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Xu Zhou,1,2,&ast; Aolin Tang,2,3,&ast; Chengjie Xiong,2,&ast; Guoquan Zhang,2 Liangliang Huang,1,2 Feng Xu1,2 1The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Orthopaedics, General Hospital of Central Theater Command, Wuhan, 430070, People’s Republic of China; 3Department of Orthopaedics, Minda Hospital of Hubei Minzu University, Enshi, 445000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangliang Huang; Feng Xu, Department of Orthopaedics, General Hospital of Central Theater Command, Wuhan, 430070, People’s Republic of China, Email hll666789@163.com; fengxu1969@163.comBackground: Treating peripheral nerve injuries (PNI) with defects remains challenging in clinical practice. The commercial conduits have shown suboptimal nerve regeneration and functional recovery due to their basic tubular design without electroactive and oriented topographical cues.Purpose: To develop a new scaffold with oriented microstructure and electroactive Graphene oxide (GO) and investigate its’ therapeutic effect on nerve regeneration in vitro and in vivo.Methods: This study employed a straightforward approach to co-spin PCL and GO, yielding an oriented hybrid nanofibrous scaffold known as the O-GO/PCL scaffold. The physical and chemical properties of nanofibrous scaffold were tested by scanning electron microscopy (SEM), transmission electron microscope (TEM), tensile test and so on. Primary Schwann cells (SCs) and dorsal root ganglia (DRG) were used to investigate the impact of the newly developed scaffolds on the biological behavior of neural cells in vitro. Transcriptome sequencing (mRNA-seq) was employed to probe the underlying mechanisms of the synergistic effect of electroactive GO and longitudinal topographic guidance on nerve regeneration. Furthermore, the developed O-GO/PCL scaffold was utilized to bridge a 10-mm sciatic nerve defect in rat, aiming to investigate its therapeutic potential for peripheral nerve regeneration in vivo.Results and discussion: The SEM and TEM revealed that the newly developed O-GO/PCL scaffold showed longitudinally oriented microstructure and GO particles were homogenously and uniformly distributed inside the nanofibers. Primary SCs were utilized to assess the biocompatibility of the GO-based scaffold, revealing that negligible cytotoxicity when GO concentration does not exceed 0.5%. In vitro analysis of nerve regeneration demonstrated that axons in the O-GO/PCL group exhibited an average length of 1054.88 ± 161.32 μm, significant longer than those in the other groups (P < 0.05). Moreover, mRNA sequencing results suggested that the O-GO/PCL scaffold could enhance nerve regeneration by upregulating genes associated with neural regeneration, encompassing ion transport, axon guidance and cell–cell interactions. Most importantly, we employed the O-GO/PCL scaffold to repair a 10-mm sciatic nerve defect in rat, resulting in augmented nerve regeneration, myelination, and functional recovery.Conclusion: The O-GO/PCL scaffold with oriented microstructure and electroactive GO represents a promising heral nerve reconstruction. Keywords: nanofibers, topographical guidance, electroactive, graphene oxide, nerve regeneration

Chuanhao Xiong,1,&ast; Jingzhu Wu,1,&ast; Yuhang Ma,1,&ast; Na Li,1 Xuejiao Wang,1 Yao Li,2 Xiaoying Ding1 1Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoying Ding, Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai, 200080, People’s Republic of China, Email xiaoyingding@126.com Yao Li, Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, People’s Republic of China, Email yao.li@shsmu.edu.cnPurpose: Polycystic ovary syndrome (PCOS) is a frequent cause of infertility in reproductive-age women. Our work aims to evaluate the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on gut microbiota, with metabolic parameters including body weight and the hormone profile in PCOS.Patients and Methods: Dehydroepiandrosterone (DHEA)-induced PCOS mice were established and then treated with two GLP-1RAs: liraglutide and novel form semaglutide for four weeks. Changes in body weight and metabolic parameters were measured. Fecal samples were collected and analyzed using metagenomic sequencing.Results: Liraglutide and semaglutide modulated both alpha and beta diversity of the gut microbiota in PCOS. Liraglutide increased the Bacillota-to-Bacteroidota ratio through up-regulating the abundance of butyrate-producing members of Bacillota like Lachnospiraceae. Moreover, liraglutide showed the ability to reverse the altered microbial composition and the disrupted microbiota functions caused by PCOS. Semaglutide increased the abundance of Helicobacter in PCOS mice (p < 0.01) which was the only bacteria found negatively correlated with body weight. Moreover, pathways involving porphyrin and flavonoids were increased after semaglutide intervention.Conclusion: Liraglutide and semaglutide improved reproductive and metabolic disorders by modulating the whole structure of gut microbiota in PCOS. The greater efficacy in weight loss compared with liraglutide observed after semaglutide intervention was positively related with Helicobacter. The study may provide new ideas in the treatment and the underlying mechanisms of GLP-1RAs to improve PCOS.Keywords: PCOS, GLP-1 receptor agonists, gut microbiota, metabolism

Xu Zhou,1,2,&ast; Aolin Tang,2,3,&ast; Chengjie Xiong,2,&ast; Guoquan Zhang,2 Liangliang Huang,1,2 Feng Xu1,2 1The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Department of Orthopaedics, General Hospital of Central Theater Command, Wuhan, 430070, People’s Republic of China; 3Department of Orthopaedics, Minda Hospital of Hubei Minzu University, Enshi, 445000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangliang Huang; Feng Xu, Department of Orthopaedics, General Hospital of Central Theater Command, Wuhan, 430070, People’s Republic of China, Email hll666789@163.com; fengxu1969@163.com

Yinhui Deng,1 Na Li,2 Yaru Wang,2 Chen Xiong,2 Xiaofang Zou1 1Department of Nursing, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2School of Nursing, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Xiaofang Zou, Department of Nursing, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China, Tel +8618998321627, Fax +86-20-81292949, Email 1037189214@qq.comPurpose: Diabetes is a well-recognized risk factor for cognitive frailty. This study aimed to investigate the influencing factors of cognitive frailty in elderly patients with diabetes and develop a nomogram for its assessment.Methods: We collected the clinical data of diabetic patients aged 60 years or older and the patients were divided into training and validation cohorts at a ratio of 7:3. In the training cohort, logistic regression was used to screen out the influencing factors of cognitive frailty in elderly diabetic patients, and a risk prediction model and nomogram were constructed and verified in the validation cohort. The performance of the model was evaluated using various measures, including the area under the receiver operating characteristic curve, calibration curve, Hosmer-Lemeshow test and decision curve analysis.Results: A total of 315 elderly diabetic patients were included, of which 87 (27.6%) patients had cognitive frailty. Age, albumin levels, calf circumference, duration of diabetes, intellectual activity, and depressive state were identified as independent risk factors for cognitive frailty in older patients with diabetes (P < 0.05). The training cohort and validation cohort demonstrated area under curve (AUC) values of 0.866 and 0.821, respectively.Conclusion: Older patients with diabetes have a higher prevalence of cognitive frailty. The nomogram model exhibited satisfactory calibration and identification, providing a reliable tool for assessing the risk of cognitive frailty in individuals with diabetes.Keywords: cognitive frailty, diabetes, nomogram, prediction, risk factors

Rui Zhou,&ast; Yanhua Peng,&ast; Xuemeng Chen,&ast; Chao Xiong, Wenhu Zhai, Xianjie Zhang, Leqiang Xia, Yukai Zhou Department of Anesthesiology, Deyang People’s Hospital, Deyang City, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yukai Zhou, Department of Anesthesiology, Deyang People’s Hospital, NO. 173, Section 1 of Taishan North Road, Deyang City, Sichuan Province, People’s Republic of China, Tel +8618781054070, Email christianziege@163.comPurpose: Parturients suffer severe pain during the stages of labor, especially the first and second. Epidural anesthesia is an effective method to alleviate labor pain. L2-3, L3-4 and L4-5 spaces have been reported to be the recommendable puncture points owing to the adequate analgesia effect and high safety. However, the speed of pain alleviation via the three points has hardly been determined, which is of great importance to parturients. Thus, the aim of this study is to compare the onset time of parturients’ painless uterine contraction after epidural labor analgesia through different puncture points.Study Design and Methods: It is a prospective, randomized, controlled, and subject- and assessor-blinded study. Totally, 150 subjects scheduled for vaginal delivery are going to be randomly assigned into the L2-3 and L3-4 group. Puncture point in L2-3 group is lumbar 2– 3 space, while in L3-4 group it is lumbar 3– 4 space. Analgesia initiation and maintenance are the same between the two groups. Primary outcome will be percentage of painless uterine contraction 15 min after epidural labor analgesia initiation. Secondary outcomes will be the sensory blocking level, motor blocking score, adverse effects of parturients, drug liquid consumption in unit interval, apgar score and degree of satisfaction of the parturients.Discussion: This study estimates the onset time of parturients’ painless uterine contraction after epidural labor analgesia through L2-3 or L3-4 space. The results may provide a better choice to relieve labor pain as soon as possible.Keywords: labor analgesia, epidural anesthesia, puncture points, rapid analgesia

