Search

Mountainous watersheds are characterized by variability in functional traits, including vegetation, topography, geology, and geomorphology, which determine nitrogen (N) retention, and release. Coal Creek and East River are two contrasting catchments within the Upper Colorado River Basin that differ markedly in total nitrate (NO3−) export. The East River has a diverse vegetation cover, and sinuous floodplains, and is underlain by N-rich marine shale. At 0.21 ± 0.14 kg ha−1 yr−1, the East River exports ∼3.5 times more NO3− relative to the conifer-dominated Coal Creek (0.06 ± 0.02 kg ha−1 yr−1). While this can partly be explained by the larger size of the East River, the distinct watershed traits of these two catchments imply different mechanisms controlling the aggregate N-export signal. A causality analysis shows physical and biogenic processes were critical in determining NO3− export from the East River catchment. Stable isotope ratios of NO3− (δ15NNO3 and δ18ONO3) show the East River catchment is a strong hotspot for biogeochemical processing of NO3− at the hillslope soil-saprolite. By contrast, the conifer-dominated Coal Creek retained nearly all atmospherically deposited NO3−, and its export was controlled by catchment hydrological traits (i.e., snowmelt periods and water table depth). The conservative N-cycle within Coal Creek is likely due to the abundance of conifer trees, and smaller riparian regions, retaining more NO3− overall and reduced processing prior to export. This study highlights the value of integrating isotope systematics to link watershed functional traits to mechanisms of watershed element retention and release.

Yu-Yan Qin,1,* Hui Yu,1,2,* Yong Huang,1,* Xiaoyi Yang,1 Songpei Li,1 Ao Shen,1 Yinshan Lin,1 Mei Zhang,1 Qiulian Zhu,1 Jingwei Zhang,1 Lingmin Zhang,1 Xi-Yong Yu1 1Key Laboratory of Molecular Target & Clinical Pharmacology and the State & NMPA Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, People’s Republic of China; 2Hutchison Whampoa Guangzhou Baiyunshan Chinese Medicine Co., Ltd, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi-Yong Yu; Lingmin Zhang, School of Pharmaceutical Sciences, Guangzhou Medical University, Xinzao Road, Panyu District, Guangzhou, 511436, People’s Republic of China, Email yuxycn@gzhmu.edu.cn; zhanglm@gzhmu.edu.cnBackground: Acute lung injury (ALI) leads to diffuse pulmonary interstitial and alveolar edema, further developing into acute respiratory distress syndrome (ARDS). The present therapeutic approaches showed limited effects with poor clinical efficacy or severe side effects. This study aims to develop novel pharmaceutical agents to reduce lung damage with acceptable side effects for ALI.Methods: Naked gene delivery system based on epigallocatechin 3-gallate (EGCG) was synthesized to deliver plasmid expressing DNA damage regulated autophagy modulator 1 (DRAM1), designated as EGCG/DRAM1 (ED). ED was characterized by dynamic light scattering analysis and transmission electron microscope. The biodistribution of ED in mice was measured by an in vivo small animal imaging system. The therapeutic potentials of ED were evaluated in MLE12 cells and LPS-induced ALI mice.Results: Our results showed that ED was nearly spherical with a diameter of ~100 nm and increased the stability of DRAM1 plasmid that encapsulated. The synthesized ED showed negligible toxicity at the selected experimental concentration in MLE12 cells. ED could be taken up by MLE12 cells with high efficiency and escape from the lysosome. In ALI mice, ED facilitated the accumulation and retention of DRAM1 plasmid in lung, and attenuated pulmonary edema and pulmonary vascular permeability. The therapeutic effects of ED on ALI were associated with increased autophagy and reduced oxidative stress in lung.Conclusion: In summary, ED attenuated pulmonary edema and pulmonary vascular permeability, and improved pulmonary dysfunction in ALI mice. This naked gene delivery system for autophagy enhancement may serve as a potential therapeutic strategy to attenuate ALI. Keywords: acute lung injury, EGCG, DRAM1, autophagy, oxidative stress

