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Da Ke,1 Jian Ni,1 Yuan Yuan,1 Mingzhen Cao,1 Si Chen,2 Heng Zhou1 1Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People’s Republic of China; 2Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People’s Republic of ChinaCorrespondence: Heng Zhou, Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China, Email hengzhou@whu.edu.cnPurpose: Studies have shown that neutrophil-mediated formation of neutrophil extracellular traps (NETs) leads to increased inflammatory response and cellular tissue damage during myocardial infarction (MI). We aimed to identify and validate possible hub genes in the process of NETs-mediated cell damage.Methods: We performed an immune cell infiltration analysis of the MI transcriptome dataset based on CIBERSORT and ssGSEA algorithms. Gene expression profiles of NETs formation (GSE178883) were used to analyze the physiological processes of peripheral blood neutrophils after phorbol myristate acetate (PMA) stimulation. Bioinformatics and machine learning algorithms were utilized to find candidate hub genes based on NETs-related genes and transcriptome datasets (GSE66360 and GSE179828). We generated the receiver operating curve (ROC) to evaluate the diagnostic value of hub genes. Next, the correlation between hub genes and immune cells was analyzed using CIBERSORT, ssGSEA and xCell algorithms. Finally, we used quantitative real-time PCR (qRT-PCR) and immunohistochemistry to verify gene expression.Results: Immune cell infiltration analysis revealed that inflammatory cells such as neutrophils were highly expressed in the peripheral blood of patients with MI. Functional analysis of differentially expressed genes (DEGs) in GSE178883 indicated that the potential pathogenesis lies in immune terms. Using weighted gene co-expression network analysis (WGCNA) and machine learning algorithms, we finally identified the seven hub genes (FCAR, IL1B, MMP9, NFIL3, CXCL2, ICAM1, and ZFP36). The qRT-PCR results showed that IL-1B, MMP9, and NFIL3 mRNA expression was up-regulated in the MI group compared to the control. Immunohistochemical results showed high MMP9, IL-1B, and NFIL3 expression in the infarcted area compared to the non-infarcted area and sham-operated groups.Conclusion: We identified seven hub genes associated with NETs-mediated cellular damage during MI. Our results may provide insights into the mechanisms of neutrophil-mediated cell injury during MI. Keywords: myocardial infarction, neutrophils, cell damage, neutrophil extracellular traps, bioinformatics, endothelial cells

Abstract Background The relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging. Methods We included 3269 participants from the National Health and Nutrition Examination Survey (2009–2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera–Doubal method’s calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging. Results Periodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging. Conclusions Periodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk.

Abstract Ionogels are promising material candidates for ionotronics due to their excellent ionic conductivity, stretchability, and thermal stability. However, it is challenging to develop 3D printable ionogels with both excellent electrical and mechanical properties. Here, we report a highly conductive and stretchable nanostructured (CSN) ionogel for 3D printing ionotronic sensors. We propose the photopolymerization-induced microphase separation strategy to prepare the CSN ionogels comprising continuous conducting nanochannels intertwined with cross-linked polymeric framework. The resultant CSN ionogels simultaneously achieves high ionic conductivity (over 3 S m−1), high stretchability (over 1500%), low degree of hysteresis (0.4% at 50% strain), wide-temperature-range thermostability (−72 to 250 °C). Moreover, its high compatible with DLP 3D printing enables the fabrication of complex ionogel micro-architectures with high resolution (up to 5 μm), which allows us to manufacture capacitive sensors with superior sensing performances. The proposed CSN ionogel paves an efficient way to manufacture the next-generation capacitive sensors with enhanced performance.

Abstract Organic light-emitting diodes (OLEDs) offer the advantage of flexibility; however, the use of traditional transparent anode ITO limits further extension of their flexible characteristics. In this study, we propose employing an polymer polybenzodifuranedione (PBFDO) as a flexible transparent anode instead of the rigid ITO. To address the issue encountered during the PBFDO solution spin-coating process, we introduced n-butanol into the PBFDO conductive solution to reduce its viscosity and freezing point by modulating intermolecular hydrogen bonding interactions. Consequently, high-quality PBFDO films with high conductivity, superior transmittance, and low surface roughness were successfully obtained via spin-coating. Moreover, due to its proper work function, regular molecular stacking, and low refractive index properties, PBFDO electrode facilitate efficient carrier injection and transport as well as photon extraction. The resulting device utilizing a PBFDO anode combined with Super Yellow as the light-emitting layer exhibited excellent performance characteristics including a normal threshold voltage of 2.6 V and a maximum luminous efficiency of 12.8 cd A−1 comparable to that device based on the ITO electrode. Furthermore, flexible device also achieved satisfactory performance (7.7 cd A−1) when using the PEN substrate.

Abstract The purpose of this study was to investigate the causal association between unhealthy lifestyle style factors and the risk of colorectal cancer, with the aim of preventing the occurrence of colorectal cancer by modifying unhealthy lifestyles. A two-sample Mendelian randomization (MR) approach was employed in this study, utilizing the inverse-variance weighted method as the primary research method. This MR analysis analyzed data of 3022 colorectal cancer cases and 174,006 controls from the FinnGen database. Single nucleotide polymorphisms (SNPs) associated with unhealthy lifestyle factors were selected as instrumental variables (IVs), including two obesity-related indicators, BMI (body mass index) and WHR (waist-to-hip ratio). Four phenotypes of smoking (smoking initiation, ever smoked, smoking per day, smoking cessation) and one phenotype of alcohol consumption (drinks per week). Four phenotypes of physical activity (accelerometer-based physical activity, moderate-to-vigorous physical activity, vigorous physical activity, strenuous sports or other exercises). All SNPs were obtained from published genome-wide association studies. The study found that the obesity-related indicator, higher WHR (OR = 1.38, 95% CI 1.12–1.70; P = 0.002) were associated with an increased risk of colorectal cancer, and two smoking phenotypes, cigarettes per day(OR = 1.30, 95% CI 1.01–1.68; P = 0.042)and smoking initiation (OR = 3.48, 95% CI 1.15–10.55; P = 0.028), were potentially associated with an increased risk of colorectal cancer. However, there was no evidence to suggest that physical activities and alcohol consumption were associated with colorectal cancer (all p > 0.05). In addition, the study detected no pleiotropy (all p > 0.05). This MR analysis indicates a causal association between a higher waist-to-hip ratio and the risk of colorectal cancer and a suggestive association between smoking and the risk of colorectal cancer among Europeans. These findings contribute to the understanding of the etiology of colorectal cancer and have potential implications for its prevention.

