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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

Peng-Cheng Zhang,1,2 Yi Hong,3 Shi-Qin Zong,1,2 Long Chen,1,2 Chong Zhang,4 Dai-Zhi Tian,4 Dan Ke,5 Li-Ming Tian1,2,4 1Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Provincial Key Laboratory of Skin Infection and Immunity, Wuhan No.1 Hospital, Wuhan, 430022, People’s Republic of China; 3College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, People’s Republic of China; 4Institute of Geriatrics, Hubei University of Chinese Medicine, Wuhan, 430065, People’s Republic of China; 5Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, 400000, People’s Republic of ChinaCorrespondence: Dan Ke, Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, No. 40 of Daomenkou, Yuzhong District, Chongqing, 400000, People’s Republic of China, Tel +86 23 6390 1120, Fax +86 23 6373 1325, Email 2306896229@qq.com Li-Ming Tian, Department of Dermatology, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 215 of Zhongshan Avenue, Qiaokou District, Wuhan, 430022, People’s Republic of China, Tel +86 27 8533 2606, Fax +86 27 8583 2563, Email jolly0731@126.comObjective: To investigate the variation of ferroptosis-related markers in HaCaT cell photoaging models induced by ultraviolet-B (UVB).Methods: UVB-treated HaCaT cells served as the model (UVB group) for cellular photoaging, whereas untreated HaCaT cells served as the control group. HaCaT cells were exposed to UVB and the ferroptosis inhibitor Ferrostatin-1 (Fer-1) as part of the UVB+Fer-1 group, and co-cultured with the ferroptosis inducer Erastin as part of the UVB+Erastin group. Reactive oxygen species (ROS) detection kit and senescence-related β galactosidase (SA-β-gal) staining were used to evaluate the senescence of HaCaT cells. Lipid reactive oxygen species were detected by C11 BODIPY581/591 probe and mitochondrial morphology was observed by transmission electron microscopy. The mRNA expressions of glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor-protein 1 (FSP1) were detected by real-time reverse transcription-PCR (RT-RCP), and the level of GPX4 protein was measured by immunofluorescence assay.Results: The UVB group had considerably greater levels of ROS, SA-β-gal, and lipid reactive oxygen species than the control group. The UVB group’s mitochondrial volume was reduced, the membrane density increased, and the mitochondrial crest decreased or even disappeared. GPX4 and FSP1 expression levels were similarly found to be lower in the UVB group. Furthermore, the positive rate of SA-β-gal and lipid reactive oxygen species in the UVB+Fer-1 group was much lower than in the UVB group, but it was reverse in the UVB+Erastin group. This study showed that induced ferroptosis can aggravate aging, and vice versa.Conclusion: According to the findings, ferroptosis may be linked to UVB-induced skin photoaging, which could be attenuated by inhibition of ferroptosis.Keywords: skin aging, ferroptosis, oxidative stress

Guomei Shi,1,2,* Dongdong Ke,2,3,* Pengyu Gong,4,5 Peng Yu,2,6 Junshan Zhou,5 Meng Wang,5 Xiaohao Zhang,5 Xiaorong Wang,1,2 Minwang Guo,1,2 Mingyang Xu,1,2 Rujuan Zhou1,2 1Department of Neurology, the Taixing People’s Hospital, Taixing, Jiangsu, People’s Republic of China; 2Stroke Center, the Taixing People’s Hospital, Taixing, Jiangsu, People’s Republic of China; 3Department of Rehabilitation, the Taixing People’s Hospital, Taixing, Jiangsu, People’s Republic of China; 4Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 5Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 6Department of Radiology, the Taixing People’s Hospital, Taixing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rujuan Zhou, Tel +86-13951158499, Email zhourujuan123@163.comBackground: White matter hyperintensity (WMH) is associated with risk of acute ischemic stroke (AIS) and poor outcomes after AIS. The purpose of this prospective study was to evaluate the association between serum YKL-40 levels and WMH burden in patients with AIS.Methods: From February 2020 to March 2021, a total of 672 consecutive AIS patients with magnetic resonance imaging data were prospectively recruited form two centers. Serum YKL-40 levels were quantified using enzyme-linked immunosorbent assay. The burden of WMH was semiquantitatively measured by the Fazekas visual grading scale. According to severity of overall WMH, patients were dichotomized into none–mild WMH group (Fazekas score 0– 2) or moderate–severe WMH group (Fazekas score 3– 6). Besides, based on severity of periventricular WMH (PV-WMH) and deep WMH (D-WMH), patients were categorized as none–mild (Fazekas score 0– 1) or moderate–severe (Fazekas score 2– 3).Results: Among the 672 patients, 335 (49.9%) participants were identified with moderate–severe overall WMH, 326 (48.5%) with moderate–severe PV-WMH and 262 (39.0%) with moderate–severe D-WMH. Compared with the first quartile of serum YKL-40, the adjusted odds ratio (OR) of the fourth quartile for moderate–severe PV-WMH was 2.473 (95% confidence interval [CI] 1.316– 4.646; P=0.005). No significant association was observed between YKL-40 and overall WMH (OR 0.762; 95% CI 0.434– 1.336; P=0.343) or D-WMH (OR 0.695; 95% CI 0.413– 1.171; P=0.172).Conclusion: Our results suggested that higher YKL-40 levels appeared to be associated with PV-WMH, but not with overall WMH or D-WMH in patients with AIS.Keywords: acute ischemic stroke, YKL-40, white matter hyperintensities, biomarkers