Liping Zou,1,* Wanli Kang,2,* Chunhui Guo,3,* Juan Du,4,* Qing Chen,1 Zhengyu Shi,1 Xianzhen Tang,1 Li Liang,1 Peijun Tang,5 Qing Pan,6 Qingdong Zhu,7 Song Yang,8 Zhanlin Chang,9 Zhouli Guo,1 Guihui Wu,1 Shenjie Tang2 1Department of Tuberculosis, Public Health Clinical Center of Chengdu, Chengdu, People’s Republic of China; 2Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 3Department of Tuberculosis, Harbin Chest Hospital, Harbin, People’s Republic of China; 4Department of Tuberculosis, Wuhan Pulmonary Hotel, Wuhan, People’s Republic of China; 5Department of Tuberculosis, the Fifth People’s Hospital of Suzhou, Suzhou, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Anqing Municipal Hospital, Anqing, People’s Republic of China; 7Department of Tuberculosis, the Fourth People’s Hospital of Nanning, Nanning, People’s Republic of China; 8General Internal Medicine Department, Chongqing Public Health Medical Center, Chongqing, People’s Republic of China; 9Department of Surgery, the Third People’s Hospital of Tibet Autonomous Region, Lasa, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guihui Wu, Department of Tuberculosis, Public Health Clinical Center of Chengdu, Jingjusi 18 Street, Jingjiang District, Chengdu, Sichuan, People’s Republic of China, Tel +86-28-8455-0573, Email wghwgh2584@sina.com Shenjie Tang, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China, Tel +86-13621028338, Email tangsj1106@vip.sina.comObjective: Rifampin-resistant tuberculosis (RR-TB) remains a serious global public health concern. We assessed treatment outcomes and associated influencing factors among RR-TB patients in China.Methods: This research enrolled 1339 patients who started RR-TB treatment between May 2018 and April 2020 in China retrospectively. Data were collected from the electronic medical records. Multivariable logistic regression analysis was used to identify the influencing factors related to unfavorable outcomes.Results: Of the 1339 RR-TB patients, 78.8% (1055/1339) achieved treatment success (cured or treatment completed), 5.1% (68/1339) experienced treatment failure, 1.1% (15/1339) died during treatment, 10.1% (135/1339) were lost to follow-up, and 4.9% (66/1339) were not evaluated. About 67.7% (907/1339) of patients experienced at least one adverse event (AE). The most common AE was hypohepatia (507/1339, 37.9%), followed by hyperuricemia (429/1339, 32.0%), anemia (368/1339, 27.5%), electrolyte disturbance (318/1339, 23.7%), peripheral neuritis (245/1339, 18.3%), and gastrointestinal reactions (203/1339, 15.2%). Multivariate analysis showed that age ≥ 60 years [adjusted odds ratio (aOR): 1.96, 95% confidence interval (CI): 1.39– 2.77], national minority (aOR: 2.36, 95% CI: 1.42– 3.93), smoking (aOR: 1.50, 95% CI: 1.10– 2.04), cardiopathy (aOR: 2.90, 95% CI: 1.33– 6.31), tumors (aOR: 9.84, 95% CI: 2.27– 42.67), immunocompromise (aOR: 2.17, 95% CI: 1.21– 3.91), re-treated TB (aOR: 1.46, 95% CI: 1.08– 1.97), and experienced gastrointestinal reactions (aOR: 2.27, 95% CI: 1.52– 3.40) were associated with unfavorable outcomes. Body mass index (BMI) ≥ 18.5 kg/m2, regimens containing bedaquiline and experienced adverse events (AEs) such as hypohepatia, leukopenia, peripheral neuritis, and optic neuritis were associated with favorable outcomes.Conclusion: High rates of treatment success were achieved for RR-TB patients at tertiary tuberculosis hospitals in China. Age ≥ 60 years, national minority, smoking status, comorbidities, re-treated TB, and experienced gastrointestinal reactions were independent prognostic factors for unfavorable treatment outcomes.Keywords: RR-TB, treatment outcomes, influencing factors, China