Xiang-Zhe Shi,1,2 Sheng Zhao,3 Yan Wang,1,2 Meng-Yao Wang,1,2 Su-Wen Su,1,2 Yan-Zhao Wu,3 Chen Xiong1,2 1The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhung, 050017, People’s Republic of China; 3Department of Otorhinolaryngology-Head and Neck Surgery, 4th Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of ChinaCorrespondence: Chen Xiong; Yan-Zhao Wu, Email bearmorning@sina.com; wyz315@163.comIntroduction: Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid carcinoma. Doxorubicin (DOX) is the only drug approved for anaplastic thyroid cancer treatment, but its clinical use is restricted due to irreversible tissue toxicity. Berberine (BER), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been proposed to have antitumor activity in many cancers. However, the underlying mechanisms by which BER regulates apoptosis and autophagy in ATC remain unclear. Thus, the present study aimed to assess the therapeutic effect of BER in human ATC cell lines CAL-62 and BHT-101 as well as the underlying mechanisms. In addition, we assessed the antitumor effects of a combination of BER and DOX in ATC cells.Methods: The cell viability of CAL-62 and BTH-101 with treatment of BER for different hours was measured by CCK-8 assay, and cell apoptosis was assessed by clone formation assay and flow cytometric analysis. The protein levels of apoptosis protein, autophagy-related proteins and PI3K/AKT/mTORpathway were determined Using Western blot. Autophagy in cells was observed with GFP-LC3 plasmid using confocal fluorescent microscopy. Flow cytometry was used to detect intracellular ROS.Results: The present results showed that BER significantly inhibited cell growth and induced apoptosis in ATC cells. BER treatment also significantly upregulated the expression of LC3B-II and increased the number of GFP-LC3 puncta in ATC cells. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed BER-induced autophagic cell death. Moreover, BER induced the generation of reactive oxygen species (ROS). Mechanistically, we demonstrated that BER regulated the autophagy and apoptosis of human ATC cells through the PI3K/AKT/mTOR pathways. Furthermore, BER and DOX cooperated to promote apoptosis and autophagy in ATC cells.Conclusion: Taken together, the present findings indicated that BER induces apoptosis and autophagic cell death by activating ROS and regulating the PI3K/AKT/mTOR signaling pathway.Keywords: anaplastic thyroid carcinoma, berberine, autophagy, apoptosis, PI3K/AKT/mTOR, reactive oxygen species

Ling Feng,1,2,&ast; Tong Chen,3,&ast; Xuan Wang,1 Chongxiang Xiong,1,4 Jianhui Chen,1 Shiquan Wu,3 Jing Ning,3 Hequn Zou1,3 1Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Nephrology, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 3Department of Nephrology, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China; 4Department of Nephrology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hequn Zou, Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183, Zhongshan West Avenue, Tianhe District, Guangzhou, 510630, People’s Republic of China, Email Hequnzou@hotmail.comPurpose: Metabolic disorders are closely related to the occurrence and development of chronic kidney disease (CKD). We explored the prospective association between the Metabolic Score for Visceral Fat (METS-VF) and CKD in a 5-year follow-up study.Patients and Methods: In this cohort study, 631 adults not suffering from CKD from Wanzhai Town, in China in 2012 were included at baseline and followed up in 2017 and 2018. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between METS-VF and CKD risk. Area under the receiver operating characteristic curve (AUC) analyses were used to evaluate the ability of METS-VF, waist-to-height ratio (WhtR), visceral adiposity index (VAI), homeostatic model assessment of insulin resistance (HOMA-IR), body mass index (BMI) to predict CKD risk.Results: We identified 103 CKD cases during follow-up. After adjustment for confounding factors, comparing the lowest quartile of METS-VF, the OR (95% CI) of CKD risk in the highest quartile was 3.04 (1.39– 6.64). The per Standard deviation (SD) increase in METS-VF was positively correlated with CKD risk. The AUC of METS-VF for predicting CKD risk was, in general, higher than that for WhtR, VAI, HOMA-IR, and BMI.Conclusion: METS-VF may be an indicator for predicting CKD risk.Keywords: CKD, METS-VF, visceral obesity

Ling Feng,* Haishan Chen,* Jianhui Chen, Chongxiang Xiong, Xiaofei Shao, Xin Wang, Jing Ning, Zhicong Xiang, Xuan Wang, Tong Chen, Hua Xiao, Hongjuan Tang, Xiaolin Li, Guobao Hong, Hequn Zou Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this work.Correspondence: Hequn Zou; Xiaofei ShaoDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183, Zhongshan West Avenue, Tianhe District, Guangzhou 510630, People’s Republic of ChinaEmail Hequnzou@hotmail.com; 413151187@qq.comObjective: To explore whether the red blood cell count multiplied by hematocrit index (RBCHct) in blood routine parameters can indicate the risk of impaired fasting blood glucose (IFG), and whether it is related to insulin resistance and inflammation.Methods: In this cross-sectional study, previous history of diabetes was excluded, and people with normal and impaired IFG were included. We use Spearman analysis to evaluate the correlation between RBCHct index and fasting plasma glucose, insulin resistance homeostasis model assessment (HOMA-IR), and hypersensitive C-reactive protein (hs-CRP). Binary logistic regression analysis was used to evaluate the RBCHct index for assessing the potential risk of IFG, and the receiver operating characteristic (ROC) curve was used to evaluate the RBCHct index for diagnosing insulin resistance and chronic low-grade inflammatory efficacy among those with IFG.Results: Correlation analysis showed that the RBCHct index and fasting plasma glucose (r=0.088, P=0.003); HOMA-IR (r=0.199, P< 0.001); and hs-CRP (r=0.097, P=0.001) were positively correlated. After adjusting for confounding factors, the risk of IFG in the third and fourth quartiles of the RBCHct index increased to 1.889 and 3.048 times. The area under the ROC curve of the RBCHct index for diagnosis of insulin resistance state (HOMA-IR) was 0.695 (p< 0.001), and the area under the ROC curve of the RBCHct index for the diagnosis of chronic low-inflammatory state (hs-CRP) was 0.641 (P=0.010).Conclusion: The RBCHct index may be a potential indicator for assessing the risk of prediabetes and is closely related to whether the body is in a state of insulin resistance and inflammation under IFG.Keywords: diabetes mellitus, erythrocyte, RBCHct index, insulin resistance, inflammation

Xiaolin Li,1,2 Ting Su,3 Hua Xiao,1 Peichun Gao,4 Chongxiang Xiong,1 Jinghua Liu,3 Hequn Zou1 1Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China; 2Department of Endocrinology, Hunan University of Medicine, Huaihua 418000, Hunan, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of China; 4School of Public Health, Southern Medical University, Guangzhou 510080, People’s Republic of ChinaCorrespondence: Jinghua LiuGuangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People’s Republic of ChinaTel +86 20 61648392Fax +86 20 61648231Email liujhua@smu.edu.cnHequn ZouDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183 Zhongshan Dadao, Tianhe District, Guangzhou 510630, People’s Republic of ChinaTel +86 20 62784393Fax +86 20 62784399Email hequnzou@hotmail.comPurpose: To explore the association between the anti-inflammatory and renal protective roles of high-density lipoprotein cholesterol (HDL-c) and its different levels in type 2 diabetes mellitus (T2D), hypertension (HTN), and chronic kidney disease (CKD) and to lay a theoretical basis for precise, maximum-benefit HDL-c-raising therapy for patients with these diseases.Patients and Methods: A total of 2127 participants (195 with T2D, 618 with HTN, 162 with CKD, and 1152 controls) were selected and divided into four groups according to their baseline HDL-c level, namely, low HDL-c (L-HDL-c, ≤ 1.03 mmol/L), medium HDL-c (M-HDL-c, 1.04– 1.55 mmol/L), high HDL-c (H-HDL-c, 1.56– 2.05 mmol/L) and extremely high HDL-c (E-HDL-c, ≥ 2.06 mmol/L). Serum and morning urine samples were collected to analyze the correlation between high-sensitivity C-reactive protein (HsCRP), interleukin-6 (IL-6), urine n-acetyl-β-d-glucosidase (U-NAG), retinol binding protein (RBP), and cystatin c (Cys-C) levels with the HDL-c levels.Results: The HDL-c levels of patients with T2D, HTN and CKD were universally lower than those in the control group in both sexes (p< 0.05), while male patients also manifested a lower level of HDL-c than female patients. However, although they had lower values of the renal impairment index, female patients were found to have anomalously higher amounts of proinflammatory cytokines. In addition, the correlations between HsCRP and RBP levels and HDL-c levels were most significant in patients with HTN (p< 0.05), whereas in patients with T2D and CKD, such relevance was less significant.Conclusion: Existence of substantial differences in HDL-c levels between different types of disease and sex highlighted that a higher HDL level does not always predict a better clinical outcome of patients. Moreover, we found that both HsCRP and RBP correlated negatively with HDL-c in HTN patients, indicating that monitoring HsCRP and RBP may serve as indicators for therapeutic efficacy of HDL-c-raising medications in HTN patients.Keywords: high-density lipoprotein cholesterol, anti-inflammation, renal protection, sex difference, functional heterogeneity

