species (ROS). In addition to increased levels of cytoplasmic ROS and lipids, decreased mitochondrial volume and thickened mitochondrial membranes are markers of ferroptotic death. Gastric cancer is a common malignant tumor, but few studies on the possible role of ferroptosis in gastric cancer have been reported. Although ferroptosis is involved in multifactor-induced carcinogenesis, studies have also shown the role of ferroptosis in the selective killing of tumor cells, thereby inhibiting tumor progression and metastasis. In this paper, the definition, characteristics, and regulatory mechanism of ferroptosis and its potential role in gastric cancer are discussed. Therefore, this review is expected to provide a reference for the treatment of diseases based on ferroptosis and provide a direction for future research on the pathogenesis and development of gastric cancer and the development of anticancer drugs.

Introduction: Ubiquitination is involved in many biological processes and its predictive value for prognosis in cervical cancer is still unclear.Methods: To further explore the predictive value of the ubiquitination-related genes we obtained URGs from the Ubiquitin and Ubiquitin-like Conjugation Database, analyzed datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and then selected differentially expressed ubiquitination-related genes between normal and cancer tissues. Then, DURGs significantly associated with overall survival were selected through univariate Cox regression. Machine learning was further used to select the DURGs. Then, we constructed and validated a reliable prognostic gene signature by multivariate analysis. In addition, we predicted the substrate proteins of the signature genes and did a functional analysis to further understand the molecular biology mechanisms. The study provided new guidelines for evaluating cervical cancer prognosis and also suggested new directions for drug development.Results: By analyzing 1,390 URGs in GEO and TCGA databases, we obtained 175 DURGs. Our results showed 19 DURGs were related to prognosis. Finally, eight DURGs were identified via machine learning to construct the first ubiquitination prognostic gene signature. Patients were stratified into high-risk and low-risk groups and the prognosis was worse in the high-risk group. In addition, these gene protein levels were mostly consistent with their transcript level. According to the functional analysis of substrate proteins, the signature genes may be involved in cancer development through the transcription factor activity and the classical P53 pathway ubiquitination-related signaling pathways. Additionally, 71 small molecular compounds were identified as potential drugs.Conclusion: We systematically studied the influence of ubiquitination-related genes on prognosis in cervical cancer, established a prognostic model through a machine learning algorithm, and verified it. Also, our study provides a new treatment strategy for cervical cancer.

Microplastics (MPs) were considered as emerging pollutants in soil. Cadmium (Cd) is the typical heavy metal contaminant in paddy soil in China. It was not unraveled that the effects of the existence of MPs on soil properties and Cd adsorption after rice growth in paddy soil, one of the most important soil types in China. In this study, several typical MPs in dosage of 0.5% (w/w) with different particle sizes, including polyethylene (PE, 200μm), polyacrylonitrile (PAN, 200μm), and polyethylene terephthalate (PET, 200 and 10μm), were selected and aged for a rice season (∼6 months) in paddy soil by column experiments. Some essential physicochemical properties of paddy soil collected from different treatments and the adsorption performance of typical metal contaminants (cadmium, Cd) in paddy soil with MPs coexisting were compared. The results indicated that the 6-month existence of 200μmMPs increased water content (15.94% to 26.08-30.30%), pH value (7.05 to 7.16–7.33), organic matter (OM) content (15.1 gkg −1 to 18.2–22.9 gkg −1), the percentage of soil sand and Cd adsorption capacity of paddy soil, whereas decreased soil cation exchange capacity (CEC), the percentage of soil clay and silt. The adsorption experiments of Cd in soil showed that the adsorption behavior was consistent with the pseudo-second order and Langmuir isotherm model, and the addition of MPs would increase the adsorption capacity of Cd in soil. Besides, the particle size of MPs was found to be one of the dominant factors, in which MPs with smaller particle size (10μm) favored the increase of water content, pH, OM content, CEC, and adsorption performance with Cd. The results of this study could provide a supplemental understanding of the effect of MPs input on the paddy soil ecosystem, including the soil properties and the bioavailability and transport of metal in paddy soil.