Abstract Objective Tumor immune infiltration leads to poor prognosis of gastric cancer patients and seriously affects the life quality of gastric cancer patients. This study was based on bioinformatics to screen prognostic biomarkers in patients with high degree of immune invasion of gastric cancer. Meanwhile, the action of biomarker CCDC80 was explored in gastric cancer by cell and tumorigenesis experiments, to provide reference for the cure of gastric cancer patients. Methods Data sets and clinical massage on gastric cancer were collected from TCGA database and GEO database. ConsensusClusterPlus was used to cluster gastric cancer patients based on the 28 immune cells infiltration in ssGSEA. R “Limma” package was applied to analyze differential mRNAs between Cluster 1 and Cluster 2. Differential expression genes were screened by single factor analysis. Stemness markers (SERPINF1, DCN, CCDC80, FBLN5, SPARCL1, CCL14, DPYSL3) were identified for differential expression genes. Prognostic value of CCDC80 was evaluated in gastric cancer. Differences in genomic mutation and tumor microenvironment immune infiltration were assessed between high or low CCDC80. Finally, gastric cancer cells (HGC-27 and MKN-45) were selected to evaluate the action of silencing CCDC80 on malignant characterization, macrophage polarization, and tumor formation. Results Bioinformatics analysis showed that CCDC80, as a stemness marker, was significantly overexpressed in gastric cancer. CCDC80 was also related to the degree of gastric cancer immune invasion. CCDC80 was up-expressed in cells of gastric cancer. Silencing CCDC80 inhibited malignant characterization and subcutaneous tumor formation of gastric cancer cells. High expression of CCDC80 was positive correspondence with immune invasion. Silencing CCDC80 inhibited M2 polarization and promoted M1 polarization in tumor tissues. In addition, gastric cancer patients were likely to have mutations in CDH1, ACTRT1, GANAB, and CDH10 genes in the High-CCDC80 group. Conclusion Silencing CCDC80, a prognostic biomarker in patients with immune invasion of gastric cancer, could effectively inhibit the malignant characterization, M2 polarization, and tumor formation of gastric cancer.

Abstract Background Actinobacillus pleuropneumoniae is a serious pathogen in pigs. The abundant application of antibiotics has resulted in the gradual emergence of drugresistant bacteria, which has seriously affected treatment of disease. To aid measures to prevent the emergence and spread of drug-resistant bacteria, herein, the kill rate and mutant selection window (MSW) of danofloxacin (DAN) against A. pleuropneumoniae were evaluated. Methods For the kill rate study, the minimum inhibitory concentration (MIC) was tested using the micro dilution broth method and time-killing curves of DAN against A. pleuropneumoniae grown in tryptic soy broth (TSB) at a series drug concentrations (from 0 to 64 MIC) were constructed. The relationships between the kill rate and drug concentrations were analyzed using a Sigmoid Emax model during different time periods. For the MSW study, the MIC99 (the lowest concentration that inhibited the growth of the bacteria by ≥ 99%) and mutant prevention concentration (MPC) of DAN against A. pleuropneumoniae were measured using the agar plate method. Then, a peristaltic pump infection model was established to simulate the dynamic changes of DAN concentrations in pig lungs. The changes in number and sensitivity of A. pleuropneumoniae were measured. The relationships between pharmacokinetic/pharmacodynamic parameters and the antibacterial effect were analyzed using the Sigmoid Emax model. Results In kill rate study, the MIC of DAN against A. pleuropneumoniae was 0.016 µg/mL. According to the kill rate, DAN exhibited concentration-dependent antibacterial activity against A. pleuropneumoniae. A bactericidal effect was observed when the DAN concentration reached 4–8 MIC. The kill rate increased constantly with the increase in DAN concentration, with a maximum value of 3.23 Log10 colony forming units (CFU)/mL/h during the 0–1 h period. When the drug concentration was in the middle part of the MSW, drugresistant bacteria might be induced. Therefore, the dosage should be avoided to produce a mean value of AUC24h/MIC99 (between 31.29 and 62.59 h. The values of AUC24h/MIC99 to achieve bacteriostatic, bactericidal, and eradication effects were 9.46, 25.14, and > 62.59 h, respectively. Conclusion These kill rate and MSW results will provide valuable guidance for the use of DAN to treat A. pleuropneumoniae infections.

Abstract Background Periodontitis is strongly associated with type 2 diabetes (T2D) that results in serious complications and mortality. However, the pathogenic role of periodontitis in the development of T2D and the underlain mechanism have not been fully elucidated. Methods A Mendelian randomization (MR) was performed to estimate the causality between two diseases. Bioinformatics tools, including gene ontology and pathway enrichment analyses, were employed to analyze the common differentially expressed genes (DEGs) in periodontitis and T2D. MR and colocalization analyses were then utilized to investigate the causal associations between potential pathogenic gene expression and the risk of T2D. Single cell-type expression analysis was further performed to detect the cellular localization of these genes. Results Genetically predicted periodontitis was associated with a higher risk of T2D (OR, 1.469; 95% CI, 1.117–1.930; P = 0.006) and insulin resistance (OR 1.034; 95%CI 1.001–1.068; P = 0.041). 79 common DEGs associated with periodontitis and T2D were then identified and demonstrated enrichment mainly in CXC receptor chemokine receptor binding and interleutin-17 signaling pathway. The integration of GWAS with the expression quantitative trait locis of these genes from the peripheral blood genetically prioritized 6 candidate genes, including 2 risk genes (RAP2A, MCUR1) and 4 protective genes (WNK1, NFIX, FOS, PANX1) in periodontitis-related T2D. Enriched in natural killer cells, RAP2A (OR 4.909; 95% CI 1.849–13.039; P = 0.001) demonstrated high risk influence on T2D, and exhibited strong genetic evidence of colocalization (coloc.abf-PPH4 = 0.632). Conclusions This study used a multi-omics integration method to explore causality between periodontitis and T2D, and revealed molecular mechanisms using bioinformatics tools. Periodontitis was associated with a higher risk of T2D. MCUR1, RAP2A, FOS, PANX1, NFIX and WNK1 may play important roles in the pathogenesis of periodontitis-related T2D, shedding light on the development of potential drug targets.

Abstract Background Hepatocellular carcinoma (HCC) is a fatal malignancy with poor prognosis due to lack of effective clinical interference. DCAF1 plays a vital role in regulating cell growth and proliferation, and is involved in the progression of various malignancies. However, the function of DCAF1 in HCC development and the underlying mechanism are still unknown. This study aimed to explore the effect of DCAF1 in HCC and the corresponding molecular mechanism. Methods Quantitative real-time PCR, Western blot and immunostaining were used to determine DCAF1 expression in tumor tissues and cell lines. Subsequently, in vitro and in vivo experiments were conducted to explore the function of DCAF1 in tumor growth and metastasis in HCC. Coimmunoprecipitation, mass spectrometry and RNA sequencing were performed to identify the underlying molecular mechanisms. Results In this study, we found that DCAF1 was observably upregulated and associated with poor prognosis in HCC. Knockdown of DCAF1 inhibited tumor proliferation and metastasis and promoted tumor apoptosis, whereas overexpressing DCAF1 yielded opposite effects. Mechanistically, DCAF1 could activate the Akt signaling pathway by binding to PARD3 and enhancing its expression. We also found that the combined application of DCAF1 knockdown and Akt inhibitor could significantly suppress subcutaneous xenograft tumor growth. Conclusions Our study illustrates that DCAF1 plays a crucial role in HCC development and the DCAF1/PARD3/Akt axis presents a potentially effective therapeutic strategy for HCC. Graphical Abstract

Abstract Mouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential ‘CDCA pattern’ translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD.