Jing Ning, Zhicong Xiang, Chongxiang Xiong, Qin Zhou, Xin Wang, Hequn Zou Department of Nephropathy, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, People’s Republic of ChinaCorrespondence: Hequn ZouDepartment of Nephropathy, The Third Affiliated Hospital of Southern Medical University, 183 Zhongshan West Avenue, Tianhe District, Guangzhou 510630, People’s Republic of ChinaTel +86 20 6278 4391Email hequnzou@hotmail.comPurpose: Diabetic kidney disease (DKD), which is related to inflammation and immune response, is the primary vascular complication of diabetes mellitus and also the leading etiology of end-stage renal disease. Urinary extracellular vesicles (UEVs) are an attractive source for biomarker detection as they involve molecular constituents derived from their parental sections of the nephron. In this study, we aimed to search for a potential biomarker in UEVs for the early diagnosis and prediction of DKD, especially before the emergence of microalbuminuria.Patients and Methods: UEVs were isolated from the urine of healthy subjects, pre-diabetic, and diabetic patients with varying degrees of kidney damage by ultracentrifugation, and the extracted UEVs were used to measure alpha1-antitrypsin (α 1-AT) by Western blot. To explore the function of α 1-AT in the inflammatory process leading to DKD, we silenced the expression of α 1-AT in renal tubular epithelial cells using cell transfection techniques to assess the differential expression of the inflammatory factors such as MCP-1 and TNF-α using qRT-PCR.Results: There was no expression of α 1-AT in the UEVs of either healthy or pre-diabetic subjects. Its expression was significantly increased in the UEVs of diabetic patients with normoalbuminuria (prior to microalbuminuria), which was more sensitive and more stable than other renal indexes to predict DKD. Additionally, the expression of α 1-AT in UEVs was gradually upregulated with the aggravation of DKD and the decline of renal function. In vitro, the mRNA expression of MCP-1 and TNF-α was significantly decreased when the generation of α 1-AT in tubular epithelial cells was inhibited under high glucose stimulation.Conclusion: Our results suggest that α 1-AT derived from UEVs, especially in diabetic patients with normoalbuminuria, might serve as a potential noninvasive biomarker for diagnosis of DKD early in the development of the disease and may predict the future decline of renal function.Keywords: diabetic kidney disease, urinary extracellular vesicles, biomarker, alpha1-antitrypsin, inflammation, tubular epithelial cell

Xin Wang,1,* Jin Deng,2,* Chongxiang Xiong,1 Haishan Chen,1 Qin Zhou,1 Yue Xia,1 Xiaofei Shao,1 Hequn Zou1 1Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hequn Zou Tel +86 020-62784391Email zhq1962@smu.edu.cnPurpose: Hyperuricemia is an independent risk factor for renal damage and can promote the progression of chronic kidney disease (CKD). In the present study, we employ a rat model to investigate the effects of rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor-gamma agonist, on the development of hyperuricemic nephropathy (HN), and we elucidate the mechanisms involved.Methods: An HN rat model was established by oral administration of a mixture of adenine and potassium oxonate daily for 3 weeks. Twenty-four rats were divided into 4 groups: sham treatment, sham treatment plus RGTZ, HN, and HN treated with RGTZ.Results: Administration of RGTZ effectively preserved renal function, decreased urine microalbumin, and inhibited interstitial fibrosis and macrophage infiltration in a rat HN model. RGTZ treatment also inhibited TGF-β and NF-κB pathway activation, decreased expression of fibronectin, collagen I, α-SMA, vimentin, MCP-1, RANTES, TNF-α, and IL-1β, and increased E-cadherin expression in the kidneys of HN rats. Furthermore, RGTZ treatment preserved expression of OAT1 and OAT3 in the kidney of HN rats.Conclusion: RGTZ attenuates the progression of HN through inhibiting TGF-β signaling, suppressing epithelial-to-mesenchymal transition, reducing inflammation, and lowering serum uric acid levels by preserving expression of urate transporters.Keywords: hyperuricemic nephropathy, peroxisome proliferator-activated receptor-gamma, rosiglitazone, renal fibrosis, epithelial-to-mesenchymal transition, inflammation

Xin Wang,* Haishan Chen,* Xiaofei Shao, Chongxiang Xiong, Guobao Hong, Jianhui Chen, Xiaolin Li, Xu You, Peichun Gao, Yunying Chen, Ziliang Zou, Jing Ning, Hua Xiao, Hequn Zou, Lixin Wei Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hequn ZouDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183, Zhongshan West Avenue, Tianhe District, Guangzhou 510630, People’s Republic of ChinaEmail Hequnzou@hotmail.comLixin WeiDepartment of Nephrology, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, Fujian 350001, People’s Republic of ChinaEmail lixinwei66@126.comObjective: To investigate which plasma lipid parameters are useful for detecting chronic kidney disease (CKD) in a Chinese population without known CKD or renal impairment.Methods: This was a prospective study. In southern Chinese cities from 2012 to 2013, a total of 1037 subjects aged ≥ 18 years old received a survey. Logistic regression and multiple linear regression analyses were performed. The lipid parameters studied included total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (nHDL-C), TG/HDL-C ratio, TC/HDL-C ratio and nHDL-C/HDL-C ratio.Results: After adjusting for confounding factors, the fourth percentile of logTG/HDL-C was observed to be an independent risk factor for CKD (OR = 2.453, P < 0.001), and the highest quantile of the logTG/HDL-C ratio was associated with a higher prevalence of CKD (P < 0.05). This risk was reduced when the model was adjusted with Insulin resistance (IR) (OR = 2.034, P < 0.05). In the group of women, glucose metabolism disorders, high uric acid, and obesity, this risk was increased. Multiple regression models showed that log TG and nonHDL-C/HDL-C were negatively correlated with eGFR (P < 0.05), while log TG and TC were positively correlated with logACR (P < 0.05). The area under the curve (ROC) of lgTG/HDL was 0.623 (p < 0.001).Conclusion: The serum logTG/HDL-C ratio is the only suitable predictor of CKD, and IR may be the mechanism. This risk needs to be controlled in a specific population. Log TG and nonHDL-C/HDL-C were negatively correlated with eGFR, while log TG and TC were positively correlated with logACR.Keywords: lipid, chronic kidney disease, CKD, urinary albumin to creatinine ratio, ACR, estimated glomerular filtration rate, eGFR

Yu Hei,1 Binhong Teng,2,3 Ziqian Zeng,2,3 Siqi Zhang,3 Qian Li,3 Jijia Pan,3 Zuyuan Luo,3 Chunyang Xiong,1 Shicheng Wei2,3 1Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of China; 3Laboratory of Biomaterials and Regenerative Medicine, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Chunyang XiongDepartment of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of ChinaTel +86 10 62757940Email cyxiong@pku.edu.cnShicheng WeiDepartment of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of ChinaTel +86 10 82195780Email sc-wei@pku.edu.cnBackground: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia.Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma.Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro.Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity.Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.Keywords: immunotherapy, programmed death ligand 1 monoclonal antibodies, aPDL1s, tumor hypoxia, melanoma, liposomes

Hua Xiao,* Chongxiang Xiong,* Xiaofei Shao,* Peichun Gao, Haishan Chen, Jing Ning, Yunying Chen, Ziliang Zou, Guobao Hong, Xiaolin Li, Xu You, Jieli Sheng, Fan Wu, Xin Wang, Hequn Zou Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China *These authors contributed equally to this workCorrespondence: Hequn ZouDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183, Zhongshan West Avenue, Tianhe District, Guangzhou 510630, People’s Republic of ChinaTel +86 20 6278 4391Email hequnzou@hotmail.comPurpose: To investigate the correlation between visceral obesity and pathogenesis of chronic kidney disease (CKD) among non-diabetic individuals, and to evaluate the potential of visceral adiposity index (VAI) as a predictor of CKD.Patients and Methods: From December 2017 to March 2018, 1877 non-diabetic participants (male n=699, female n=1208) in southern China were recruited for a cross-sectional survey. Males and females were divided into four groups according to gender-specific quartiles of VAI scores. A logistic regression model was established to analyze the correlation between visceral adiposity index and CKD.Results: Visceral adiposity index was positively correlated with CKD and was negatively associated with estimated glomerular filtration rate (eGFR). Using group one as the control, odds ratios (ORs) were calculated to determine the risk of developing CKD as VAI increased (male: group four 2.73 [P< 0.005]; female: Group three 1.76 [P< 0.05], Group four 2.88 [P< 0.005]). When related factors such as history of hypertension, smoking, alcohol use, and physical inactivity were normalized in the logistic model before calculation, ORs became 2.73 (male: P< 0.05), and 2.18 (female: P< 0.05), respectively. The results differed after normalizing further for systolic blood pressure (SBP), diastolic blood pressure (DBP), hypersensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), homocysteine (Hcy), superoxide dismutase (SOD), and retinol-binding protein (RBP). There were no significant differences in ORs among the female groups.Conclusion: Visceral adiposity index was significantly associated with CKD in non-diabetic individuals. It may be a good predictor of the pathogenesis of CKD and was dependent on hsCRP, IL-6, Hcy, SOD, RBP, and blood pressure levels in females and males with VAI scores of 1.41 and higher. Visceral adiposity index may be used to predict CKD in males with VAI less than 0.983.Keywords: visceral adiposity index, chronic kidney disease, non-diabetic population