The cellulose-based hydrogel has been widely applied for soil water retention and nutrient release agents for several decades. Embedding the inorganic materials into hydrogels is an excellent strategy to improve the inherent limits of the cellulose-based hydrogel. Notably, municipal sludge-derived hydrochar (HC) has reduced the environmental burden and offered a potential hydrogel carrier to control water-retention and nutrient-release. However, the above function for plant growth of hydrochar-embedded carboxymethyl cellulose-g-poly(acrylic acid) (CMC-g-PAA/HC) is unknown, and relevant reports are lacking. This study investigated the water retention, nutrient release behavior, and effect of germination and plant growth of CMC-g-PAA/HC hydrogel. Characterization results showed that HC was successfully incorporated into CMC-g-PAA/HC with 6.0% higher thermostability, 7.2–21.0% lower swelling ratio (SR) in water, and substantial SR in phosphate solution (P-solution). The water loss rate of CMC-g-PAA/HC in P-solution or water owned a more significant temperature response (7.9–15.0 folds) than CMC-g-PAA (8.2–10.0 folds). Moreover, 4.0% higher n value and more 18.5% released P for CMC-g-PAA/HC were also observed. These phenomena were due to restricting the polymer chains movement and the water molecules diffusion inside the hydrogels with HC. Phytotoxicity assessments showed that HC in CMC-g-PAA/HC could effectively alleviate the inhibition effects on rape germination retained with 78.3% germination vigor and 80.0% germination ratio, even dramatically improved plant growth to 28 d. The results of this study demonstrated a new route for developing eco-friendly CMC-g-PAA/HC hydrogel, advantageous as a water retention agent and nutrient carrier in arid and semiarid regions.

The instability of bare slopes is a prevalent concern. The root system of herbaceous vegetation enhances the shear strength of shallow slope soil. This study investigated the mechanism of the root-soil system as well as the effects of different influencing factors on the shear strength of the soil and slope stability. In particular, indoor experiments were conducted on rootless undisturbed soil (RUS) and undisturbed soil with a root system (USRS) using a triaxial compression apparatus to analyze the slope stability of composite soil with a Tagetes erecta root system. Significance tests and correlation analysis of the factors affecting shear performance were conducted. The slope reinforcement effect by the plant root system was simulated under 24 working conditions using the MIDAS finite element method. The results revealed the influence of the root content, moisture content, and stress on the shear strength of USRS, as well as the contribution degree and influence of these variables on the slope stability. Both RUS and USRS exhibited strain hardening during shearing. A strong negative (positive) correlation was observed between the internal friction angle (φ) (cohesion (c)) of the USRS and the root content (moisture content). The maximum deviatoric stress during shear failure of the USRS was 1.29 times higher than that of the RUS. Moreover, the root content was positively correlated with the slope safety coefficient and the slope of the line under different working conditions, whereas the slope angle was negatively correlated with the slope safety coefficient. The reinforcement effect by the root system resulted in a 11.2% increase in the safety coefficient and the improved stability of slopes with an angle larger than 1.5%. The findings of this study provide new insights into shallow slope stability in practical slope protection projects.

Gastric cancer (GC) remains one of the most common malignancies worldwide. Despite immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment and obtained durable clinical responses, only a fraction of GC patients benefit from it. As an important component of T cells, regulatory T cells (Tregs) play a vital role in the pathogenesis of GC, keep a core balance between immune suppression and autoimmunity, and function as predictive biomarkers for prognosis of GC patients. In this review, we discuss the role of Tregs in the pathogenesis of GC, and targeting Tregs via influencing their transcription factor, migration, co-stimulatory receptors, immune checkpoints, and cytokines. We also focus on the currently important findings of Tregs metabolism including amino acid, fatty acid, and lactic acid metabolism of GC. The emerging role of microbiome and clinical combined therapy in modulating Tregs in GC treatment is also summarized. Meanwhile, this review recapitulates a novel regulator, magnesium, is involved in mediating Tregs in GC. These research advances on Treg-related strategies provide new insights and challenges for GC progression, treatment, and prognosis. And we hope our review can stimulate further discovery and implication of mediators and pathways targeting Tregs.