Xiaohong Liu,1 Dedong Cao,1 Hui Liu,2 Dong Ke,3 Xiaokang Ke,4 Ximing Xu1 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Department of Hematology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 3Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 4Department of Pathology; Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of ChinaCorrespondence: Ximing Xu, Department of Oncology, Renmin Hospital of Wuhan University, 99 Ziyang Road, Wuhan, 430060, People’s Republic of China, Tel +8627-88041911, Email doctorxu120@aliyun.comPurpose: This study aimed to analyze the clinical features and survival of primary small intestinal diffuse large B-cell lymphoma (PsI-DLBCL), and establish and independently validate a prognostic nomogram for individual risk prediction.Patients and methods: Data for 24 patients from the Renmin Hospital of Wuhan University were used as an independent validation cohort, data for 1144 patients with PsI-DLBCL from the SEER database were randomly assigned to training (N=817) and internal validation (N=327) sets. The survival nomogram was constructed with the most significant factors associated with OS using Univariate and multivariate analyses on the training set. Decision curve analysis (DCA) was conducted. Internal validation was SEER validation set. Our cancer center cohort was used as an external validation set to further verify the survival nomogram.Results: Five clinicopathological feature factors associated with OS of the training set yielded (age, marital status, Ann Arbor stage, surgery for primary site and chemotherapy), which were used to create a survival nomogram. Additionally, the calibration curves of the prognostic nomogram revealed good agreement between the predicted survival probabilities and the ground truth values. The stability of our survival nomogram was explained by internal and external validation data.Conclusion: Our nomogram proposes the clinical and therapeutic factors affecting OS for patients with PsI-DLBCL. It shows that chemotherapy and surgery are beneficial to patients in the choice of treatment options. These results suggest that a survival nomogram may be better at predicting OS for PsI-DLBCL patients.Keywords: large B-cell lymphoma, non-Hodgkin, small intestine, SEER, nomogram

DanDan Ke,1 YiYi Hong,2 XinNan Jiang,1 XuFang Sun1 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Research Center of Ophthalmic Diseases, Guangxi Academy of Medical Sciences & Department of Ophthalmology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, People’s Republic of ChinaCorrespondence: XuFang Sun, Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie-Fang Road, Wuhan, People’s Republic of China, Email sunxufang2016@163.comPurpose: To compare the clinical features and vitreous biomarkers of proliferative diabetic retinopathy (PDR) between patients with early-onset and late-onset type 2 diabetes mellitus (T2DM).Materials and Methods: This case-control study analyzed the clinical data of 74 patients with PDR who underwent vitrectomy. The patients were divided into the early-onset (T2DM diagnosis age ≤ 40 years, n = 39) and late-onset (T2DM diagnosis age > 40 years, n = 35) groups. Thirty-six specimens were collected, and the liquid chip technology was used to detect the content of 27 types of cytokines in the vitreous. Differences in clinical features and cytokine levels between the two groups were evaluated. Bonferroni correction was applied for multiple comparisons.Results: Compared with the late-onset group, the levels of hemoglobin A1c (HbA1c) and total cholesterol were significantly higher in the early-onset group (P < 0.001 and P = 0.009, respectively). Patients with early-onset T2DM PDR had worse visual prognoses and a higher rate of postoperative recurrent vitreous hemorrhage. The results of cytokine detection showed that the levels of interleukin-4 (IL-4), IL-6, IL-8, IL-9, granulocyte colony-stimulating factor, interferon-γ, interferon-inducible 10 kDa, monocyte chemotactic protein 1, macrophage inflammatory protein (MIP)-1α, and MIP-1β in the early-onset group were significantly higher than those in the late-onset group (p < 0.0026). Age at diabetes diagnosis and HbA1c, IL-4, and regulated upon activation, normal T cell expressed and secreted levels were independent risk factors for visual acuity after undergoing vitrectomy.Conclusion: Early-onset T2DM PDR patients had poor blood glucose and lipid metabolism, higher levels of inflammatory factors, and worse visual prognosis. Stricter metabolic management and earlier anti-inflammatory interventions may be required for patients with early-onset T2DM.Keywords: early-onset type 2 diabetes mellitus, proliferative diabetic retinopathy, vitrectomy, cytokines, hemoglobin A1c