Guo-bao Hong,1,2 Pei-chun Gao,1,3 Yun-yin Chen,1 Yue Xia,1 Xiao-su Ke,1 Xiao-fei Shao,1 Chong-xiang Xiong,1 Hai-shan Chen,1 Hua Xiao,1 Jing Ning,1 He-qun Zou1 1Department of Nephrology, Institute of Nephrology and Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of China; 2Department of Nephrology, The Affiliated Nanhai Hospital of Southern Medical University, Foshan 528200, People’s Republic of China; 3School of Public Health, Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of ChinaCorrespondence: He-qun ZouDepartment of Nephrology, Institute of Nephrology and Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of ChinaTel +86-20-6278-4391Email hequnzou@hotmail.comPurpose: Metabolic syndrome (MetS), characterized by a constellation of insulin resistance, central obesity, hypertension, and hyperlipidemia, is a global health threat. High-sensitivity C-reactive protein (hs-CRP) has been shown to be associated with type 2 diabetes and cardiovascular disease; however, its association with incident MetS is less known. Therefore, the aim of this study was to examine the prospective association between hs-CRP and MetS among a Chinese population in a 5-year follow-up study.Patients and Methods: The levels of hs-CRP were measured using serum samples collected at baseline recruitment in 2012 from 886 participants without MetS. Follow-up interviews were conducted in 2018, and MetS was diagnosed by 2017 criteria from the Chinese Diabetes Society. Multivariate logistic regression models were used to assess the overall and sex-specific associations between hs-CRP and incident MetS. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were computed with adjustment for demographic, socioeconomic, clinical, and lifestyle factors.Results: After a mean follow-up duration of 5.40 ± 0.56 years, 116 (13.3%) participants developed MetS. In the total study population, increased hs-CRP levels were associated with a higher risk of MetS (OR comparing extreme quartiles of hs-CRP: 4.06 [95% CI: 1.91– 8.65]) in the fully-adjusted model. When stratified by sex, the positive association was only observed in women (OR: 4.82 [1.89– 12.3]) but not in men (OR: 3.15 [0.82– 12.1]; P-interaction = 0.039).Conclusion: In this study of a Chinese population, a positive association between hs-CRP and incident MetS was found only in women and not in men. Sex-specific prediction and intervention of MetS using hs-CRP as a target should be further evaluated.Keywords: inflammation, high-sensitivity C-reactive protein, metabolic syndrome, cohort study, follow up

Haishan Chen,* Chongxiang Xiong, Xiaofei Shao,* Jing Ning, Peichun Gao, Hua Xiao, Yunying Chen, Ziliang Zou, Guobao Hong, Xiaolin Li, Mengjiao Shao, Jieli Sheng, Xingyan Yang, Xu You, Hequn Zou Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hequn ZouDepartment of Nephrology, The Third Affiliated Hospital, Southern Medical University, 183 Zhongshan West Avenue, Tianhe District, Guangzhou 510630, People’s Republic of ChinaEmail Hequnzou@hotmail.comPurpose: Metabolic syndrome (MetS), which is a global public health problem, is a state of chronic low-grade inflammation. This study looked at the changes in hematological parameters and the predictive value of the lymphocyte to high-density lipoprotein cholesterol (HDL-C) ratio (LHR) as a new index in subjects with and without MetS in coastal cities in southern China.Patients and methods: In this cross-sectional study, there were 852 participants (n = 598 with MetS and n = 254 without MetS). MetS was defined in accordance with the National Cholesterol Education Program, Adult Treatment Panel III (NCEP-ATP III) criteria.Results: MetS was positively correlated with white blood cell count, total lymphocyte count, neutrophil count, red blood cell count, hematocrit, hemoglobin, and high-sensitivity C-reactive protein levels (p

Yang Liu,1,* Wei Huang,2,* Chuanfeng Xiong,2 Yuxian Huang,2 Benny J Chen,2,3 Luigi Racioppi,2,4 Nelson Chao,2,3 Tuan Vo-Dinh1,3,5–61Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA; 2Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; 3Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA; 4Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples 80131, Italy; 5Fitzpatrick Institute for Photonics, Duke University, Durham, NC 27708, USA; 6Department of Chemistry, Duke University, Durham, NC 27708, USA*These authors contributed equally to this work Aim: To quantitatively and sensitively investigate the biodistribution of immune cells after systemic administration.Methods: Immune cells were loaded with plasmonic gold nanostars (GNS) tracking probes. Inductively coupled plasma mass spectrometry (ICP-MS) was used for quantitative gold mass measurement and two-photon photoluminescence (TPL) was used for high-resolution sensitive optical imaging.Results: GNS nanoparticles were loaded successfully into immune cells without negative effect on cellular vitality. Liver and spleen were identified to be the major organs for macrophage cells uptake after systematic administration. A small amount of macrophage cells were detected in the tumor site in our murine lymphoma animal model.Conclusion: GNS has great potential as a biocompatible marker for quantitative tracking and high-resolution imaging of immune cells at the cellular level.Keywords: GNS, ICP-MS, two-photon microscopy, immune cells, biodistribution

Martin Kuete,1,2 HongFang Yuan,1 Aude Laure Tchoua Kemayou,2 Emmanuel Ancel Songo,2 Fan Yang,1 XiuLan Ma,1 ChengLiang Xiong,1 HuiPing Zhang1 1Obstetrics and Gynecology, Reproductive Center, Family Planning and Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Main Maternity of Obstetrics and Gynecology, Yaounde Central Hospital, Faculty of Medicine and Biomedical Sciences, Yaounde, Cameroon Background: Integration of family planning services (FPS) into human immunodeficiency virus (HIV) care for HIV-infected women is an important aspect of the global prevention of mother-to-child transmission (PMTCT) strategy. We assessed the integration of FPS into routine care of HIV-infected mothers by evaluating the uptake and barriers of contraception and PMTCT services. Methods: We conducted an interventional study using the interrupted time series approach in the health care facilities located in Yaounde, Cameroon. First, structured questionnaires related to family planning use, PMTCT services use, and infection risk of the sexual partner were administered to the first trimester pregnant women who were HIV infected and living with uninfected partners. Second, 2 weeks before the delivery date, the women were interviewed according to the prior counseling interventions received, in order to assess their behavior on FPS, antiretroviral therapy (ART) use, delivery option, and infant nourishment to be adopted. P-values below 0.05 were considered statistically significant in the statistical analyses. Results: Of 94 HIV-infected women, 69% were stable couples. Only 13% of women had attended FPS before conception. Although the vast majority were knowledgeable about modern and traditional contraception methods, only 19% had experienced effective contraceptive methods. However, 66% preferred condom use, 45% having three children still expressed a desire to conceive, while 44% reported abortions, 65% had tried to avoid the current pregnancy, and 12% of women were ART naïve. Several predictors such as education, abortion rate, unplanned pregnancies, and partners’ decision were associated with the nonuse of effective contraceptive methods. Moreover, barriers including sex inequity, lack of partner support, ART shortages, and lack of HIV viral load monitoring were prevalent among the participants (P=0.001). However FPS use, ART compliance, and safe options to PMTCT significantly increased after the educational counseling interventions (P=0.001).Conclusion: Scaling up the FPS by incorporating routine PMTCT services into reproductive health care should contribute to preventing both horizontal and vertical transmission of HIV. Keywords: contraception, HIV infected women, transmission, interventions, education

Background The prevalence of overweight and obesity among children and adolescents is continuously rising. As countries have developed several school-based nutrition policies to control overweight and obesity, it is important to examine the effectiveness of nutrition policies. Objective To evaluate the effect of the centralized distribution of food material system on overweight and obesity rates among children and adolescents aged 6-15 years. Methods In April 2023, a total of 104 749 BMI data from sixteen schools aged 6 to 15 years (8 schools were included in the unified food distribution system and recorded as the unified distribution group, and 8 schools were not included in the unified food distribution and supply system and recorded as the non-unified distribution group) in Wuxi were retrospectively collected between 2017 and 2021. The data of physical examination was collected from Student Health Monitoring System in Jiangsu Province. The overweight and obesity epidemiologic trends among children and adolescents were analyzed from 2017 to 2021 in Wuxi, and the changes in BMI-Z scores and trends in overweight and obesity rates among children and adolescents were compared before and after the implementation of the centralized distribution of food material system by the Joinpoint regression and grey GM (1, 1) model. Results The prevalence of overweight and obesity among in children and adolescents aged 6-15 years was increasing from 2017 to 2021. The results of the Joinpoint regression analysis indicated that the prevalence of overweight (APC 1.8% vs 4.6%) and obesity (APC 6.9% vs 13.3%) among students included in the system exhibited a slower rate of increase than among those not included. The disparity in the increase of BMI-Z scores among students included in the system and those not included changed from -0.055 (95%CI=-0.108--0.002) to -0.195 (95%CI=-0.246--0.145) before and after the implementation of the system. The results of grey GM (1, 1) model showed that the incidence rate of overweight among children and adolescents in Wuxi in 2022, 2023 and 2024 was 22.02%, 22.39% and 22.77% respectively, with the incidence rate of overweight being 17.02%, 18.50% and 20.12% respectively. Conclusion The increasing trend in the prevalence of overweight and obesity, as well as the increase in BMI-Z scores among children and adolescents, has slowed down after the implementation of the centralized distribution of food material system. The system may be an effective method of improving the nutritional status of children and adolescents. Therefore, it is recommended that the centralized distribution of food material system still needs to be implemented and the monitoring area needs to be expanded.