Background: The only curative option for patients with locally or locally advanced adrenocortical carcinoma is primary tumor curative sexual resection (ACC). However, overall survival remains low, with most deaths occurring within the first 2 years following surgery. The 5-year survival rate after surgery is less than 30%. As a result, more accurate prognosis-related predictive biomarkers must be investigated urgently to detect patients’ disease status after surgery.Methods: Data from FerrDb were obtained to identify ferroptosis-related genes, and ACC gene expression profiles were collected from the GEO database to find differentially expressed ACC ferroptosis-related genes using differential expression analysis. The DEFGs were subjected to Gene Ontology gene enrichment analysis and KEGG signaling pathway enrichment analysis. PPI network building and predictive analysis were used to filter core genes. The expression of critical genes in ACC pathological stage and pan-cancer was then investigated. In recent years, immune-related factors, DNA repair genes, and methyltransferase genes have been employed in diagnosing and prognosis of different malignancies. Cancer cells are mutated due to DNA repair genes, and highly expressed DNA repair genes promote cancer. Dysregulation of methyltransferase genes and Immune-related factors, which are shown to be significantly expressed in numerous malignancies, also plays a crucial role in cancer. As a result, we investigated the relationship of AURKA with immunological checkpoints, DNA repair genes, and methyltransferases in pan-cancer.Result: The DEGs found in the GEO database were crossed with ferroptosis-related genes, yielding 42 differentially expressed ferroptosis-related genes. Six of these 42 genes, particularly AURKA, are linked to the prognosis of ACC. AURKA expression was significantly correlated with poor prognosis in patients with multiple cancers, and there was a significant positive correlation with Th2 cells. Furthermore, AURKA expression was positively associated with tumor immune infiltration in Lung adenocarcinoma (LUAD), Liver hepatocellular carcinoma (LIHC), Sarcoma (SARC), Esophageal carcinoma (ESCA), and Stomach adenocarcinoma (STAD), but negatively correlated with the immune score, matrix score, and calculated score in these tumors. Further investigation into the relationship between AURKA expression and immune examination gene expression revealed that AURKA could control the tumor-resistant pattern in most tumors by regulating the expression level of specific immune examination genes.Conclusion: AURKA may be an independent prognostic marker for predicting ACC patient prognosis. AURKA may play an essential role in the tumor microenvironment and tumor immunity, according to a pan-cancer analysis, and it has the potential to be a predictive biomarker for multiple cancers.

Endothelial-mesenchymal transition (EndMT) is a differentiation process in which endothelial cells lose their own characteristics and acquire mesenchymal-like characteristics, which contributes to the formation and development of atherosclerotic plaques. Until now, there is still a lack of effective measures to treat atherosclerosis (AS), so there is an urgent need to understand the underlying mechanisms of AS. In addition, although various studies have shown that EndMT is involved in the pathological stages of cardiovascular diseases, such as myocardial fibrosis, myocardial hypertrophy, and hypertension, the specific molecular mechanisms driving EndMT are still in the exploratory stage. In this review, we review the role of histone modifications (methylation, demethylation and acetylation, deacetylation) on EndMT in cardiovascular disease, aiming to target histone-modifying enzymes to guide cardiovascular disease therapy.

Autophagy is a conserved cellular self-digesting process that degrades obsoleting proteins and cellular components and plays a crucial role in the tumorigenesis, metastasis, and drug resistance of various tumors such as gastric cancer (GC). As a hotspot in molecular biology, non-coding RNAs (ncRNAs) are involved in the regulation of multiple biological processes, such as autophagy. Increasing evidence indicate that various ncRNAs exert double roles in the initiation and progression of GC, either serve as oncogenes or tumor suppressors. Recent studies have shown that some ncRNAs could modulate autophagy activity in GC cells, which would affect the malignant transformation and drug resistance. Whether the function of ncRNAs in GC is dependent on autophagy is undefined. Therefore, identifying the underlying moleculr targets of ncRNAs in autophagy pathways and the role of ncRNA-regulated autophagy in GC could develop new treatment interventions for this disease. This review summarizes the autophagy process and its role in GC, and the regulatory mechanisms of ncRNAs, as well as focuses on the dual role of ncRNAs-mediated autophagy in GC, for the development of potential therapeutic strategies in GC patients.