To systematically investigate the factors affecting the performance of permeable concrete on road surfaces, blocks with different porosity, particle sizes, water-to-cement ratios, and cement-to-aggregate ratios were prepared. Additionally, varying amounts of admixtures were added to some blocks to explore the influence of the admixture types and content on the performance of permeable concrete. The results indicate that the larger the particle size of the aggregate used in the block preparation, the higher the permeability coefficient of the blocks and the lower the compressive strength. The water-to-cement ratio affects the strength of the cement matrix, resulting in variations in the block strength. A higher cement-to-aggregate ratio leads to a lower porosity in the permeable concrete, a higher cement matrix content, a reduced permeability coefficient, and an increased compressive strength of the blocks.

Abstract Multi-modal combination therapy is regarded as a promising approach to cancer treatment. Combining chemotherapy and phototherapy is an essential multi-modal combination therapy endeavor. Ivermectin (IVM) is a potent antiparasitic agent identified as having potential antitumor properties. However, the fact that it induces protective autophagy while killing tumor cells poses a challenge to its further application. IR780 iodide (IR780) is a near-infrared (NIR) dye with outstanding photothermal therapy (PTT) and photodynamic therapy (PDT) effects. However, the hydrophobicity, instability, and low tumor uptake of IR780 limit its clinical applications. Here, we have structurally modified IR780 with hydroxychloroquine, an autophagy inhibitor, to synthesize a novel compound H780. H780 and IVM can form H780-IVM nanoparticles (H-I NPs) via self-assembly. Using hyaluronic acid (HA) to modify the H-I NPs, a novel nano-delivery system HA/H780-IVM nanoparticles (HA/H-I NPs) was synthesized for chemotherapy-phototherapy of colorectal cancer (CRC). Under NIR laser irradiation, HA/H-I NPs effectively overcame the limitations of IR780 and IVM and exhibited potent cytotoxicity. In vitro and in vivo experiment results showed that HA/H-I NPs exhibited excellent anti-CRC effects. Therefore, our study provides a novel strategy for CRC treatment that could enhance chemo-phototherapy by modulating autophagy.

BackgroundThe adenosine–adenosine receptor pathway plays important roles in the immune system and inflammation. Four adenosine receptors (i.e., A1R, A2AR, A2BR, and A3R) have been identified. However, the roles of these receptors were different in the disease progress and even play opposite roles in the same disease. This study aims to investigate the roles of A1R/A2AR/A2BR/A3R activation in liver fibrosis.MethodsIntraperitoneal injection of CCl4 into C57BL/6 mice was used to induce liver fibrosis in the models. Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were used to evaluate the liver function. Hematoxylin and eosin (H&E) staining was used to investigate the pathological damage. Masson staining and Sirius Red staining were performed to evaluate the degree of collagen deposition. CCK8 and scratch assays were used to investigate the proliferation and migration ability of hepatic stellate cells (HSCs).ResultsBy using liver fibrosis mouse models, we observed that the A1R and A2AR agonists aggravated liver fibrosis, characterized by increasing ALT and AST levels, more serious liver pathological damage, and collagen deposition. However, the A2BR and A3R agonists alleviated liver fibrosis. Moreover, the A1R and A2AR agonist treatment promotes the proliferation and migration of HSC line LX2, while A2BR and A3R agonist treatment inhibited LX2 proliferation and migration. Consistently, A1R and A2AR agonist treatment elevated the expression of α-SMA and Col1α1 in LX2, whereas A2BR and A3R agonist treatment inhibited the expression of α-SMA and Col1α1 in LX2 cells. Additionally, 5′-N-ethyl-carboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration.ConclusionThis study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation.

IntroductionInsomnia is a common comorbidity symptom in major depressive disorder (MDD) patients. Abnormal brain activities have been observed in both MDD and insomnia patients, however, the central pathological mechanisms underlying the co-occurrence of insomnia in MDD patients are still unclear. This study aimed to explore the differences of spontaneous brain activity between MDD patients with and without insomnia, as well as patients with different level of insomnia.MethodsA total of 88 first-episode drug-naïve MDD patients including 44 with insomnia (22 with high insomnia and 22 with low insomnia) and 44 without insomnia, as well as 44 healthy controls (HC), were enrolled in this study. The level of depression and insomnia were evaluated by HAMD-17, adjusted HAMD-17 and its sleep disturbance subscale in all subjects. Resting-state functional and structural magnetic resonance imaging data were acquired from all participants and then were preprocessed by the software of DPASF. Regional homogeneity (ReHo) values of brain regions were calculated by the software of REST and were compared. Finally, receiver operating characteristic (ROC) curves were conducted to determine the values of abnormal brain regions for identifying MDD patients with insomnia and evaluating the severity of insomnia.ResultsAnalysis of variance showed that there were significant differences in ReHo values in the left middle frontal gyrus, left pallidum, right superior frontal gyrus, right medial superior frontal gyrus and right rectus gyrus among three groups. Compared with HC, MDD patients with insomnia showed increased ReHo values in the medial superior frontal gyrus, middle frontal gyrus, triangular inferior frontal gyrus, calcarine fissure and right medial superior frontal gyrus, medial orbital superior frontal gyrus, as well as decreased ReHo values in the left middle occipital gyrus, pallidum and right superior temporal gyrus, inferior temporal gyrus, middle cingulate gyrus, hippocampus, putamen. MDD patients without insomnia demonstrated increased ReHo values in the left middle frontal gyrus, orbital middle frontal gyrus, anterior cingulate gyrus and right triangular inferior frontal gyrus, as well as decreased ReHo values in the left rectus gyrus, postcentral gyrus and right rectus gyrus, fusiform gyrus, pallidum. In addition, MDD patients with insomnia had decreased ReHo values in the left insula when compared to those without insomnia. Moreover, MDD patients with high insomnia exhibited increased ReHo values in the right middle temporal gyrus, and decreased ReHo values in the left orbital superior frontal gyrus, lingual gyrus, right inferior parietal gyrus and postcentral gyrus compared to those with low insomnia. ROC analysis demonstrated that impaired brain region might be helpful for identifying MDD patients with insomnia and evaluating the severity of insomnia.ConclusionThese findings suggested that MDD patients with insomnia had wider abnormalities of brain activities in the prefrontal-limbic circuits including increased activities in the prefrontal cortex, which might be the compensatory mechanism underlying insomnia in MDD. In addition, decreased activity of left insula might be associated with the occurrence of insomnia in MDD patients and decreased activities of the frontal–parietal network might cause more serious insomnia related to MDD.

Abstract Siberian wildfire is of paramount importance in the carbon cycle and climate change as it is a major disturbance in the pan‐Arctic ecosystems. In recent decades, the Siberian wildfire regime has been shifting; however, less is known about its process‐based feedback mechanisms. By integrating in‐situ and satellite observational data sets as well as chemistry‐climate coupled modeling, we find that central Siberia has featured the most prominent wildfire escalation during the past two decades, which is closely related to hydrological drought with decreasing rainfall and drying soil under a fast‐warming Arctic. Furthermore, fire‐emitted aerosols compound the increasing wildfires via serving as cloud condensation nuclei and suppressing precipitation, forming self‐amplifying feedback. As the Arctic warming is projected to continue, wildfires are estimated to more than double by the end of this century. This work highlights the great importance of fire risk management based on a fundamental scientific understanding of the complex climate system.