BackgroundsInsomnia is frequent in schizophrenia and is found to be negatively affected by stressful life events， psychotic symptoms and depressive disorder， while the relationship among the four remains understudied in community-dwelling patients with schizophrenia.ObjectiveTo analyze the effect of stressful life events on insomnia in community-dwelling patients with schizophrenia， and to explore the mediation effect of psychotic symptoms and depression， so as to provide references for the intervention of insomnia in community-dwelling patients with schizophrenia.MethodsFrom April to June 2023， a sample of 1 105 patients with schizophrenia attending 48 community health centers in Chengdu， Sichuan province and fulfilling the International Classification of Diseases， tenth edition （ICD-10） diagnostic criteria were included. All subjects were assessed using Stressful Life Event Scale （SLEs）， Athens Insomnia Scale （AIS）， Psychosis Screening Questionnaire （PSQ）， and Patient Health Questionnaire Depression Scale （PHQ-9）. Spearman correlation analysis was used to determine the correlation among the scales. Then the mediation model was constructed using Smart PLS 4.0， and tested with partial least squares algorithm and Bootstrap techniques.Results332 patients （30.05%） with community schizophrenia were found to have insomnia. AIS scores in patients with schizophrenia were positively correlated with the scores on SLEs， PSQ and PHQ-9 （r=0.165， 0.322， 0.554， P

Abstract Nasopharyngeal carcinoma (NPC) presents a significant medical challenge due to its high incidence rate and poor prognosis, which are attributed primarily to tumor metastasis and drug resistance. Sine oculis homeobox homolog 1 (SIX1) has been identified as a crucial target for cancer treatment. However, its role in NPC remains incompletely understood. This study investigated the mechanisms by which the degradation of the SIX1 protein, which is mediated by ubiquitin, affects the malignant characteristics of NPC throughout the cell cycle. Our findings reveal that reduced expression of the itchy E3 ubiquitin ligase E3 (ITCH) in NPC impedes the degradation of the SIX1 protein, leading to enhance oncogenic properties. Knockdown experiments which SIX1 was inhibited demonstrated a decrease in the proliferation, migration, and invasion of NPC cell lines, whereas overexpression of SIX1 yielded the opposite effects. Further experimental validation revealed that SIX1 promotes NPC progression via the cell division cycle 27 (CDC27)/cyclin B1 axis. These findings provide valuable insights into potential therapeutic targets and prognostic indicators for NPC treatment, emphasizing the ITCH/SIX1/CDC27/cyclin B1 axis as a promising target for novel therapies.

Abstract Background Depression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation. Methods This study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005–2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study. Results In the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02–1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85–70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03–1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05). Conclusions Depression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

Abstract Eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and pica, are psychobehavioral conditions characterized by abnormal eating behaviors and an excessive preoccupation with weight and body shape. This review examines changes in brain regions and functional connectivity in ED patients over the past decade (2013–2023) using resting-state functional magnetic resonance imaging (rs-fMRI). Key findings highlight alterations in brain networks such as the default mode network (DMN), central executive network (CEN), and emotion regulation network (ERN). In individuals with AN, there is reduced functional connectivity in areas associated with facial information processing and social cognition, alongside increased connectivity in regions linked to sensory stimulation, aesthetic judgment, and social anxiety. Conversely, BED patients show diminished connectivity in the dorsal anterior cingulate cortex within the salience network and increased connectivity in the posterior cingulate cortex and medial prefrontal cortex within the DMN. These findings suggest that rs-fMRI could serve as a valuable biomarker for assessing brain function and predicting treatment outcomes in EDs, paving the way for personalized therapeutic strategies.

Abstract Background Hypoxia plays an important role in the chemotherapy resistance of nasopharyngeal carcinoma (NPC). Ferroptosis is a newly discovered form of programmed cell death and ferroptosis inducers showed promising therapeutic effects in some cancers. However, the sensibility of NPC cells to ferroptosis under the hypoxic microenvironment is still unclear, and this study was designed to clarify it. Methods NPC cells, treated with erastin, were placed in a normoxia or hypoxic environment (5% CO2, 94% N2 and 1% O2) at 37℃for 24 h. After exposed to hypoxia, ferroptosis-associated phenotypes were detected by CCK8, MDA, GSH, lipid ROS and Fe. The gene expression profiles of head and neck squamous cell carcinoma (HNSCC) tissues were downloaded from the TCGA database to screen construction molecule. BAP1 was screened out and its functions on erastin-induced ferroptosis in NPC cells were detected by knockdown of BAP1. Luciferase reporter assay and co-IP experiment were performed to explore the molecular mechanism. Finally, the tumour xenograft model was applied to further verify these results in vivo. Results CCK8 assay showed that IC50 of NPC cells treated with erastin under hypoxia was significantly lower than that under normoxia. Hypoxia significantly increased the levels of lipid ROS and MDA, and decreased GSH content induced by erastin. A prognostic risk model for HNSCC with six ferroptosis-related genes was constructed and validated based on TCGA database. BAP1 was significantly up-regulated under hypoxia, and luciferase reporter assay showed that HIF-1α was an upstream transcription regulator of BAP1. Knockdown of BAP1 in NPC cells significantly increased the IC50 value of erastin under hypoxia and significantly ameliorated erastin-induced ferroptosis under hypoxia in aspect of lipid ROS, MDA content and GSH. Co-IP results showed that BAP1 mediated deubiquitination of H2A and decreased SLC7A11 expression. Finally, knockdown of BAP1 reduced sensitivity to erastin-induced ferroptosis in a tumour xenograft model. And the level of H2A was significantly decreased in xenograft tumors of BAP1 knockdown cells. Conclusion Hypoxia-induced BAP1 enhances erastin-induced ferroptosis in NPC by stabilizing H2A. Ferroptosis inducers targeting BAP1 may be an effective way to improve chemotherapy resistance in NPC, especially in the hypoxic microenvironment. Graphical Abstract

In this paper, we investigated the potential use of a new organic-inorganic hybrid crystal structure based on KNO3 in ignition compositions. H2dabco[K(NO3)3] (DAN-2) with organic-inorganic hybrid crystal structure is synthesized through intermolecular assembly technology. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were used to detect the crystal morphology, structure and molecular structure of DAN-2, which has a regular cubic structure. Experimental data were obtained using thermogravimetric/differential scanning calorimetry (TG-DSC), closed bomb test and high-speed photography, which were then used to study and analyze the thermal decomposition properties and combustion properties of DAN-2. The initial thermal decomposition temperature of DAN-2 was low (194 °C) and the activation energy of the thermal decomposition was 154 kJ/mol. Possible thermal decomposition mechanisms are further discussed and proposed. This research pushed forward the application of organic-inorganic hybrid crystal structure oxidant DAN-2 in ignition system.

Abstract Aluminum (Al) is usually added to solid propellants to improve the combustion performance, however the condensed combustion products (CCPs) especially the large agglomerates generated from aluminum combustion can reduce the specific impulse of the engine, and result in two-phase loss, residue accumulation and throat liner ablation. Al and ammonium perchlorate (AP), as important components of NEPE propellants, can affect the formation process of the CCPs of aluminized NEPE propellants. To clarify the effect of Al and AP particle sizes on the properties of the CCPs of aluminized NEPE propellants, a constant-pressure quench vessel was adopted to collect the combustion products of four different formulations of NEPE propellants. It was found that the condensed combustion products are mainly divided into aluminum agglomerates and oxide particles, the diameter of the aluminum agglomerates of these four different formulations of NEPE propellants at 7 MPa was smaller than that in 3 MPa, and the shells of the aluminum agglomerates were smoother and the spherical shape was more perfect. X-ray diffraction analysis of the CCPs of the four NEPE propellants under 3 MPa revealed the presence of both Al and Al2O3. With the increase of the particle size of Al and AP, the oxidation degree of aluminum particles decreases. The particle size of the CCPs of the four different formulations of NEPE propellants under 1 and 3 MPa was analyzed by using a laser particle size analyzer, it is found that the increase of AP particle size is helpful to reduce the size of condensate combustion products. Based on the classical pocket theory, establishing a new agglomeration size prediction model, which can be used to predict the agglomeration size on the burning surface. Compared with the empirical model, the new agglomeration size prediction model is in good agreement with the experimental results.