Ente Li,1,2,* Qingfeng Zhu,3,* Ziman Lv,1,2,* Songsong Xie,3 Chunju Zhang,4 Wei Li,5 Ligu Mi,1,2 Quan Liu,6 Yuanzhi Wang,1,2 Xiaobo Lu2 1Department of Basic Medicine, School of Medicine, Shihezi University, Shihezi City, Xinjiang Uygur Autonomous Region, 832002, People’s Republic of China; 2Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, the Xinjiang Production and Construction Corps, Shihezi University, Shihezi City, Xinjiang Uygur Autonomous Region, 832002, People’s Republic of China; 3The First Affiliated Hospital of Shihezi University Medical College, Shihezi City, Xinjiang Uygur Autonomous Region, 832002, People’s Republic of China; 4Tumxuk Center for Disease Prevention and Control, Tumxuk City, Xinjiang Uygur Autonomous Region, 843806, People’s Republic of China; 5Department of Basic Medicine, School of Medicine, Tarim University, Alaer City, Xinjiang Uygur Autonomous Region, 843300, People’s Republic of China; 6Department of Infectious Diseases and Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Key Laboratory of Zoonotic Diseases, The First Hospital of Jilin University, Changchun City, Jilin Province, 30061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanzhi Wang; Xiaobo Lu, Email wangyuanzhi621@126.com; xjykdluxiaobo@126.comAbstract: Visceral leishmaniasis (VL), also known as kala-azar. It is characterized by prolonged intermittent fever, anemia, splenomegaly, hepatomegaly, and skin darkening. VL is primarily endemic in regions, such as Brazil, East Africa, and India. However, Northern Xinjiang, which is located in northwestern China, is considered a low-incidence area for VL, contributing to its status as a neglected infectious disease. In this report, we present a case of VL caused by Leishmania donovani that was diagnosed using metagenomic next-generation sequencing (mNGS). This case underscores the diagnostic value of mNGS, particularly in regions with low incidence of VL. Keywords: Visceral leishmaniasis, Leishmania donovani, metagenomic next-generation sequencing, northwestern China

Jing Lin,1 Fenglu Wu,2 Yanwen Zhu,2 Qianqian Zhu,2 Tong Du,2 Jiaying Lin2 1Center for Reproductive Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Jiaying Lin; Tong Du, Department of Assisted Reproduction, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Zhizaoju Road No. 639, Shanghai, People’s Republic of China, Email lemon_1114@126.com; ocyte@qq.comObjective: Our objective was to investigate the efficacy of letrozole co-treatment in an antagonist protocol for infertile women with polycystic ovary syndrome (PCOS).Patients and Methods: This retrospective cohort study included infertile women with PCOS undergoing IVF/ICSI with and without letrozole co-treatment in an antagonist protocol from 2007– 2021 at Shanghai Ninth People’s Hospital (Shanghai, China). A total of 1559 participants were enrolled, with 1227 women in the antagonist group and 332 women in the letrozole co-treatment group. Propensity score-based patient-matching model was conducted to balance covariates between the groups. The primary outcome was the number of retrieved oocytes, with secondary outcomes including endocrine parameters, ovarian stimulation outcomes, pregnancy outcomes, and obstetrical and neonatal complications.Results: Letrozole co-treatment induced significant changes in hormonal regulation, increased the percentage of large follicles, and resulted in fewer retrieved oocytes (P < 0.05). However, there was no negative impact on the number of usable embryos or good-quality embryos (P > 0.05). The live birth rates following fresh embryo transfer were comparable between the letrozole and control groups (single embryo transfer: 28.9% vs 29.7%, P > 0.05; double embryo transfer: 37.3% vs 45.6%, P > 0.05). Additionally, there were no significant differences between the two groups in the live birth rate per patient after frozen embryo transfer and the cumulative live birth rate (P > 0.05). No significant differences in obstetrical and neonatal complications were observed between the groups (P > 0.05).Conclusion: The addition of letrozole to the antagonist protocol for women with PCOS undergoing IVF induces a higher percentage of large follicles during oocyte retrieval, while reducing the overall number of retrieved oocytes. Moreover, the use of letrozole demonstrates comparable clinical outcomes following embryo transfers. These findings highlight the potential application of letrozole in an antagonist protocol for women with PCOS.Keywords: letrozole, antagonist protocol, polycystic ovary syndrome, follicle, in vitro fertilization