Abstract The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG‐M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG‐M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC‐MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH‐mediated OXPHOS pathway, thereby inducing MG‐M2 polarization, promoting neuronal survival and exerting an anti‐AD role is elucidated.

The current popular traffic classification methods based on feature engineering and machine learning are difficult to obtain suitable traffic feature sets for multiple traffic classification tasks. Besides, data privacy policies prohibit network operators from collecting and sharing traffic data that might compromise user privacy. To address these challenges, we propose FedETC, a federated learning framework that allows multiple participants to learn global traffic classifiers, while keeping locally encrypted traffic invisible to other participants. In addition, FedETC adopts one-dimensional convolutional neural network as the base model, which avoids manual traffic feature design. In the experiments, we evaluate the FedETC framework for the tasks of both application identification and traffic characterization in a publicly available real-world dataset. The results show that FedETC can achieve promising accuracy rates that are close to centralized learning schemes.

Polyphenols are a group of naturally occurring compounds that possess a range of biological properties capable of potentially mitigating or preventing the progression of age-related cognitive decline and Alzheimer’s disease (AD). AD is a chronic neurodegenerative disease known as one of the fast-growing diseases, especially in the elderly population. Moreover, as the primary etiology of dementia, it poses challenges for both familial and societal structures, while also imposing a significant economic strain. There is currently no pharmacological intervention that has demonstrated efficacy in treating AD. While polyphenols have exhibited potential in inhibiting the pathological hallmarks of AD, their limited bioavailability poses a significant challenge in their therapeutic application. Furthermore, in order to address the therapeutic constraints, several polymer nanoparticles are being explored as improved therapeutic delivery systems to optimize the pharmacokinetic characteristics of polyphenols. Polymer nanoparticles have demonstrated advantageous characteristics in facilitating the delivery of polyphenols across the blood–brain barrier, resulting in their efficient distribution within the brain. This review focuses on amyloid-related diseases and the role of polyphenols in them, in addition to discussing the anti-amyloid effects and applications of polyphenol-based polymer nanoparticles.

Abstract Wildfires have long been regarded as one chief culprit in regional air pollution, and pose great impacts on climate change. Although climate forcing of wildfire smoke has been widely investigated, its influence on synoptic systems remains unclear. Based on measurement and modeling analysis, the impact of wildfire smoke on the development of a mid‐latitude cyclone was revealed for Canadian wildfires in early June of 2023. The radiative forcing induced by smoke at surface and in the atmosphere reached up to −150 and 100 W m−2, posing opposite tendencies of atmospheric stratification over the land and ocean. Such perturbations contributed to the enhancement and stagnation of the cyclone, which favored the transport of smoke from the fire‐intensive region, indicated by nearly 40% increment of PM2.5 mass flux. With escalating wildfire risk in the future, the inclusion of smoke aerosols' impacts on meteorology in weather forecast models is of great importance.

Abstract The applications of silica-based glass have evolved alongside human civilization for thousands of years. High-precision manufacturing of three-dimensional (3D) fused silica glass objects is required in various industries, ranging from everyday life to cutting-edge fields. Advanced 3D printing technologies have emerged as a potent tool for fabricating arbitrary glass objects with ultimate freedom and precision. Stereolithography and femtosecond laser direct writing respectively achieved their resolutions of ~50 μm and ~100 nm. However, fabricating glass structures with centimeter dimensions and sub-micron features remains challenging. Presented here, our study effectively bridges the gap through engineering suitable materials and utilizing one-photon micro-stereolithography (OμSL)-based 3D printing, which flexibly creates transparent and high-performance fused silica glass components with complex, 3D sub-micron architectures. Comprehensive characterizations confirm that the final material is stoichiometrically pure silica with high quality, defect-free morphology, and excellent optical properties. Homogeneous volumetric shrinkage further facilitates the smallest voxel, reducing the size from 2.0 × 2.0 × 1.0 μm3 to 0.8 × 0.8 × 0.5 μm3. This approach can be used to produce fused silica glass components with various 3D geometries featuring sub-micron details and millimetric dimensions. This showcases promising prospects in diverse fields, including micro-optics, microfluidics, mechanical metamaterials, and engineered surfaces.

Abstract Outdoor air pollution, particularly volatile organic compounds (VOCs), significantly contributes to the global health burden. Previous analyses of VOC exposure have typically focused on regional and national scales, thereby limiting global health burden assessments. In this study, we utilized a global chemistry-climate model to simulate VOC distributions and estimate related cancer risks from 2000 to 2019. Our findings indicated a 10.2% rise in global VOC emissions during this period, with substantial increases in Sub-Saharan Africa, the Rest of Asia, and China, but decreases in the U.S. and Europe due to reductions in the transportation and residential sectors. Carcinogenic VOCs such as benzene, formaldehyde, and acetaldehyde contributed to a lifetime cancer burden affecting 0.60 [95% confidence interval (95CI): 0.40–0.81] to 0.85 [95CI: 0.56–1.14] million individuals globally. We projected that between 36.4% and 39.7% of the global population was exposed to harmful VOC levels, with the highest exposure rates found in China (82.8–84.3%) and considerably lower exposure in Europe (1.7–5.8%). Open agricultural burning in less-developed regions amplified VOC-induced cancer burdens. Significant disparities in cancer burdens between high-income and low-to-middle-income countries were identified throughout the study period, primarily due to unequal population growth and VOC emissions. These findings underscore health disparities among different income nations and emphasize the persistent need to address the environmental injustice related to air pollution exposure.

Abstract Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle. Herein, we report a convenient and robust process to assemble a unique electrophile, an α-acyloxyenamide, through a one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups and facilitates ligand-directed labeling in proteins of interest. The reactive group has been successfully incorporated into a clinical drug targeting the EGFR L858R mutant, erlotinib, and a pan-kinase inhibitor. The resulting probes have been shown to be able to covalently engage a lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg2+, ATP-binding sites of kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine residues in kinases with covalent inhibition. Further application of this methodology to natural products has demonstrated its success in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new targeted covalent inhibitors (TCIs).

Abstract Osteoarthritis (OA) is a degenerative disease that significantly impairs quality of life. There is a pressing need for innovative OA therapies. While small extracellular vesicles (sEVs) show promising therapeutic effects against OA, their limited yield restricts clinical translation. Here, we devised a novel production system for sEVs that enhances both their yield and therapeutic properties. By stimulating mesenchymal stem cells (MSCs) using electromagnetic field (EMF) combined with ultrasmall superparamagnetic iron oxide (USPIO) particles, we procured an augmented yield of EMF-USPIO-sEVs. These vesicles not only activate anabolic pathways but also inhibit catabolic activities, and crucially, they promote M2 macrophage polarization, aiding cartilage regeneration. In an OA mouse model triggered by anterior cruciate ligament transection surgery, EMF-USPIO-sEVs reduced OA severity, and augmented matrix synthesis. Moreover, they decelerated OA progression through the microRNA-99b/MFG-E8/NF-κB signaling axis. Consequently, EMF-USPIO-sEVs present a potential therapeutic option for OA, acting by modulating matrix homeostasis and macrophage polarization.