Miao Han,1,&ast; Heng Li,2,&ast; Dan Ke,3 Li-Ming Tian,4 Yi Hong,5 Chong Zhang,6 Dai-Zhi Tian,6 Long Chen,4 Li-Rui Zhan,4 Shi-Qin Zong4 1Department of Dermatology, School of Medicine, Jianghan University, Wuhan, People’s Republic of China; 2Department of Dermatology, Hubei Provincial Hospital of Traditional Chinese Medicine, Hospital Affiliated to Hubei University of Chinese Medicine, Wuhan, People’s Republic of China; 3Department of Dermatology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 4Department of Dermatology, Wuhan No.1 Hospital, Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine Affiliated to Tongji Medicine College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 5College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People’s Republic of China; 6Institute of Geriatrics, Hubei University of Chinese Medicine, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li-Ming Tian, Department of Dermatology, Wuhan No.1 Hospital, Hospital of Traditional Chinese and Western Medicine Affiliated to Hubei University of Chinese Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine Affiliated to Tongji Medicine College of Huazhong University of Science and Technology, No. 215 of Zhongshan Avenue, Qiaokou District, Wuhan, 430022, People’s Republic of China, Tel +86 27 8533 2606, Fax +86 27 8583 2563, Email jolly0731@126.comPurpose: To study the efficacy of Ba Zhen Tang in delaying skin photoaging and its potential mechanism based on network pharmacology and molecular docking.Methods: First, we screened the active components and targets of Ba Zhen Tang by Traditional Chinese Medicine Database and Analysis Platform (TCMSP) and The Universal Protein Resource (UniProt). The target genes of skin photoaging were obtained from GeneCards and GeneMap database. Then, we analyzed the protein–protein interaction (PPI) by STRING database. The network map was constructed by Cytoscape. Finally, we performed Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis by Metascape database. The molecular docking via Autodock Vina and Pymol. Furthermore, skin photoaging cellular models were established, and the effects of Ba Zhen Tang on ameliorating skin photoaging were investigated.Results: A total of 160 active ingredients in Ba Zhen Tang and 60 targets of Ba Zhen Tang for delaying skin photoaging were identified. By GO enrichment analysis, 1153 biological process entries, 45 cellular component entries and 89 molecular functional entries were obtained. A total of 155 signal pathways were obtained by KEGG analysis. Ba Zhen Tang is related to MAPK signaling pathway, TNF signaling pathway and AGE-RAGE signaling pathway in diabetic complications, etc., which directly affect the key nodes of photoaging. The molecular docking results showed that there was a certain affinity between the main compounds (kaempferol, quercetin, β-sitosterol, naringenin) and core target genes (PTGS2, CASP3, MAPK1, MAPK3, TP53). Ba Zhen Tang-treated mouse serum inhibited the senescence and p16INK4a expression of human immortalized keratinocyte (HaCaT) cells irradiated by ultraviolet-B (UVB).Conclusion: Our study elucidated the potential pharmacological mechanism of Ba Zhen Tang in the treatment of photoaging through multiple targets and pathways. The therapeutic effects of Ba Zhen Tang on skin photoaging were validated in cellular models.Keywords: Ba Zhen Tang, skin photoaging, network pharmacology, molecular docking, mechanism

Xian Zhang,1,&ast; Liting Chen,2,&ast; Gaoxiang Wang,2,&ast; Liwen Chen,1 Lifang Huang,2 Yang Cao,2 Xing Chen,2 Chaohua Deng,1 Xuhui Chen,1 Dandan Ke,1 Yuanjun Qin,1 Bo Chen,1 Xufang Sun1 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Chen; Xufang SunDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, People’s Republic of ChinaEmail eyechen@aliyun.com; sunxufang2016@163.comPurpose: This study detects SARS-CoV-2 in the ocular surface through one-step reverse-transcription droplet digital PCR (one-step RT-ddPCR) and evaluates the possibility of the ocular surface as a possible transmission route.Methods: A single-center prospective observational study was designed to investigate the viral loads in ocular surface. Specimens including the conjunctival swabs, nasopharyngeal swabs and blood were synchronously collected at a single time point for all COVID-19 patients. SARS-CoV-2 loads in nasopharyngeal swabs were tested by real-time polymerase chain reaction (PCR); the blood samples and conjunctival swabs were tested by real-time PCR and one-step RT-ddPCR.Results: Sixty-eight COVID-19 patients confirmed by nasopharyngeal real-time PCR were recruited. In the single time point test, 40 cases showed positive SARS-CoV-2 detection in either the blood, tears, or nasopharynx, of which four cases were triple-positive, 10 were dual-positive, and 26 were single-positive. The positive rate of nasopharyngeal swab real-time PCR test was 22.1% (15/68). The positive rate of blood and conjunctival swabs by one-step RT-ddPCR was 38.2% (26/68) and 25% (17/68), respectively, whereas real-time PCR was all negative. Positive conjunctival swabs were significantly correlated with positive nasopharyngeal swabs (P = 0.028). The sampling lags from illness onset to sampling day in 3 out of 4 triple-positive patients and in 9 out of 10 dual-positive patients were respectively less than 9 days and less than 20 days.Conclusion: Our results indicate that the positive rate of SARS-CoV-2 on the ocular surface is much higher than expected. Transmission possibility through the ocular surface may be greatly underestimated.Keywords: absolute quantification, virus detection, transmission, nasopharyngeal specimens, blood samples, tear samples