Abstract This work revisits the notion of complex step derivative approximation (CSDA) and presents its use in constitutive model of a class of nonlinear viscoelastic materials. The effectiveness of a CSDA is evaluated by putting it through a series of straightforward examples. After that, the idea of the CSDA is put to use in order to carry out a numerical evaluation of the algorithmic tangent moduli of a viscoelastic constitutive model. The performance of the constitutive models is evaluated through the use of three different numerical tests, and the results are compared to those that were achieved by the application of an analytical method. In comparison to other numerical differentiation techniques, It has been found that the CSDA scheme is the most computationally efficient and robust method of numerical differentiation, regardless of the size of the finite difference interval.

Abstract Background The 2-phenylethanol (2-PE) tolerance phenotype is crucial to the production of 2-PE, and Pdr1p mutation can significantly increase the tolerance of 2-PE in Saccharomyces cerevisiae. However, its underlying molecular mechanisms are still unclear, hindering the rational design of superior 2-PE tolerance performance. Results Here, the physiology and biochemistry of the PDR1_862 and 5D strains were analyzed. At 3.5 g/L 2-PE, the ethanol concentration of PDR1_862 decreased by 21%, and the 2-PE production of PDR1_862 increased by 16% than those of 5D strain. Transcriptome analysis showed that at 2-PE stress, Pdr1p mutation increased the expression of genes involved in the Ehrlich pathway. In addition, Pdr1p mutation attenuated sulfur metabolism and enhanced the one-carbon pool by folate to resist 2-PE stress. These metabolic pathways were closely associated with amino acids metabolism. Furthermore, at 3.5 g/L 2-PE, the free amino acids content of PDR1_862 decreased by 31% than that of 5D strain, among the free amino acids, cysteine was key amino acid for the enhancement of 2-PE stress tolerance conferred by Pdr1p mutation. Conclusions The above results indicated that Pdr1p mutation enhanced the Ehrlich pathway to improve 2-PE production of S. cerevisiae, and Pdr1p mutation altered the intracellular amino acids contents, in which cysteine might be a biomarker in response to Pdr1p mutation under 2-PE stress. The findings help to elucidate the molecular mechanisms for 2-PE stress tolerance by Pdr1p mutation in S. cerevisiae, identify key metabolic pathway responsible for 2-PE stress tolerance.

Objective To explore the correlation between functional connectivity (FC) in the brains of Parkinson's disease (PD) patients with depression and the improvement rate of depression after subthalamic nucleus deep brain stimulation (STN-DBS). Methods This study included 38 PD patients (25 with depression and 13 without depression) who underwent STN -DBS at The First Affiliated Hospital of University of Science and Technology of China from September 2019 to April 2020. All participants underwent resting-state fMRI. The severity of depression was assessed using Hamilton Depression Rating Scale-17 Items (HAMD-17) before and 2 years after the surgery, and the improvement rate of depression was calculated. Spearman rank correlation analysis was used to investigate the relationship between FC and the improvement rate of depression in PD patients with depression. Results There were 34 different FC between PD patients with and without depression compared to control group (P = 0.000, for all). Among patients with PD, those with depression showed 4 distinct FC compared to those without depression, including left precuneus -right supplementary motor area (t = 6.028, P = 0.000), right insula -right lateral orbital gyrus (t = 5.525, P = 0.000), left paracentral lobule-left precuneus (t = 5.545, P = 0.000), and right paracentral lobule - left precuneus (t = 5.578, P = 0.000). Spearman rank correlation analysis revealed a negative correlation between the zFC values of right precuneus-right insula (rs = - 0.544, P = 0.009) and left temporal pole-left insula (rs = - 0.765, P = 0.010) and the improvement rate of depression in PD patients with depression. Conclusions The FC of right precuneus-right insula and left temporal pole-left insula in PD patients with depression is negatively associated with the improvement rate of depression.

Abstract The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA. Graphical abstract

Abstract Introduction and objectives In diseases characterized by fibrosis, hepatic stellate cells (HSCs) are mesenchymal cells that play an important role in liver fibrosis. circRNAs are involved in regulating hydatid exocyst formation through miRNA sponge adsorption. The mechanisms of hepatic cystic hydatid outer cyst formation, HSC, and liver fibrosis are unclear. Materials and methods Based on our sequencing data, we validated the mechanism by which circRNA-049637 regulated hepatic cystic hydatid growth and promoted outer fibrocystic wall formation. Results Our results revealed that circRNA_049637 silencing promoted the proliferation of LX-2 human HSCs, affected the cell cycle, and increased the mRNA and protein expression levels of liver fibrosis-related indicators such as α-SMA, COL1A1, COL3A1, and TGFβRII. Conclusions CircRNA_049637 may induce the formation of hepatic hydatid cysts by promoting hepatic fibrosis via HSC activation.

Abstract Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress‐related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome‐related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte‐specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive‐like behaviors by inhibiting lysosomal exocytosis‐mediated adenosine 5′‐triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive‐like behaviors induced by astrocyte‐specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress‐sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

Abstract Obstructive sleep apnea (OSA) is a common sleep disorder characterized by intermittent hypoxia (IH) and is associated with the occurrence and development of nonalcoholic fatty liver disease (NAFLD). However, the specific mechanism by which OSA induces NAFLD remains unclear. Therefore, effective interventions are lacking. This study aims to investigate the role and mechanism of ferroptosis in OSA‐related NAFLD using clinical data analyses, cell‐based molecular experiments, and animal experiments. Indicators of liver function, lipid accumulation, and ferroptosis are also examined. RNA‐seq, qPCR, western blotting, gene intervention, and E3 ligase prediction using UbiBrowser and co‐IP are used to explore the potential underlying mechanisms. The results show that ferroptosis increases in the liver tissues of patients with OSA. Chronic IH promotes NAFLD progression in mice and is alleviated by a ferroptosis inhibitor Fer‐1. The increased secretion of IL6 by macrophages can promote the expression of MARCH3 in hepatocytes under intermittent conditions, and subsequently promote the ubiquitination and degradation of GPX4 to regulate ferroptosis and lipid accumulation in hepatocytes. Hence, targeted inhibition of MARCH3 may alleviate IH‐induced ferroptosis and lipid accumulation in liver tissues and inhibit the progression of NAFLD.

Abstract Background Bone marrow is the leading site for metastasis from neuroblastoma and affects the prognosis of patients with neuroblastoma. However, the accurate diagnosis of bone marrow metastasis is limited by the high spatial and temporal heterogeneity of neuroblastoma. Radiomics analysis has been applied in various cancers to build accurate diagnostic models but has not yet been applied to bone marrow metastasis of neuroblastoma. Methods We retrospectively collected information from 187 patients pathologically diagnosed with neuroblastoma and divided them into training and validation sets in a ratio of 7:3. A total of 2632 radiomics features were retrieved from venous and arterial phases of contrast‐enhanced computed tomography (CT), and nine machine learning approaches were used to build radiomics models, including multilayer perceptron (MLP), extreme gradient boosting, and random forest. We also constructed radiomics‐clinical models that combined radiomics features with clinical predictors such as age, gender, ascites, and lymph gland metastasis. The performance of the models was evaluated with receiver operating characteristics (ROC) curves, calibration curves, and risk decile plots. Results The MLP radiomics model yielded an area under the ROC curve (AUC) of 0.97 (95% confidence interval [CI]: 0.95–0.99) on the training set and 0.90 (95% CI: 0.82–0.95) on the validation set. The radiomics‐clinical model using an MLP yielded an AUC of 0.93 (95% CI: 0.89–0.96) on the training set and 0.91 (95% CI: 0.85–0.97) on the validation set. Conclusions MLP‐based radiomics and radiomics‐clinical models can precisely predict bone marrow metastasis in patients with neuroblastoma.

Several studies have documented a relationship between short-term exposure to atmospheric sulfur dioxide (SO2) and chronic obstructive pulmonary disease (COPD). However, findings vary across different regions. This meta-analysis employed a random-effects model to calculate the combined risk estimate for each 10-μg/m3 increase in ambient SO2 concentration. Subgroup analysis aimed to identify sources of heterogeneity. To assess potential bias, studies were evaluated using a domain-based assessment tool developed by the World Health Organization. Sensitivity analyses, based on bias risk, explored how model assumptions influenced associations. An evidence certainty framework was used to evaluate overall evidence quality. The study protocol was registered with PROSPERO (CRD42023446823). We thoroughly reviewed 191 full-text articles, ultimately including 15 in the meta-analysis. The pooled relative risk for COPD was 1.26 (95 % CI 0.94–1.70) per 10-μg/m3 increase in ambient SO2. Eleven studies were deemed high risk due to inadequate handling of missing data. Overall evidence certainty was rated as medium. Given SO2's significant public health implications, continuous monitoring is crucial. Future research should include countries in Africa and Oceania to enhance global understanding of atmospheric SO2-related health issues.