Primary health care institutions should be the main force of China's medical and health service system and the cornerstone of the national health care system. During the COVID-19 pandemic, China's primary health care institutions played a critical role, but many deficiencies and weaknesses were also highlighted. Through systematic literature search and analysis, this article finds that China's primary health care institutions have some problems such as low demand for patient care, weak integration of the health system, weak service foundation, and insufficient emergency response capacity for public health emergencies. Accordingly, we put forward a strategy for the construction of primary health care institutions based on the 'Three Forces Theory', which aims to improve the primary medical and health care service system, upgrade the capacity of primary medical and health care services, and better fulfill the strategic goal of 'Healthy China 2030'.

Abstract The utilization of the dispersive Fourier transformation approach has enabled comprehensive observation of the birth process of dissipative solitons in fiber lasers. However, there is still a dearth of deep understanding regarding the extinction process of dissipative solitons. In this study, we have utilized a combination of experimental and numerical techniques to thoroughly examine the breathing dynamics of dissipative solitons during the extinction process in an Er-doped mode-locked fiber laser. The results demonstrate that the transient breathing dynamics have a substantial impact on the extinction stage of both steady-state and breathing-state dissipative solitons. The duration of transient breathing exhibits a high degree of sensitivity to variations in pump power. Numerical simulations are utilized to produce analogous breathing dynamics within the framework of a model that integrates equations characterizing the population inversion in a mode-locked laser. These results corroborate the role of Q-switching instability in the onset of breathing oscillations. Furthermore, these findings offer new possibilities for the advancement of various operational frameworks for ultrafast lasers. Graphical abstract

To understand the stability of deep underground engineering rocks at high temperatures, it is necessary to conduct comprehensive tests on the mechanical properties of the rocks. In this study, a series of true triaxial tests (TTT) were conducted on sandstones using a self-developed true triaxial testing system combined with XRD, FE-SEM and CT analyses. The study systematically examined the microstructural characteristics, physical phase behavior, deformation properties and internal fracture development of the sandstone before and after heat treatment. The results of the study show that sandstone has temperature-dependent true triaxial mechanical properties after heat treatment. The stress-strain characteristic curves of the post-peak portion from room temperature to 800 °C show a significant stress-reducing segment, indicating the presence of brittle behavior. In addition, when the temperature exceeds 1000 °C, the sandstone exhibits brittle-ductile change characteristics, with a peak stress threshold observed at 800 °C. Notably, the peak stresses corresponding to 800 °C increased by 84.5 %, 63.1 %, 47 %, and 49.8 %, respectively, compared with the room temperature intermediate principal stresses(IPS) ranging from 20 MPa to 50 MPa, respectively. Importantly, the linear Mogi-Coulomb criterion remains valid for the peak strength of the high-temperature sandstone, while the internal fracture damage pattern of the specimens shows an inverted ''Y'' or inverted ''W'' configuration. The internal fracture network of rock samples above 800 °C is more complex. Intergranular crack is the main form of microcracking. This experimental study on the mechanical properties of sandstone under the combined effects of high temperature and real triaxial stresses provides valuable guidance for the selection of sandstone parameters and safety evaluation of coal underground gasification roofs.

ObjectivesWilson disease (WD) is a rare autosomal recessive disorder caused by a mutation in the ATP7B gene. Neurological symptoms are one of the most common symptoms of WD. This study aims to construct a model that can predict the occurrence of neurological symptoms by combining clinical multidimensional indicators with machine learning methods.MethodsThe study population consisted of WD patients who received treatment at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from July 2021 to September 2023 and had a Leipzig score ≥ 4 points. Indicators such as general clinical information, imaging, blood and urine tests, and clinical scale measurements were collected from patients, and machine learning methods were employed to construct a prediction model for neurological symptoms. Additionally, the SHAP method was utilized to analyze clinical information to determine which indicators are associated with neurological symptoms.ResultsIn this study, 185 patients with WD (of whom 163 had neurological symptoms) were analyzed. It was found that using the eXtreme Gradient Boosting (XGB) to predict achieved good performance, with an MCC value of 0.556, ACC value of 0.929, AUROC value of 0.835, and AUPRC value of 0.975. Brainstem damage, blood creatinine (Cr), age, indirect bilirubin (IBIL), and ceruloplasmin (CP) were the top five important predictors. Meanwhile, the presence of brainstem damage and the higher the values of Cr, Age, and IBIL, the more likely neurological symptoms were to occur, while the lower the CP value, the more likely neurological symptoms were to occur.ConclusionsTo sum up, the prediction model constructed using machine learning methods to predict WD cirrhosis has high accuracy. The most important indicators in the prediction model were brainstem damage, Cr, age, IBIL, and CP. It provides assistance for clinical decision-making.

Summary: Background: Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM. Methods: This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18–75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%–11.0% [58.47–96.73 mmol/mol], body mass index (BMI) of 18–40 kg/m2, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%–10.5% [53.0–91.3 mmol/mol] and fasting plasma glucose (FPG)

Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.

Summary: Hydrodesulfurization (HDS) is a commonly used route for producing clean fuels in modern refinery. Herein, ammonium/amine-intercalated MoS2 catalysts with various content of 1T phase and S vacancies have been successfully synthesized. Along with the increment of 1T phase and S vacancies of MoS2, the initial reaction rate of the HDS of dibenzothiophene (DBT) can be improved from 0.09 to 0.55 μmol·gcat−1·s−1, accounting for a remarkable activity compared to the-state-of-the-art catalysts. In a combinatory study via the activity evaluation and catalysts characterization, we found that the intercalation species of MoS2 played a key role in generating more 1T phase and S vacancies through the ‘intercalation-deintercalation’ processes, and the hydrogenation and desulfurization of HDS can be significantly promoted by 1T phase and S vacancies on MoS2, respectively. This study provides a practically meaningful guidance for developing more advanced HDS catalysts by the intercalated MoS2-derived materials with an in-depth understanding of structure-function relationships.

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.

Gynostemma pentaphyllum (Thunb.) Makino is an important producer of dammarene-type triterpenoid saponins. These saponins (gypenosides) exhibit diverse pharmacological benefits such as anticancer, antidiabetic, and immunomodulatory effects, and have major potential in the pharmaceutical and health care industries. Here, we employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomes of more than 50,000 cells derived from G. pentaphyllum shoot apexes and leaves. Following cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Each cell type displayed substantial transcriptomic heterogeneity both within and between tissues. Examining gene expression patterns across various cell types revealed that gypenoside biosynthesis predominantly occurred in mesophyll cells, with heightened activity observed in shoot apexes compared to leaves. Furthermore, we explored the impact of transposable elements (TEs) on G. pentaphyllum transcriptomic landscapes. Our findings the highlighted the unbalanced expression of certain TE families across different cell types in shoot apexes and leaves, marking the first investigation of TE expression at the single-cell level in plants. Additionally, we observed dynamic expression of genes involved in gypenoside biosynthesis and specific TE families during epidermal and vascular cell development. The involvement of TE expression in regulating cell differentiation and gypenoside biosynthesis warrant further exploration. Overall, this study not only provides new insights into the spatiotemporal organization of gypenoside biosynthesis and TE activity in G. pentaphyllum shoot apexes and leaves but also offers valuable cellular and genetic resources for a deeper understanding of developmental and physiological processes at single-cell resolution in this species.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiple etiological factors. Immune disorder contributes to SLE development and is an important clinical manifestation of SLE patients. Immune dysfunction is characterized by abnormal of B cells, T cells, monocyte-macrophages and dendritic cells (DCs), in both quantity and quality. Adenosine is a critical factor for human immune homeostasis, which acts as an immunosuppressive signal and can prevent the hyperactivity of human immune system. Adenosine levels are significant decreased in serum from SLE patients. Adenosine level is regulated by the CD39, CD73 and adenosine deaminase (ADA). CD39/CD73/ADA catalyzed the cascade enzymatic reaction, which contained the adenosine generation and degradation. Adenosine affects the function of various immune cells via bind to the adenosine receptors, which are expressed on the cell surface. This review aims to export the changes of immune cells and adenosine signal pathway in SLE, as well as the effect of adenosine signal pathway in SLE development.