Gastrointestinal (GI) cancers, one of the most lethal cancers nowadays, have caused millions of deaths. The tumor microenvironment (TME) is a complex ecosystem containing multiple cells, such as immune cells, cancer cells, and endothelial cells. Tumor-associated macrophages (TAMs), the predominant cells infiltrating the TME, have been verified to play a crucial role in regulating tumor progression. Noncoding RNAs (ncRNAs) are involved in mediating tumor-infiltrating immune cells, including TAMs. GI cancer cells produce various ncRNAs to modulate TAM infiltration and polarization. Meanwhile, ncRNAs play a pivotal role in macrophage and cancer cell metabolic reprogramming. Furthermore, macrophages mediate the impact of ncRNAs on chemoresistance, metastasis, and progression of GI cancer. In this review, we summarize recent research advances in the crosstalk between macrophages and GI cancer regulated by ncRNAs. Moreover, we propose the promising role of ncRNAs as potential targets and prognostic biomarkers in cancer treatment, hoping to facilitate the identification of new targets for immunotherapy.

Abstract Background The shape of the exposure-response curve for long-term ambient fine particulate (PM2.5) exposure and cause-specific mortality is poorly understood, especially for rural populations and underrepresented minorities. Methods We used hybrid machine learning and Cox proportional hazard models to assess the association of long-term PM2.5 exposures on specific causes of death for 53 million U.S. Medicare beneficiaries (aged ≥65) from 2000 to 2008. Models included strata for age, sex, race, and ZIP code and controlled for neighborhood socio-economic status (SES) in our main analyses, with approximately 4 billion person-months of follow-up, and additionally for warm season average of 1-h daily maximum ozone exposures in a sensitivity analysis. The impact of non-traffic PM2.5 on mortality was examined using two stage models of PM2.5 and nitrogen dioxide (NO2). Results A 10 μg /m3 increase in 12-month average PM2.5 prior to death was associated with a 5% increase in all-cause mortality, as well as an 8.8, 5.6, and 2.5% increase in all cardiovascular disease (CVD)-, all respiratory-, and all cancer deaths, respectively, in age, gender, race, ZIP code, and SES-adjusted models. PM2.5 exposures, however, were not associated with lung cancer mortality. Results were not sensitive to control for ozone exposures. PM2.5-mortality associations for CVD- and respiratory-related causes were positive and significant for beneficiaries irrespective of their sex, race, age, SES and urbanicity, with no evidence of a lower threshold for response or of lower Risk Ratios (RRs) at low PM2.5 levels. Associations between PM2.5 and CVD and respiratory mortality were linear and were higher for younger, Black and urban beneficiaries, but were largely similar by SES. Risks associated with non-traffic PM2.5 were lower than that for all PM2.5 and were null for respiratory and lung cancer-related deaths. Conclusions PM2.5 was associated with mortality from CVD, respiratory, and all cancer, but not lung cancer. PM2.5-associated risks of CVD and respiratory mortality were similar across PM2.5 levels, with no evidence of a threshold. Blacks, urban, and younger beneficiaries were most vulnerable to the long-term impacts of PM2.5 on mortality.

Path planning algorithms for unmanned aerial or ground vehicles rely on Global Positioning System (GPS) information for localization in many surveillance and reconnaissance applications. However, disruption of GPS signals, by intention or otherwise, can render these algorithms ineffective. This paper provides a way of addressing this issue by leveraging range information from additionally placed stationary objects in the environment called Landmarks (LMs). The placement of LMs and the route followed by the vehicle is posed as an integer program such that the total travel and LM placement cost is minimized. The proposed formulation of the optimization problem also allows for a limited field-of-view of the sensor on-board the vehicle. For instances that are hard to solve for optimal solutions using the integer program, we present two fast heuristics to find good feasible solutions. We provide a systematic framework and algorithms for the problem, and evaluate the system using numerical, simulation and experimental results.