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.

The solute carrier family 12 (SLC12) of cation-chloride cotransporters (CCCs) comprises potassium chloride cotransporters (KCCs, e.g. KCC1, KCC2, KCC3, and KCC4)-mediated Cl− extrusion, and sodium potassium chloride cotransporters (N[K]CCs, NKCC1, NKCC2, and NCC)-mediated Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues. In recent years, there have been considerable advances in our understanding of CCCs' control mechanisms in cell volume regulations, with many techniques developed in studying the functions and activities of CCCs. Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs. These techniques include the ammonium pulse technique, radioactive or nonradioactive rubidium ion uptake-assay, and thallium ion-uptake assay. CCCs' activity can also be indirectly observed by measuring γ-aminobutyric acid (GABA) activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes, radiotracer 36Cl−, and fluorescent dyes. Other techniques include directly looking at kinase regulatory sites phosphorylation, flame photometry, 22Na+ uptake assay, structural biology, molecular modeling, and high-throughput drug screening. This review summarizes the role of CCCs in genetic disorders and cell volume regulation, current methods applied in studying CCCs biology, and compounds developed that directly or indirectly target the CCCs for disease treatments.

Abstract Background Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. Methods Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. Results We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. Conclusions The model in our work is a novel assessment tool to measure immunotherapy’s effectiveness and anticipate BLCA patients’ prognosis, offering new avenues for immunological biomarkers and targeted treatments.

Abstract The anomalous Hall effect (AHE) that emerges in antiferromagnetic metals shows intriguing physics and offers numerous potential applications. Magnets with a rutile crystal structure have recently received attention as a possible platform for a collinear-antiferromagnetism-induced AHE. RuO2 is a prototypical candidate material, however the AHE is prohibited at zero field by symmetry because of the high-symmetry [001] direction of the Néel vector at the ground state. Here, we show AHE at zero field in Cr-doped rutile, Ru0.8Cr0.2O2. The magnetization, transport and density functional theory calculations indicate that appropriate doping of Cr at Ru sites reconstructs the collinear antiferromagnetism in RuO2, resulting in a rotation of the Néel vector from [001] to [110] while maintaining a collinear antiferromagnetic state. The AHE with vanishing net moment in the Ru0.8Cr0.2O2 exhibits an orientation dependence consistent with the [110]-oriented Hall vector. These results demonstrate that material engineering by doping is a useful approach to manipulate AHE in antiferromagnetic metals.

Abstract Titanium (Ti) dental implants face risks of early failure due to bacterial adhesion and biofilm formation. It is thus necessary to endow the implant surface with antibacterial ability. In this study, magnesium oxide (MgO) coatings were prepared on Ti by combining micro-arc oxidation (MAO) and electrophoretic deposition (EPD). The MgO nanoparticles homogeneously deposited on the microporous surface of MAO-treated Ti, yielding increasing coverage with the EPD time increased to 15 to 60 s. After co-culture with Porphyromonas gingivalis (P. gingivalis) for 24 h, 48 h, and 72 h, the coatings produced antibacterial rates of 4–53 %, 27–71 %, and 39–79 %, respectively, in a dose-dependent manner. Overall, EPD for 45 s offered satisfactory comprehensive performance, with an antibacterial rate 79 % at 72 h and a relative cell viability 85 % at 5 d. Electron and fluorescence microscopies revealed that, both the density of adherent bacterial adhesion on the surface and the proportion of viable bacteria decreased with the EPD time. The morphology of cells on the surface of each group was intact and there was no significant difference among the groups. These results show that, the MgO coating deposited on MAO-treated Ti by EPD had reasonably good in vitro antibacterial properties and cytocompatibility.