Abstract Vibrio is a salt‐tolerant heterotrophic bacterium that occupies an important ecological niche in marine environments. However, little is known about the contribution of resource diversity to the marine Vibrio diversity and community stability. In this study, we investigated the association among resource diversity, taxonomic diversity, phylogenetic diversity, and community stability of marine Vibrio in the Beibu Gulf. V. campbellii and V. hangzhouensis were the dominant groups in seawater and sediments, respectively, in the Beibu Gulf. Higher alpha diversity was observed in the sediments than in the seawater. Marine Vibrio community assembly was dominated by deterministic processes. Pearson's correlation analysis showed that nitrite (NO2−‐N), dissolved inorganic nitrogen (DIN), ammonium (NH4+‐N), and pH were the main factors affecting marine Vibrio community stability in the surface, middle, and bottom layers of seawater and sediment, respectively. Partial least‐squares path models (PLS‐PM) demonstrated that resource diversity, water properties, nutrients, and geographical distance had important impacts on phylogenetic and taxonomic diversity. Regression analysis revealed that the impact of resource diversity on marine Vibrio diversity and community stability varied across different habitats, but loss of Vibrio diversity increases community stability. Overall, this study provided insights into the mechanisms underlying the maintenance of Vibrio diversity and community stability in marine environments.

Microorganisms, especially rare microbial species, are crucial in estuarine ecosystems for driving biogeochemical processes and preserving biodiversity. However, the understanding of the links between ecosystem multifunctionality (EMF) and the diversity of rare bacterial taxa in estuary ecosystems remains limited. Employing high-throughput sequencing and a variety of statistical methods, we assessed the diversities and assembly process of abundant and rare bacterioplankton and their contributions to EMF in a subtropical estuary. Taxonomic analysis revealed Proteobacteria as the predominant phylum among both abundant and rare bacterial taxa. Notably, rare taxa demonstrated significantly higher taxonomic diversity and a larger species pool than abundant taxa. Additionally, our findings highlighted that deterministic assembly processes predominantly shape microbial communities, with heterogeneous selection exerting a stronger influence on rare taxa. Further analysis reveals that rare bacterial beta-diversity significantly impacts to EMF, whereas alpha diversity did not. The partial least squares path modeling (PLS-PM) analysis demonstrated that the beta diversity of abundant and rare taxa, as the main biotic factor, directly affected EMF, while temperature and total organic carbon (TOC) were additional key factors to determine the relationship between beta diversity and EMF. These findings advance our understanding of the distribution features and ecological knowledge of the abundant and rare taxa in EMF in subtropical estuaries, and provide a reference for exploring the multifunctionality of different biospheres in aquatic environments.

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Exploring species diversity along elevational gradients is important for understanding the underlying mechanisms. Our study focused on analyzing the species diversity of fungal communities and their subcommunities at different trophic and taxonomic levels across three high mountains of the Korean Peninsula, each situated in a different climatic zone. Using high-throughput sequencing, we aimed to assess fungal diversity patterns and investigate the primary environmental factors influencing fungal diversity. Our results indicate that soil fungal diversity exhibits different elevational distribution patterns on different mountains, highlighting the combined effects of climate, soil properties, and geographic topology. Notably, the total and available phosphorus contents in the soil emerged as key determinants in explaining the differences in diversity attributed to soil properties. Despite the varied responses of fungal diversity to elevational gradients among different trophic guilds and taxonomic levels, their primary environmental determinants remained remarkably consistent. In particular, total and available phosphorus contents showed significant correlations with the diversity of the majority of the trophic guilds and taxonomic levels. Our study reveals the absence of a uniform diversity pattern along elevational gradients, underscoring the general sensitivity of fungi to soil conditions. By enriching our understanding of fungal diversity dynamics, this research enhances our comprehension of the formation and maintenance of elevational fungal diversity and the response of microbial communities in mountain ecosystems to climate change. This study provides valuable insights for future ecological studies of similar biotic communities.

Elucidating the water utilization strategy of trees during forest succession is a prerequisite for predicting the direction of forest succession. However, the water utilization characteristics of trees in forests across a successional gradient remain unclear. Here, we utilized the hydrogen and oxygen stable isotopes combined with the Bayesian mixed model (MixSIAR) to analyze the water utilization of dominant trees (Pinus massoniana, Castanea henryi, and Schima superba) in forests along a successional gradient in the Dinghushan Biosphere Reserve of China. Furthermore, we determined the primary factor affecting the water utilization of various trees based on variation partitioning analysis and a random forest model. Our results illustrated that in the early-successional forest, the water utilization ratios from shallow soil layers by P. massoniana were significantly lower than that in the mid-successional forest (51.3%–61.7% vs. 75.3%–81.4%), while its water utilization ratios from deep soil layers exhibited the opposite pattern (26.1%–30.1% vs. 9.0%–15.0%). Similarly, the ratios of water utilization from shallow soil layers by C. henryi (18.9%–29.5% vs. 32.4%–45.9%) and S. superba (10.0%–25.7% vs. 29.2%–66.4%) in the mid-successional forest were relatively lower than in the late-successional forest, whereas their water utilization ratios from deep soil layers showed the contrary tendency. Moreover, our results demonstrated that the diverse water utilization of each tree in different successional forests was mainly attributed to their distinct plant properties. Our findings highlight the increased percentage of water utilization of trees from shallow soil layers with forest succession, providing new insights for predicting the direction of forest succession under changing environments.

In the present study, the mitochondrial genomic characteristics of Acanthopsetta nadeshnyi have been reported and have depicted the phylogenetic relationship among Pleuronectidae. Combined with a comparative analysis of 13 PCGs, the TN93 model was used to review the neutral evolution and habitat evolution catalysis of the mitogenome to verify the distancing and purification selectivity of the mitogenome in Pleuronectidae. At the same time, a species differentiation and classification model based on mitogenome analysis data was established. This study is expected to provide a new perspective on the phylogenetic relationship and taxonomic status of A. nadeshnyi and lay a foundation for further exploration of environmental and biological evolutionary mechanisms.