Background: Our understanding of the impact of long-term exposures to PM2.5 constituents and sources on mortality is limited. Objectives: To examine associations between long-term exposures to PM2.5 constituents and sources and cause-specific mortality in US older adults. Methods: We obtained demographic and mortality data for 15.4 million Medicare beneficiaries living within the conterminous United States (US) between 2000 and 2008. We assessed PM2.5 constituents exposures for each beneficiary and used factor analysis and residual-based methods to characterize PM2.5 sources and mixtures, respectively. In age-, sex-, race- and site- stratified Cox proportional hazard models adjusted for neighborhood socio-economic status (SES), we assessed associations of individual PM2.5 constituents, sources, and mixtures and cause-specific mortality and examined modification of these associations by participant demographics and location of residence. We assessed the robustness of our findings to additional adjustment for behavioral risk factors and to alternate exposure definitions and exposure windows. Results: Hazard ratios (HR) were highest for all causes of death, except COPD, for PM2.5 constituents and the coal combustion-related PM2.5 components, with no evidence of confounding by behavioral covariates. We further found Pb and metal-related PM2.5 components to be significantly associated with increased HR of all causes of death, except COPD and lung cancer mortality, and nitrate (NO3–) and silicon (Si) and associated source-related PM2.5 components (traffic and soil, respectively) to be significantly associated with increased all-cause, CVD, respiratory and all cancer-related mortality HR. Associations for other examined constituents and mortality were inconsistent or largely null. Our analyses of mixtures were generally consistent with these findings. Mortality HRs were greatest for minority, especially Black, low-income urban, younger, and male beneficiaries. Discussion: PM2.5 components related to coal combustion, traffic, and to a lesser extent, soil were strongly associated with mortality from CVD, respiratory disease, and cancer.

Background. The objective of this study was to develop a nomogram that can predict lymph node metastasis (LNM) in patients with cervical adenocarcinoma (cervical AC). Methods. A total of 219 patients with cervical AC who had undergone radical hysterectomy and lymphadenopathy between 2005 and 2021 were selected for this study. Both univariate and multivariate logistic regression analyses were performed to analyze the selected key clinicopathologic features and develop a nomogram and underwent internal validation to predict the probability of LNM. Results. Lymphovascular invasion (LVI), tumor size≥4 cm, and depth of cervical stromal infiltration were independent predictors of LNM in cervical AC. However, the Silva pattern was not found to be a significant predictor in the multivariate model. The Silva pattern was still included in the model based on the improved predictive performance of the model observed in the previous studies. The concordance index (C-index) of the model increased from 0.786 to 0.794 after the inclusion of the Silva pattern. The Silva pattern was found to be the strongest predictor of LNM among all the pathological factors investigated, with an OR of 4.37 in the nomogram model. The nomogram developed by incorporation of these four predictors performed well in terms of discrimination and calibration capabilities (C−index=0.794; 95% confidence interval (CI), 0.727–0.862; Brier score=0.127). Decision curve analysis demonstrated that the nomogram was clinically effective in the prediction of LNM. Conclusion. In this study, a nomogram was developed based on the pathologic features, which helped to screen individuals with a higher risk of occult LNM. As a result, this tool may be specifically useful in the management of individuals with cervical AC and help gynecologists to guide clinical individualized treatment plan.

Atherosclerosis is associated with various pathological manifestations, such as ischemic heart disease, ischemic stroke, and peripheral arterial disease, and remains a leading cause of public health concern. Atherosclerosis is an inflammatory disease characterized by endothelial dysfunction; vascular inflammation; and the deposition of lipids, cholesterol, calcium, and cellular debris within the vessel wall intima. In-depth studies of gut flora in recent years have shown that bacterial translocation and the existence of bacterial active products in blood circulation can affect the inflammatory state of the whole blood vessel. The gut flora is considered to be a large “secretory organ,” which produces trimethylamine-N-oxide (TMAO), short-chain fatty acids and secondary bile acids by breaking down the ingested food. Studies have shown that TMAO is an independent risk factor for the occurrence of malignant adverse cardiovascular events, but whether it is harmful or beneficial to patients with cardiovascular diseases with mild or no clinical manifestations remains controversial. We review the relationship between TMAO and its precursor (L-carnitine) and coronary atherosclerosis and summarize the potential molecular mechanism and therapeutic measures of TMAO on coronary atherosclerosis.