Yue Han,1,&ast; Chao Guo,2,&ast; Qianmei Zhu,1 Zijia Liu,1 Yuelun Zhang,3 Shanqing Li,2 Le Shen1 1Department of Anesthesiology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China; 2Department of Thoracic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Department of Medical Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zijia Liu, Department of Anesthesiology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China, Tel/Fax +861069155580, Email liu-zj02@126.comBackground: Atrial fibrillation (AF) has become the most common postoperative arrhythmia of thoracic surgery. This study aimed to investigate the risk factors and complications of perioperative atrial fibrillation (PoAF) in elderly patients who underwent video-assisted thoracoscopic surgery (VATS).Methods: Data were collected from patients who underwent VATS between January 2013 and December 2022 at Peking Union Medical College Hospital (PUMCH). Univariable analyses and multivariable logistic regression analyses were used to determine the factors correlated with PoAF. Receiver operating characteristic (ROC) curve was used to evaluate the discrimination of the indicators to predict PoAF.Results: The study enrolled 2920 patients, with a PoAF incidence of 5.2% (95% CI 4.4%-6.0%). In the logistic regression analyses, male sex (OR=1.496, 95% CI 1.056– 2.129, P=0.024), left atrial anteroposterior dimension (LAD) ≥ 40 mm (OR=2.154, 95% CI 1.235– 3.578, P=0.004), hypertension (HTN) without regular treatment (OR=2.044, 95% CI 0.961– 3.921, P=0.044), a history of hyperthyroidism (OR=4.443, 95% CI 0.947– 15.306, P=0.030), surgery of the left upper lobe (compared to other lung lobes) (OR=1.625, 95% CI 1.139– 2.297, P=0.007), postoperative high blood glucose (BG) (OR=2.482, 95% CI 0.912– 5.688, P=0.048), and the time of chest tube removal (per day postoperatively) (OR=1.116, 95% CI 1.038– 1.195, P=0.002) were found to be significantly associated with PoAF. The area under the ROC curve was 0.707 (95% CI 0.519– 0.799). 86.9% patients were successfully converted to sinus rhythm. Compared with the non-PoAF group, the PoAF group had significantly greater risks of prolonged air leakage, postoperative acute coronary syndrome, longer ICU stays, and longer hospital stays.Conclusion: Male sex, LAD≥ 40 mm, HTN without regular treatment, a history of hyperthyroidism, surgery of the left upper lobe, postoperative BG, and the time of chest tube removal were associated with PoAF. These findings may help clinicians identify high-risk patients and take preventive measures to minimize the incidence and adverse prognosis of PoAF.Keywords: video-assisted thoracoscopic surgery, aged, atrial fibrillation, risk factor

Jianwen Zhao,1– 5,&ast; Xintian Cai,1– 5,&ast; Junli Hu,1– 5 Shuaiwei Song,1– 5 Qing Zhu,1– 5 Di Shen,1– 5 Wenbo Yang,1– 5 Qin Luo,1– 5 Xiaoguang Yao,1– 5 Delian Zhang,1– 5 Jing Hong,1– 5 Nanfang Li1– 5 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, People’s Republic of China; 2Xinjiang Hypertension Institute, Urumqi, Xinjiang, 830001, People’s Republic of China; 3NHC Key Laboratory of Hypertension Clinical Research, Urumqi, Xinjiang 830001 People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region ”Hypertension Research Laboratory”, Urumqi, Xinjiang, 830001, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, 830001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumuqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8564818, Email lnanfang2016@sina.comBackground: A newly introduced obesity-related index, the weight-adjusted-waist index (WWI), emerges as a promising predictor of cardiovascular disease (CVD). Given the known synergistic effects of hypertension and obstructive sleep apnea (OSA) on cardiovascular risk, we aimed to explore the relationship between the WWI and CVD risk specifically within this high-risk cohort.Methods: A total of 2265 participants with hypertension and OSA were included in the study. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD events. The restricted cubic spline (RCS) was used to further evaluate the nonlinear dose-response relationship.Results: During a median follow-up period of 6.8 years, 324 participants experienced a CVD event. Multivariate Cox regression analysis revealed that compared to the reference group, the HRs for the second, third, and fourth groups were 1.12 (95% CI, 0.79– 1.59), 1.35 (95% CI, 0.96– 1.89), and 1.58 (95% CI, 1.13– 2.22), respectively. Moreover, RCS analysis illustrated a clear J-shaped relationship between the WWI and CVD risk, particularly notable when WWI exceeded 11.5 cm/, signifying a significant increase in CVD risk.Conclusion: There was a J-shaped relationship between WWI and CVD in hypertensive patients with OSA, especially when the WWI was greater than 11.5 cm/, the risk of CVD was significantly increased.Keywords: hypertensive, obstructive sleep apnea, weight-adjusted-waist index, cardiovascular disease, visceral obesity