PurposeTo explore whether tumor-associated lymphatic vessel density (LVD) could be a biomarker for the prognosis of patients with esophageal cancer after radical resection.MethodsA systematic literature search was performed through PubMed, EMBASE, Wanfang Data, and Cochrane Library from the inception of databases until March 19, 2024. The selected studies investigated overall survival (OS) and/or recurrence-free survival (RFS) of patients with esophageal cancer with different levels of LVD after radical resection. The OS and RFS data were pooled as hazard ratios (HR) and 95% confidential interval (CI). Furthermore, the standardized mean differences (SMDs) and 95% CI were aggregated to evaluate the correlation between LVD and clinicopathological features.ResultsA total of 10 retrospective studies of 1,201 patients were finally included for the meta-analysis. Patients with esophageal cancer with a high level of LVD exhibited worse OS (HR 1.65, 95% CI 1.18 to 2.31) and RFS (HR 1.57, 95% CI 1.09 to 2.26) than those with a low level of LVD. Subgroup analysis of different pathological subtypes revealed that patients with esophageal adenocarcinoma with a high level of LVD had significantly worse RFS (HR 2.84, 95% CI 1.61 to 5.02) than those with a low level of LVD; while patients with esophageal squamous cell carcinoma with a high level of LVD had similar OS (HR 1.52, 95% CI 0.93 to 2.47) and RFS (HR 1.03, 95% CI 0.72 to 1.48) to those with a low level of LVD. Furthermore, tumors with lymph node metastasis had significantly higher levels of LVD than those without lymph node metastasis (SMD = 1.11, 95% CI 0.54 to 1.67). Tumors at the stages III-IV had significantly higher levels of LVD than those at the stages I-II (SMD = 1.62, 95% CI 0.90 to 2.34).ConclusionA high level of LVD in tumor was associated with worse survival of patients with esophageal cancer after radical resection, especially in patients with esophageal adenocarcinoma. Tumor-associated LVD is a new parameter that should be measured in postoperative pathology for predicting the prognosis of patients with esophageal cancer.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42024553766.

Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disease that primarily affects the synovium of diarthrodial joints. Inflammatory macrophages and fibroblast-like synoviocytes (FLS) in the synovial microenvironment produce pathogenic mediators such as cytokines and proteases that perpetuate immune-mediated inflammation and contribute to the destruction of cartilage and bone. Polydatin (PD), a natural active compound, has demonstrated potential anti-inflammatory and anti-arthritic effects. However, drug development and delivery of PD is still a great challenge owing to its low solubility, short half-life, and high dose requirement. In order to overcome these drawbacks, we developed a novel nanodrug system named HA-M@PB@Ag@PD NPs. This system is composed of hybrid membrane (M), hyaluronic acid (HA), Prussian blue nanoparticles (PB NPs), PD, and chitosan-silver (Chi-Ag). In vitro experiments demonstrated that HA-M@PB@Ag@PD NPs effectively cleared ROS, promoted the repolarization of inflammatory macrophages, and induced apoptosis of RA-FLS. Using a rat model of RA, HA-M@PB@Ag@PD NPs markedly suppressed joint inflammation, inhibited synovial hyperplasia, and protected joints against destruction of cartilage and bone. Moreover, HA-M@PB@Ag@PD NPs significantly improved the synovial microenvironment of arthritic rats by reducing the number of RA-FLS and inflammatory macrophages, and facilitating the repolarization of inflammatory macrophages.

Environmental heavy metals pollution have seriously threatened the health of human beings. An increasing number of researches have demonstrated that environmental heavy metals can influence the telomere length of Peripheral Blood Mononuclear Cells (PBMCs), which implicate biological aging as well as predicts diseases. Our previous study has shown that methylmercury (MeHg)-induced telomere shortening in rat brain tissue was associated with urinary melatonin metabolite 6-sulfatoxymelatonin (aMT6s) levels. Here, we aimed to further elucidate the impact of 4 typical heavy metals (As, Hg, Cd and Pb) on telomere length of PBMCs and their association with urinary aMT6s in rats. In this study, eighty-eight male Sprague-Dawley rats were randomized grouped into eleven groups. Among them, forty 3-month-old (young) and forty 12-month-old (middle-aged) rats were divided into young or middle-aged control groups as well as typical heavy metals exposed groups, respectively. Eight 24-month-old rats (old) was divided into aging control group. The results showed that MeHg exposure in young rats while sodium arsenite (iAs), MeHg, cadmium chloride (CdCl2), lead acetate (PbAc) exposure in middle-aged rats for 3 months significantly reduced the levels of and urinary aMT6s, as well as telomere length of PBMCs. In addition, they also induced abnormalities in serum oxidative stress (SOD, MDA and GPx) and inflammatory (IL-1β, IL-6 and TNF-α) indicators. Notably, there was a significant positive correlation between declined level of urinary aMT6s and the shortening of telomere length in PBMCs in rats exposed to 4 typical heavy metals. These results suggested that 4 typical heavy metals exposure could accelerate the reduction of telomere length of PBMCs partially by inducing oxidative stress and inflammatory in rats, while ageing may be an important synergistic factor. Urinary aMT6s detection may be a alternative method to reflect telomere toxic effects induced by heavy metal exposure.

Tetraphyllum Griff. ex C. B. Clarke, a newly recorded genus of Gesneriaceae from Guangxi, China is reported. Tetraphyllum has only three species. The morphological description and the distinctive features to the species of Tetraphyllum are provided, and the detailed morphological description and photos of T. confertiflorum (Drake) B. L. Burtt are provided. The voucher specimens are preserved in the Herbarium of Guangxi Institute of Botany (IBK) and Shanghai Chenshan Herbarium (CSH).

Abstract Background Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model. Methods A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4–8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). Results A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram’s predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort. Conclusions We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID.

Abstract Epigenetic mechanisms bridge genetic and environmental factors that contribute to the pathogenesis of major depression disorder (MDD). However, the cellular specificity and sensitivity of environmental stress on brain epitranscriptomics and its impact on depression remain unclear. Here, we found that ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), was increased in MDD patients’ blood and depression models. ALKBH5 in astrocytes was more sensitive to stress than that in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons and endothelial cells, produced antidepressant-like behaviors. Astrocytic ALKBH5 in the mPFC regulated depression-related behaviors bidirectionally. Meanwhile, ALKBH5 modulated glutamate transporter-1 (GLT-1) m6A modification and increased the expression of GLT-1 in astrocytes. ALKBH5 astrocyte-specific knockout preserved stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy and defective Ca2+ activity. Moreover, enhanced m6A modification with S-adenosylmethionine (SAMe) produced antidepressant-like effects. Our findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors and that astrocytic ALKBH5 may be a therapeutic target for depression.

High-Speed Rail (HSR) stations can influence the expansion of the surrounding construction land. However, relevant studies face three main limitations: influence scope estimation lacking a theoretical foundation, less focus on whether the impacts of HSR stations on construction land expansion vary, and misjudgment of the drivers of HSR stations on construction land expansion. To address these research questions, this study first conducts a literature review to theoretically analyze the influence of HSR stations on the surrounding construction land expansion and then identifies the ideal curve for the influence distance of HSR on construction land expansion based on location theory and distance decay theory. Using the 24 stations of the Hainan Roundabout Railway (HRR) as an example, we revealed differences in the influence of various HRR stations on construction land expansion through GIS technology, buffer analysis, and nonlinear fitting to quantitatively analyze the expansion of construction land around HRR stations, identifying the impact range and direction of different HRR stations on the expansion of construction land. Building on the identification of heterogeneous impact results, the study further employed Geodetector to analyze the factors and reasons for the differentiated results of construction land expansion around different HRR stations from four dimensions: attributes of the socioeconomic environment, location conditions, HRR station attributes, and natural conditions. The results show that: (1) after the construction and operation of each HRR station, the surrounding construction land has expanded; the Hainan Eastern Ring HSR (the East Ring) has increased 1.70 km2 around each station per year and the Hainan Western Ring HSR (the West Ring) has increased 1.25 km2 around each station per year. (2) The changing trend of construction land expansion around 20 of 24 HRR stations conforms to the ideal curve, with the impact range of construction land expansion concentrated within 0.5-3.5 km, and the influence intensity of impact ranging from 0.06 to 6.64 km2. (3) The impact directions of construction land expansion around 20 HRR stations are mainly in three types of directions: "HSR-main urban area," "HSR-town center," and "HSR-scenic spot." This is because the expansion of construction land around HRR stations is not only influenced by the spillover effects of the stations, but also by the traction effect of the main urban areas, town centers, or tourist areas where the HRR stations are located. The stations along the East Ring of Hainan mainly expanded towards the main urban areas, whereas the stations along the West Ring of Hainan mainly expanded towards town centers. (4) Differences in the scope of the influence of each HRR station on the surrounding construction land expansion were mainly related to several variables, ordered as follows: socioeconomic environment, location conditions, attributes of the HRR station, and natural conditions. The GDP density of the towns where the HRR stations were located had the highest impact intensity at 0.51, followed by population density at 0.49, whereas the average elevation had the lowest impact intensity at 0.12. This study analyzed the mechanism and ideal curve of construction land expansion around HSR stations, establishing a logical basis for studying the spillover effects of HSR stations. In addition, this study analyzes the various impacts of HSR stations on the expansion of surrounding construction land and the reasons for these differences, providing a scientific basis for the current operation and future location of HSR stations. This study also offers methodological insights into the impacts of other infrastructures on the expansion of construction land in surrounding areas.