Compared with the young, the elderly (age greater than or equal to 60 years old) vulnerable road users (VRUs) face a greater risk of injury or death in a traffic accident. A contributing vulnerability is the aging processes that affect their brain structure. The purpose of this study was to investigate the injury mechanisms and establish head AIS 4+ injury tolerances for the elderly VRUs based on various head injury criteria. A total of 30 elderly VRUs accidents with detailed injury records and video information were selected and the VRUs’ kinematics and head injuries were reconstructed by combining a multi-body system model (PC-Crash and MADYMO) and the THUMS (Ver. 4.0.2) FE models. Four head kinematic-based injury predictors (linear acceleration, angular velocity, angular acceleration, and head injury criteria) and three brain tissue injury criteria (coup pressure, maximum principal strain, and cumulative strain damage measure) were studied. The correlation between injury predictors and injury risk was developed using logistical regression models for each criterion. The results show that the calculated thresholds for head injury for the kinematic criteria were lower than those reported in previous literature studies. For the brain tissue level criteria, the thresholds calculated in this study were generally similar to those of previous studies except for the coup pressure. The models had higher (>0.8) area under curve values for receiver operator characteristics, indicating good predictive power. This study could provide additional support for understanding brain injury thresholds in elderly people.

Background: The impact of long-term exposure to nitrogen dioxide (NO2) on cause-specific mortality is poorly understood. Objective: To assess mortality risks associated with long-term NO2 exposure and evaluate confounding of this association. Methods: We examined the association between 12-month moving average NO2 exposure and cause-specific mortality in 14.1 million US Medicare beneficiaries between 2000 and 2008. Associations were examined using age, gender, and race-stratified and state-adjusted Poisson regression models. We assessed the potential for confounding by PM2.5 and behavioral covariates and unmeasured confounding by decomposing NO2 into its spatial and spatio-temporal components. Results: We found significant associations between 12-month NO2 exposure and increased mortality from all-causes [risk ratio (RR): 1.052; 95% CI: 1.051, 1.054; per 10 ppb], cardiovascular (CVD) (1.133; 95% CI: 1.130, 1.137) and respiratory disease (1.050; 95% CI: 1.044, 1.056), all cancers (1.021; 95% CI: 1.017, 1.025), ischemic heart disease (IHD) (1.221; 95% CI: 1.217, 1.226), cerebrovascular (CBV) disease (1.092; 95% CI: 1.085, 1.100), and for the first time pneumonia (1.275; 95% CI: 1.263, 1.287). Associations generally remained positive and statistically significant after adjustment for PM2.5 and behavioral factors. Conclusions: Our findings provide additional evidence of the increased risk posed by long-term NO2 exposures on increased mortality from all-causes, CVD, respiratory disease, IHD, CBV, and cancer and provide new evidence of their impact on mortality from pneumonia. Unmeasured confounding of these associations was present, however, demonstrating the need to understand sources of this confounding.

BackgroundThe aim was to develop a personalized survival prediction deep learning model for adenosarcoma patients using the surveillance, epidemiology and end results (SEER) database.MethodsA total of 797 uterine adenosarcoma patients were enrolled in this study. Duplicated and useless variables were excluded, and 15 variables were selected for further analyses, including age, grade, positive lymph nodes or not, marital status, race, tumor extension, stage, and surgery or not. We created our deep survival learning (DSL) model to manipulate the data, which was randomly split into a training set (n = 519, 65%), validation set (n = 143, 18%) and testing set (n = 143, 18%). The Cox proportional hazard (CPH) model was also included comparatively. Finally, personalized survival curves were plotted for randomly selected patients.ResultsThe c-index for the CPH model was 0.726, and the Brier score was 0.17. For our deep survival learning model, we achieved a c-index of 0.774 and a Brier score of 0.14 in the external testing set. In addition, the limitations of the traditional staging system were revealed, and a personalized survival prediction system based on our risk scoring grouping was developed.ConclusionsOur study developed a deep neural network model for adenosarcoma. The performance of this model was superior to that of the traditional Cox proportional hazard model. In addition, a personalized survival prediction system was developed based on our deep survival learning model, which provided more accurate prognostic information for adenosarcoma patients.