The timing of potato tuberization is affected by potato ripeness, environmental factors, and polygene regulation. The accurate control of the transition to tuberization has both scientific and practical production value, but the key factors regulating this transition remain unclear. This study grafted an early-maturing potato variety (Favorita) scion to the late-maturing Qingshu 9 variety and demonstrated that a heterologous early-maturing scion can induce early potato formation on a late-maturing rootstock. The transcriptome of functional leaves and stolons of grafted plants was comprehensively analyzed and 593 differentially expressed genes (DEGs) were identified, including 38 transcription factors. Based on gene molecular function analysis and previous reports, we propose that PIF5, bHLH93, CBF3, ERF109, TCP19, and YABBY1 are the key DEGs that induce tuber formation in early- and late-maturing potatoes. The YABBY1 gene was subjected to functional verification. The leaf area of StYABBY1-overexpressing plants was smaller than the wild type and no potato tubercles were formed, while an RNA interference plant line showed no change in leaf area and formed tubers, indicating that StYABBY1 has a role in leaf size regulation and tuber formation.

Abstract China's severe particle pollution could affect the regional climate and weather conditions that consequently threaten local to global food security. Yet, the underlying mechanisms and quantitative assessment of aerosols on crop yields remain unknown. Here, by integrating a meteorology–chemistry model and a crop model, we show the impacts of atmospheric aerosols on China's meteorology and soybean yields. We find that the potential yields of soybean would decrease in most parts of China due to direct aerosol radiation effects, while showing diverse responses in parts of the Northeast and North China Plain. Moreover, because of the high sensitivity of soybean growth to water, potential yield fluctuations are closely related to aerosol‐induced precipitation changes in most soybean‐growing regions of China. In particular, aerosols play the most important role during soybean's pod‐filling stage, in which the influence of both precipitation perturbations and negative solar radiative forcing is about 5–10 times that of air temperature on crop yield. Our study thereby identifies aerosol mitigation can bring a notable increase in crop yields, highlighting the potential for important co‐benefits in food security across polluting developing countries.

In this paper, computational fluid dynamics (CFD) and reduced order method (ROM) are developed for predicting the velocity time series during the initial stage of projectile launching. The overlapping grid technique is firstly applied to perform high accuracy CFD simulations of the underwater launch of a submarine-launched projectile under two-parameter varying working conditions (i.e., different piston velocities and pipe interface radii). After that, the proper orthogonal decomposition (POD)–based ROM is used for decomposing the launching process into several spatial dependent mode functions and the corresponding time coefficients. The prediction of the initial stage of the launching velocity (which is the most important part of the launching process) is realized by establishing the neural network between the working condition parameters and the POD basis coefficients. The analysis results show that this method of CFD and ROM can accurately predict the complex dynamic process such as projectile launching process.

BIM technology is an important method to solve the problem of collaborative design and construction processes in the construction process of engineering projects. Based on BIM, this paper proposes a corresponding optimization model from the perspective of collaborative design and construction processes, respectively. In the collaborative design optimization model, the engineering collaborative management theory is utilized to extract indicators of schedule, cost, and quality to establish an IFC-based collaborative design optimization model. A multi-objective genetic algorithm is employed to solve the construction process optimization model by establishing the optimal scheduling model with schedule and cost minimization objectives. As instance, a second-class residential land use project in Chaoyang District, Beijing, is the subject of collaborative design and construction process optimization analysis. The optimization rate of the crossbeam floor cover solution compared with the slab floor cover solution without secondary beams is 13.5%, and the optimization effect of the co-design process is evaluated at 81.48 points, which reaches the standard of “good”. During the construction of the 6# building, the shortest duration of wall panel construction is 0.8416d, and the duration practice is shortened by 0.1467d. The overall construction quality score is 81.126, which reaches the level of “good”.

Food-borne Campylobacter jejuni infections constitute serious threats to human health worldwide. Since antibiotic treatment is usually not indicated in infected immune-competent patients, antibiotic-independent treatment approaches are needed to tackle campylobacteriosis. To address this, we orally applied carvacrol, deferoxamine, deoxycholate, and 2-fucosyl-lactose either alone or all in combination to human microbiota-associated IL-10−/− mice from day 2 until day 6 following oral C. jejuni infection. Neither treatment regimen affected C. jejuni loads in the colon, whereas carvacrol lowered the pathogen numbers in the ileum on day 6 post-infection (p.i.). The carvacrol and combination treatment regimens resulted in alleviated diarrheal symptoms, less distinct histopathological and apoptotic epithelial cell responses in the colon, as well as diminished numbers of colonic neutrophils and T lymphocytes on day 6 p.i., whereas the latter cells were also decreased upon deferoxamine, deoxycholate, or 2-fucosyl-lactose application. Remarkably, the carvacrol, deferoxamine, and combination treatment regimens dampened ex-vivo IFN-γ secretion in the colon, the kidneys, and even in the serum to basal concentrations on day 6 p.i. In conclusion, carvacrol alone and its combination with deferoxamine, deoxycholate, and 2-fucosyl-lactose constitute promising antibiotics-independent treatment options to fight acute campylobacteriosis.

The rates of twin pregnancies and cesarean section have increased in recent years, and both of them are at high risks of postpartum hemorrhage (PPH). However, few studies have concentrated on the risks of PPH in twin pregnancies and cesarean deliveries. In this study, we aimed to identify the risk factors for PPH among twin-pregnant women with cesarean section. This was a retrospective observational study including 1,649 women with twin pregnancies delivered by cesarean section from 2016 to 2022 in the Second Affiliated Hospital of Wenzhou Medical University, China. The eligible women were divided into PPH group (n = 116) and non-PPH group (n = 1,533) according to the blood loss after delivery within 24 h. The baseline maternal and perinatal characteristics were compared between the two groups. Logistic regression analysis was conducted to identify the potential risk factors for PPH. We found nulliparity, assisted reproductive technology (ART) usage, preeclampsia or HELLP syndrome, placenta previa, placenta accreta and general anesthesia were more common in PPH group than non-PPH group (P < 0.05). Women in PPH group had higher maternal body mass index at delivery and higher combined birthweight of the twins than non-PPH group, but had lower parity (P < 0.05). Seven independent risk factors for PPH were identified after logistic regression analysis: ART usage (OR 2.354 95% CI 1.357–4.083, P = 0.002), preeclampsia or HELLP syndrome (OR 2.605, 95% CI 1.471–4.616, P = 0.001), placenta previa (OR 7.325, 95% CI 3.651–14.697, P < 0.001), placenta accreta (OR 6.296, 95% CI 1.316–30.12, P = 0.021), thrombocytopenia (OR 1.636, 95% CI 1.056–2.535, P = 0.027), general anesthesia (OR 2.394, 95% CI 1.223–4.686, P = 0.011), and combined birthweight (OR 1.00032, 95% CI 1.00005–1.00059, P = 0.020). Collectively, in women with twin pregnancies delivered by cesarean section, the use of ART, preeclampsia or HELLP syndrome, placenta previa, placenta accreta, thrombocytopenia, general anesthesia and the combined birthweight were identified as independent risk factors for PPH. More attention should be paid to women with these risk factors.