Qing Zhu,1,2,&ast; Yijia He,1,2,&ast; Sijia Chen,1,2 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Hebei Provincial Innovation Center of Dermatology and Medical Cosmetology Technology, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqiang Zhang, Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China, Email 57702800@hebmu.edu.cnAbstract: Vitiligo has been reported to occur in association with lupus erythematosus (LE) and other autoimmune diseases. However, it remains unclear whether this association occurs because of shared immunopathogenesis. We hereby describe a case of discoid lupus erythematosus (DLE) in a 51-year-old man with a 3 years history of skin lesions on his face, arms, and the V zone of the neck, and with the coexistence of vitiligo for 12 years, who developed from DLE to hypertrophic discoid lupus erythematosus (HDLE) after 10 months. We reviewed the previously reported cases to summarize the clinical characteristics of these patients and hope it may provide a reference for dermatologists.Keywords: hypertrophic discoid lupus erythematosus, lupus erythematosus, vitiligo, association

Sifan Ji,1,2,&ast; Hang Qi,1,2,&ast; Li Yan,1,2,&ast; Duo Zhang,1,2 Yang Wang,1,2 HaLiSai MuDanLiFu,1,2 Chuqing He,1,2 Wei Xia,1,2 Qian Zhu,1,2 Yan Liang,1,2 Jian Zhang1,2 1Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Zhang, Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86 18017316017, Email zhangjian_ipmch@sjtu.edu.cnIntroduction: Endometriosis (EM) is an estrogen-dependent benign gynecologic disease affecting approximately 10% of reproductive-age women with a high recurrence rate, but lacks reliable biomarkers. No previous studies have investigated the possible use of extracellular vesicle (EV)-associated micro RNAs (miRNAs) from menstrual blood (MB) as candidate diagnostic or prognostic markers of EM.Methods: Specimens were obtained from endometriosis and non-endometriosis patients at the International Peace Maternity and Child Health Hospital in Shanghai. Microarray was used to screen differentially expressed miRNAs among peritoneal fluid (PF), fallopian tube fluid (FF), and MB. Dual-luciferase reporter gene assay was carried out to verify the relationship between miR-4443 and ACSS2. Cell proliferation and Transwell invasion assays were performed in vitro after intervention on miR-4443 and ACSS2 in hEM15A human endometrial stromal cells and primary human endometrial stromal cells (hESCs). Spearman correlation analysis, receiver operating characteristic (ROC) curve analysis, and survival analysis were applied to clinical data, including severity of symptoms and relapse of EM among EM patients.Results: EV-associated miR-4443 was abundant in MB of endometriosis patients. ACSS2 knockdown and miR-4443 overexpression promoted cell proliferation and migration via the PI3K/AKT pathway. miR-4443 levels in MB-EVs were positively correlated with the degree of dyspareunia (r=0.64; P< 0.0001) and dysmenorrhea (r=0.42; P< 0.01) in the endometriosis group. ROC curve analyses showed an area under the curve (AUC) of 0.741 (95% CI 0.624– 0.858; P< 0.05) for miR-4443 and an AUC of 0.929 (95% CI 0.880– 0.978; P< 0.05) for the combination of miR-4443 and dysmenorrhea.Conclusion: MB-derived EV-associated miR-4443 might participate in endometriosis development, thus providing a new candidate biomarker for the noninvasive prediction of endometriosis recurrence. Keywords: endometriosis, menstrual blood, biomarker, extracellular vesicles, miR-4443