Xianglian pill (XLP) is a typical traditional Chinese herbal medicine prescription composed of Coptidis Rhizoma and Aucklandiae Radix. It has been used to treat gastrointestinal disease for centuries. In the present study, the potential mechanisms of XLP in the treatment of ulcerative colitis (UC) were predicted by integrative pharmacology-based approach. Then, the main compounds of XLP were detected by liquid chromatography-mass spectrometry (LC-MS/MS). Finally, we verified the mechanism of XLP in the treatment of UC in a dextran sulfate sodium (DSS) model. C57BL/6 mice were randomly divided into the control group, DSS group, 5-aminosalicylic acid (5-ASA) group which was used as the positive drug control, XLP low, medium, and high dose group, with 10 mice per group. Except for the control group, acute colitis model was induced in the other mice by administering 3% DSS for consecutive 7 days. Mice in 5-ASA and XLP groups were administered with 5-ASA (50 mg/kg) or XLP (0.8, 1.6, 3.2 g/kg) via oral gavage once per day respectively. Body wight and disease activity index were assay during drug intervention. On day 8, all animals in this experiment were sacrificed and colon tissues were collected for analysis after measurement of the length. The results showed that XLP alleviate DSS -induced acute colitis in mice, including inhibition the secretion of pro-inflammatory cytokines, repairing the dysfunction of intestinal epithelial barrier, enhanced autophagy, and blocked the activation of PI3K/Akt/mTOR pathway. Furthermore, inhibiting autophagy by 3-methyladenine attenuated the protective effects of XLP on colitis. The underlying mechanism may be that Xianglian pill promote autophagy by blocking the activation of PI3K/Akt/mTOR signaling pathway.

Abstract Background Systems of governance play a key role in the operation and performance of health systems. In the past six decades, China has made great advances in strengthening its health system, most notably in establishing a health insurance system that enables residents of rural areas to achieve access to essential services. Although there have been several studies of rural health insurance schemes, these have focused on coverage and service utilization, while much less attention has been given to the role of governance in designing and implementing these schemes. Methods Information from publications and policy documents relevant to the development of two rural health insurance policies in China was obtained, analysed, and synthesise. 92 documents on CMS (Cooperative Medical Scheme) or NCMS (New Rural Cooperative Medical Scheme) from four databases searched were included. Data extraction and synthesis of the information were guided by a framework that drew on that developed by the WHO to describe health system governance and leadership. Results We identified a series of governance practices that were supportive of progress, including the prioritisation by the central government of health system development and certain health policies within overall national development; strong government commitment combined with a hierarchal administrative system; clear policy goals coupled with the ability for local government to adopt policy measures that take account of local conditions; and the accumulation and use of the evidence generated from local practices. However these good practices were not seen in all governance domains. For example, poor collaboration between different government departments was shown to be a considerable challenge that undermined the operation of the insurance schemes. Conclusions China’s success in achieving scale up of CMS and NCMS has attracted considerable interest in many low and middle income countries (LMICs), especially with regard to the schemes’ designs, coverage, and funding mechanisms. However, this study demonstrates that health systems governance may be critical to enable the development and operation of such schemes. Given that many LMICs are expanding health financing system to cover populations in rural areas or the informal sectors, we argue that strengthening specific practices in each governance domain could inform the adaptation of these schemes to other settings.

Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa.