IntroductionAutism spectrum disorder (ASD) is a multifaceted developmental condition that commonly appears during early childhood. The etiology of ASD remains multifactorial and not yet fully understood. The identification of biomarkers may provide insights into the underlying mechanisms and pathophysiology of the disorder. The present study aimed to explore the causes of ASD by investigating the key biomedical markers, trace elements, and microbiota factors between children with autism spectrum disorder (ASD) and control subjects.MethodsMedline, PubMed, ProQuest, EMBASE, Cochrane Library, PsycINFO, Web of Science, and EMBSCO databases have been searched for publications from 2012 to 2023 with no language restrictions using the population, intervention, control, and outcome (PICO) approach. Keywords including “autism spectrum disorder,” “oxytocin,” “GABA,” “Serotonin,” “CRP,” “IL-6,” “Fe,” “Zn,” “Cu,” and “gut microbiota” were used for the search. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the article quality, and a random model was used to assess the mean difference and standardized difference between ASD and the control group in all biomedical markers, trace elements, and microbiota factors.ResultsFrom 76,217 records, 43 studies met the inclusion and exclusion criteria and were included in this meta-analysis. The pooled analyses showed that children with ASD had significantly lower levels of oxytocin (mean differences, MD = −45.691, 95% confidence interval, CI: −61.667, −29.717), iron (MD = −3.203, 95% CI: −4.891, −1.514), and zinc (MD = −6.707, 95% CI: −12.691, −0.722), lower relative abundance of Bifidobacterium (MD = −1.321, 95% CI: −2.403, −0.238) and Parabacteroides (MD = −0.081, 95% CI: −0.148, −0.013), higher levels of c-reactive protein, CRP (MD = 0.401, 95% CI: 0.036, 0.772), and GABA (MD = 0.115, 95% CI: 0.045, 0.186), and higher relative abundance of Bacteroides (MD = 1.386, 95% CI: 0.717, 2.055) and Clostridium (MD = 0.281, 95% CI: 0.035, 0.526) when compared with controls. The results of the overall analyses were stable after performing the sensitivity analyses. Additionally, no substantial publication bias was observed among the studies.InterpretationChildren with ASD have significantly higher levels of CRP and GABA, lower levels of oxytocin, iron, and zinc, lower relative abundance of Bifidobacterium and Parabacteroides, and higher relative abundance of Faecalibacterium, Bacteroides, and Clostridium when compared with controls. These results suggest that these indicators may be a potential biomarker panel for the diagnosis or determining therapeutic targets of ASD. Furthermore, large, sample-based, and randomized controlled trials are needed to confirm these results.

The purpose of this study was to explore the protective effect of SeMet on renal injury induced by AFB1 in rabbits and its molecular mechanism. Forty rabbits of 35 days old were randomly divided into control group, AFB1 group (0.3 mg AFB1/kg b.w), 0.2 mg/kg Se + AFB1 group (0.3 mg AFB1/kg b.w + 0.2 mg SeMet/kg feed) and 0.4 mg/kg Se + AFB1 group (0.3 mg AFB1/kg b.w + 0.4 mg SeMet/kg feed). The SeMet treatment group was fed different doses of SeMet diets every day for 21 days. On the 17–21 day, the AFB1 treatment group, the 0.2 mg/kg Se + AFB1 group and the 0.4 mg/kg Se + AFB1 group were administered 0.3 mg AFB1 /kg b.w by gavage (dissolved in 0.5 ml olive oil) respectively. The results showed that AFB1 poisoning resulted in the changes of renal structure, the increase of renal coefficient and serum biochemical indexes, the ascent of ROS and MDA levels, the descent of antioxidant enzyme activity, and the significant down-regulation of Nrf2, HO-1 and NQO1. Besides, AFB1 poisoning increased the number of renal apoptotic cells, rised the levels of PTEN, Bax, Caspase-3 and Caspase-9, and decreased the levels of PI3K, AKT, p-AKT and Bcl-2. In summary, SeMet was added to alleviate the oxidative stress injury and apoptosis of kidney induced by AFB1, and the effect of 0.2 mg/kg Se + AFB1 is better than 0.4 mg/kg Se + AFB1.

Carnivore protoparvovirus-1, feline parvovirus (FPV), and canine parvovirus (CPV) continue to spread in companion animals all over the world. As a result, FPV and CPV underwent host-to-host transfer in carnivorous wild-animal hosts. Here, a total of 82 fecal samples of suspected cat FPV infections were collected from Henan Province from 2020 to 2022. The previously published full-length sequence primers of VP2 and NS1 genes were used to amplify the targeted genes of these samples, and the complete gene sequences of 11 VP2 and 21 NS1 samples were obtained and analyzed. Analysis showed that the amino acid homology of the VP2 and NS1 genes of these isolates was 96.1–100% and 97.6–100%, respectively. The phylogenetic results showed that the VP2 and NS1 genes of the local isolates were mainly concentrated in the G1 subgroup, while the vaccine strains were distributed in the G3 subgroup. Finally, F81 cells were inoculated with the local endemic isolate Luoyang-01 (FPV-LY strain for short) for virus amplification, purification, and titer determination, and the pathogenesis of FPV-LY was detected. After five generations of blind transmission in F81 cells, cells infected with FPV-LY displayed characteristic morphological changes, including a round, threadlike, and wrinkled appearance, indicative of viral infection. The virus titer associated with this cytopathic effect (CPE) was measured at 1.5 × 106 TCID50/mL. Subsequent animal regression tests confirmed that the virus titer of the PFV-LY isolate remained at 1.5 × 106 TCID50/mL, indicating its highly pathogenic nature. Cats exposed to the virus exhibited typical clinical symptoms and pathological changes, ultimately succumbing to the infection. These results suggest that the gene mutation rate of FPV is increasing, resulting in a complex pattern of gene evolution in terms of host preference, geographical selection, and novel genetic variants. The data also indicate that continuous molecular epidemiological surveillance is required to understand the genetic diversity of FPV isolates.

Mycotoxins are secondary metabolites produced by several fungi and moulds that exert toxicological effects on animals including immunotoxicity, genotoxicity, hepatotoxicity, teratogenicity, and neurotoxicity. However, the toxicological mechanisms of mycotoxins are complex and unclear. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric cytosolic protein complex composed of the NLRP3 sensor, ASC adapter protein, and caspase-1 effector. Activation of the NLRP3 inflammasome plays a crucial role in innate immune defence and homeostatic maintenance. Recent studies have revealed that NLRP3 inflammasome activation is linked to tissue damage and inflammation induced by mycotoxin exposure. Thus, this review summarises the latest advancements in research on the roles of NLRP3 inflammasome activation in the pathogenesis of mycotoxin exposure. The effects of exposure to multiple mycotoxins, including deoxynivalenol, aflatoxin B1, zearalenone, T-2 toxin, ochratoxin A, and fumonisim B1, on pyroptosis-related factors and inflammation-related factors in vitro and in vivo and the pharmacological inhibition of specific and nonspecific NLRP3 inhibitors are summarized and examined. This comprehensive review contributes to a better understanding of the role of the NLRP3 inflammasome in toxicity induced by mycotoxin exposure and provides novel insights for pharmacologically targeting NLRP3 as a novel anti-inflammatory agent against mycotoxin exposure.