The cost of building a lunar outpost can be greatly reduced by adopting melting of lunar regolith using concentrated solar energy beam based on in-situ additive manufacturing, there are still considerable obstacles to boosting the compactness and mechanical strength of the fabricated samples. The exploration of optimizing process parameters to address the above challenges are severely limited by solar time and space on Earth. Herein, a system for millimeter-scale energy beam melting of the lunar regolith simulant was set up to investigate the effects of process parameters, including laser power, scanning speed, hatching space (track overlapping ratio), and powder layer thickness (layer overlapping ratio) on the processes of single-track, multi-track, and multi-layer forming. The best range of single-track forming quality is the regular type with linear energy density of 27.5–100 J/mm. The surface is smooth and devoid of apparent fissures when the track overlapping rate is between 20% and 45% during the multi-track scanning procedure. For multi-layer sample forming, Samples with high density and few defects appear in the range of 45%–73% layer overlapping rate. The process parameters window for sample forming is determined by the combination of linear energy density, track overlapping rate, and layer overlapping rate. The relative density of single-track, multi-track, and multi-layer increases sequentially under the action of remelting, reaching 62.9%, 70%, and 86%, respectively. The average compressive strength of the test specimen is 5.6 MPa satisfies the specifications for the load-bearing structures on the moon. These results would provide essential data for the development of in-situ additive manufacturing.

Using FNL （Final Reanalysis Data）， ERA5 （ECMWF Reanalysis V5） reanalysis data， and GPM （Global Precipitation Measurement） global half-hourly precipitation data， a strong precipitation event in the southwestern plateau of China was selected to study the forecasting ability of two initial perturbation methods， Breeding Growth Mode （BGM） and Local Breeding Growth Mode （LBGM）， in convective-scale ensemble forecasting of complex terrain rainfall.The MODE （Method for Object-Based Diagnostic Evaluation） method based on object diagnostics was used to evaluate the model's ability to predict the location， structure， and intensity of precipitation objects， and compared with scoring methods such as Threat Score （TS） to comprehensively assess the model's forecasting performance.The results show that： （1） The ensemble forecast systems BGM-EPS and LBGM-EPS， generated using BGM and LBGM methods to produce initial perturbations， have better ensemble mean forecast scores for precipitation of all magnitude levels at 24 hours compared to the control forecast， and LBGM-EPS has a higher TS score for heavy rainfall compared to BGM-EPS， this indicates that the LBGM method has a certain improvement effect on ensemble forecasts for heavy precipitation.However， the underlying mechanisms behind the different initial perturbation methods are worthy of further investigation； （2） Overall， the WRF model can capture precipitation objects well， especially for rainfall forecasts in complex terrain of the plateau mountains， with a better overall similarity in precipitation targets for LBGM-EPS compared to BGM-EPS， highlighting the advantage of LBGM method in representing convective-scale ensemble forecasting of intense convection.The initial perturbation total energy of BGM and LBGM shows a developing trend with forecast time.In the same forecast time， LBGM has a larger perturbation total energy than BGM， which better represents the growth of forecast error.This can partially explain why the LBGM method outperforms the BGM method in terms of precipitation object matching in the MODE evaluation； （3） Compared with traditional TS scoring and other verification methods， the MODE method can better reflect the spatial position information of precipitation forecasts， and under the same convolution radius and precipitation threshold， the ensemble mean forecast based on LBGM method performs better in identifying precipitation objects.By flexibly setting the convolution radius and determining the precipitation threshold， the WRF model can capture precipitation objects in complex terrain areas during heavy precipitation events.However， the matching degree of precipitation targets in high-altitude areas is lower than that in low-lying areas.The LBGM-EPS method outperforms the BGM-EPS method in terms of the shape of precipitation objects and the matching of precipitation areas， resulting in better identification of precipitation objects.The quality of precipitation object matching using the MODE method is related to parameter settings such as precipitation threshold and convolution radius， rather than the complex terrain background related to terrain gradients.

Abstract Simulated moving bed (SMB) technology is considered one of the most successful techniques in chromatographic separation. However, due to the nonlinearity caused by discrete events and sensitivity to numerous separation performance parameters, purity control in SMB systems has been a challenging issue. Fuzzy controllers are increasingly popular in industrial environments due to their simplicity and effectiveness in handling nonlinearity. However, traditional fuzzy controllers used in industry often overlook considerations of error acceleration, resulting in slight deviations from target values under steady-state conditions and oscillatory behavior when system parameters change. This study proposes an advanced fuzzy controller, where in a series of experiments, the purity control targets for component B are set at 94% and 96%, and for component A are set at 96% and 96%, respectively. Experimental results indicate that the advanced fuzzy controller achieves higher precision, with an average deviation of around 0.1%, for both components B and A. Importantly, under variations in adsorbent parameter(from 0.01 to 0.03), feed concentration(from 4.5 to 5.2), and switching time(from 178 to 182), the experimental results demonstrate smoother control with the advanced controller, particularly when oscillations occur with conventional fuzzy controllers due to switching time variations, indicating robust control with the advanced fuzzy controller.

Agricultural brand building has been given greater value and attention in the context of brand strategy and rural revitalization. Previous studies have paid more attention to the role of regional brands and their construction paths. However, as micro-subjects, enterprises also play an important role in the construction of agricultural brands. This article discusses the spatial distribution pattern of Chinese agricultural enterprise brands and its influencing factors through analysis methods such as unbalanced index, spatial clustering test, and negative binomial regression analysis, which could provide a reference for the local construction of agricultural enterprise brands and the promotion of rural industrial revitalization. The present study found that (1) affected by natural resource endowment and economic development, agricultural enterprise brands are most distributed in East China. Shandong, Henan, Jiangsu, and other provinces have the largest number of agricultural enterprise brands. The density of agricultural enterprise brands shows a three-level ladder pattern, with the lowest in the northwest, followed by the central region, and the highest in the eastern coastal region. High-high agglomeration and hot spots have formed in the Yellow River, the middle and lower reaches of the Yangtze River, and the northeastern region, and high-low agglomeration, low-low agglomeration, and cold spots have formed in the western region. (2) The number of regional brands, gross product of primary industry, number of agricultural patents and innovation parks, and number of agricultural anchors are significantly positively correlated with the number of agricultural enterprise brands. The better the agricultural foundation, the stronger the scientific and technological innovation ability; further, the more enterprise brands can adapt and use the new marketing area, the greater the number of enterprise brands that could be constructed. The proportion of the primary industry in the GDP is significantly negatively correlated with the number of agricultural enterprise brands. This is mainly because the higher the proportion of the primary industry in the GDP, the more backward the local economy is to a certain extent, which is not conducive to the development of enterprise brands. The relationship between the number of agricultural experts and corporate brands is not significant; this is because the distribution of agricultural experts is affected by the distribution of agricultural research institutes, and dislocation with the spatial distribution of enterprise brands is observed. In general, in the process of promoting the construction of enterprise brands, localities need to vigorously support agricultural development and regional brand building and focus on the cultivation and flow of innovation as well as the development of new marketing. This study focuses on the distribution of agricultural enterprise brands from the perspective of geography and provides policy recommendations for various places, which has certain theoretical value and practical significance.

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

PURPOSEThe current meta-analysis aimed to compare the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with 18F-FDG PET/magnetic resonance imaging (MRI) in non-small cell lung cancer (NSCLC) lymph node metastasis staging.METHODSWe searched the PubMed, Web of Science, and Embase databases for relevant articles between November 1992 and September 2022. Studies evaluating the head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis in patients with NSCLC were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 tool.RESULTSThe analysis includes six studies with a total of 434 patients. The pooled sensitivity of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.78 [95% confidence interval (CI): 0.59-0.90] and 0.84 (95% CI: 0.68-0.93), and the pooled specificity was 0.87 (95% CI: 0.72-0.94) and 0.87 (95% CI: 0.80-0.92), respectively. The accuracy of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.81 (95% CI: 0.71-0.90) and 0.84 (95% CI: 0.75-0.92), respectively. When the pre-test probability was set at 50%, the post-test probability for 18F-FDG PET/CT could increase to 85%, and the post-test probability for 18F-FDG PET/MRI could increase to 87%.CONCLUSION18F-FDG PET/CT and 18F-FDG PET/MRI have similar diagnostic performance in detecting lymph node metastasis in NSCLC. However, the results of this study were from a small sample study, and further studies with larger sample sizes are needed.