Thoracic injuries occur frequently in minivan-to-pedestrian impact accidents and can cause substantial fatalities. The present research work investigates the human thoracic responses and injury risks in minivan-to-pedestrian impacts, when changing the minivan front-end design and the impact velocity, by using computational biomechanics model. We employed three typical types of minivan model of different front-end designs that are quite popular in Chinese market and considered four impact velocities (20, 30, 40, and 50 km/h). The contact time of car to thorax region (CTCTR), thorax impact velocity, chest deformation, and thoracic injury risks were extracted for the investigation. The results indicate that the predicted pedestrian kinematics, injury responses, and thoracic injury risks are strongly affected by the variation of the minivan front-end design and impact velocity. The pedestrian thoracic injury risks increase with the increasing vehicle impact velocity. It is also revealed that the application of the extra front bumper is beneficial for reducing the thoracic injury risk, and a relatively flatter minivan front-end design gives rise to a higher thoracic injury risk. This study is expected to be served as theoretical references for pedestrian protection design of minivans.

Tubeimoside-1 (TBMS1) is a triterpenoid saponin with potent anticancer properties. In this study, for the first, we examined the anti-proliferative effects of TBMS1 in human bladder cancer T24 cells and its ability to induce apoptosis and cell cycle arrest. Our results demonstrated that TBMS1 decreased the cell viability of bladder cancer T24 cells in a dose-dependent manner. Flow cytometric analysis showed that TBMS1 significantly triggered apoptosis in T24 cells and arrested cell cycle at G2/M phase in a dose-dependent manner. Further characterization demonstrated that TBMS1-induced apoptosis is associated with dissipation in mitochondrial membrane potential (ΔΨm), down-regulation of Bcl-2, and up-regulation of Bax and p21 in TBMS1-treated T24 cells. These in vitro results suggested that TBMS1 is an effective anti-bladder cancer natural compound that worth further mechanistic and therapeutic studies in human bladder cancer.

Tubeimoside-1 (TBMS1) is a triterpenoid saponin with potent anticancer properties. In this study, for the first, we examined the anti-proliferative effects of TBMS1 in human bladder cancer T24 cells and its ability to induce apoptosis and cell cycle arrest. Our results demonstrated that TBMS1 decreased the cell viability of bladder cancer T24 cells in a dose-dependent manner. Flow cytometric analysis showed that TBMS1 significantly triggered apoptosis in T24 cells and arrested cell cycle at G2/M phase in a dose-dependent manner. Further characterization demonstrated that TBMS1-induced apoptosis is associated with dissipation in mitochondrial membrane potential (??m), down-regulation of Bcl-2, and up-regulation of Bax and p21 in TBMS1-treated T24 cells. These in vitro results suggested that TBMS1 is an effective anti-bladder cancer natural compound that worth further mechanistic and therapeutic studies in human bladder cancer.

Light emission from carbon dots (CDs) is of great interest in both electroluminescence and photoluminescence. Herein, we construct electroluminescent and photoluminescent light-emitting diodes (LEDs) from emitters of CDs. The electroluminescent LED with host–guest-doped dual emissive layers (EMLs) of [poly(9-vinylcarbazole) (PVK)-CDs] × 2 gives satisfactory electro-optical properties, with maximum luminance of 560 cd m−2 at 16 V, luminous efficiency of 0.183 cd A−1, power efficiency of 0.082 lm W−1, and external quantum efficiency of 0.25%, which are superior to the counterparts with single-EML of CDs, single-EML of [PVK-CDs], and triple-EMLs of [PVK-CDs] × 3. These enhanced properties are rationally ascribed to optimization of the device architecture, carrier balance improvement, and reduction in concentration-induced quenching. The electroluminescent LEDs also show color evolution from PVK to CDs, and/or to the PVK/CDs interface, with increasing driving voltages, owing to incomplete energy transfer from PVK to CDs. Highly efficient photoluminescent LEDs with 365- and 395-nm UV excitation are demonstrated. With a CDs : polyvinyl pyrrolidone ratio of 1 : 3, the 365-nm excited photoluminescent LED gives a maximum luminance of 512 347 cd m−2 with a power efficiency of 25.2 lm W−1, while the 395-nm excited photoluminescent device gives a maximum luminance of 670 954 cd m−2 with a power efficiency of 22.0 lm W−1, with both showing yellow emission. Our experiments provide some new ideas for broadening CD applications and advancing LEDs. [ABSTRACT FROM AUTHOR]