Shuaiwei Song,1– 5,&ast; Xintian Cai,1– 5,&ast; Junli Hu,1– 5 Qing Zhu,1– 5 Di Shen,1– 5 Huimin Ma,1– 5 Yingying Zhang,1– 5 Rui Ma,1– 5 Wenbo Yang,1– 5 Jing Hong,1– 5 Delian Zhang,1– 5 Nanfang Li1– 5 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, People’s Republic of China; 2Xinjiang Hypertension Institute, Urumqi, Xinjiang, 830001, People’s Republic of China; 3NHC Key Laboratory of Hypertension Clinical Research, Urumqi, Xinjiang, 830001, People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region ”Hypertension Research Laboratory”, Urumqi, Xinjiang, 830001, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, 830001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8,564,818, Email lnanfang2016@sina.comObjective: While the role of aldosterone in bone metabolism is well established, the specific effects of the widely used aldosterone antagonist, spironolactone, on bone health are not fully understood. This study aimed to investigate the effects of spironolactone on osteoporosis and future fracture risk in middle-aged and elderly hypertensive patients, revealing its potential benefits for bone health.Methods: Propensity score matching was employed in this study to create matched groups of spironolactone users and non-users at a 1:4 ratio. We investigated the association between spironolactone use and the risk of osteoporosis using multivariate logistic regression analysis. Furthermore, we conducted multivariate linear regression analysis to explore the relationship between cumulative dosage and the FRAX score. Subgroup analysis was also performed to assess the effects under different stratification conditions.Results: In both pre-match and post-match analyses, multivariable logistic regression revealed a significant reduction in the risk of osteoporosis in the spironolactone usage group (pre-match: odds ratios [OR] 0.406, 95% confidence interval [CI], 0.280– 0.588; post-match: OR 0.385, 95% CI, 0.259– 0.571). Furthermore, post-match multivariable linear regression demonstrated a clear negative correlation between cumulative spironolactone dosage and the FRAX score. Subgroup analyses consistently supported these findings.Conclusion: This study offers evidence supporting the significant positive impact of the antihypertensive drug spironolactone on bone health, resulting in a substantial reduction in the risk of osteoporosis and future fractures in hypertensive patients. Future research should consider conducting large-scale, multicenter, randomized controlled trials to further investigate the long-term effects of spironolactone on bone health in hypertensive patients.Keywords: hypertensive, spironolactone, aldosterone, osteoporosis, FRAX score

Peng Wu,1,&ast; Xiaoyong Wang,2,&ast; Min Yin,1,&ast; Wenjie Zhu,3,&ast; Zheng Chen,1 Yang Zhang,1 Ziyu Jiang,4 Longqing Shi,5 Qiang Zhu1 1Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The People’s Hospital of Rugao, Nantong, People’s Republic of China; 3Kangda College of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, People’s Republic of China; 5Department of Hepatobiliary and Pancreatic Surgery, Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longqing Shi, Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Jiangsu, People’s Republic of China, Email 20204135017@stu.suda.edu.cn Qiang Zhu, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China, Email zhu20081023@yeah.netBackground: Liver cancer remains to be one of the leading causes of cancer worldwide. The treatment options face several challenges and nanomaterials have proven to improve the bioavailability of several drug candidates and their applications in nanomedicine. Specifically, chitosan nanoparticles (CNPs) are extremely biodegradable, pose enhanced biocompatibility and are considered safe for use in medicine.Methods: CNPs were synthesized by ionic gelation, loaded with rutin (rCNPs) and characterized by ultraviolet–visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS) and transmission electron microscopy (TEM). The rCNPs were tested for their cytotoxic effects on human hepatoma Hep3B cells, and experiments were conducted to determine the mechanism of such effects. Further, the biocompatibility of the rCNPs was tested on L929 fibroblasts, and their hemocompatibility was determined.Results: Initially, UV–vis and FTIR analyses indicated the possible loading of rutin on rCNPs. Further, the rutin load was quantitatively measured using Ultra-Performance Liquid Chromatography (UPLC) and the concentration was 88 μg/mL for 0.22 micron filtered rCNPs. The drug loading capacity (LC%) of the rCNPs was observed to be 13.29 ± 0.68%, and encapsulation efficiency (EE%) was 19.55 ± 1.01%. The drug release was pH-responsive as 88.58% of the drug was released after 24 hrs at the lysosomal pH 5.5, whereas 91.44% of the drug was released at physiological pH 7.4 after 102 hrs. The cytotoxic effects were prominent in 0.22 micron filtered samples of 5 mg/mL rutin precursor. The particle size for the rCNPs at this concentration was 144.1 nm and the polydispersity index (PDI) was 0.244, which is deemed to be ideal for tumor targeting. A zeta potential (ζ-potential) value of 16.4 mV indicated rCNPs with good stability. The IC50 value for the cytotoxic effects of rCNPs on human hepatoma Hep3B cells was 9.7 ± 0.19 μg/mL of rutin load. In addition, the increased production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (MMP) were observed. Gene expression studies indicated that the mechanism for cytotoxic effects of rCNPs on Hep3B cells was due to the activation of Unc-51-like autophagy-activating kinase (ULK1) mediated autophagy and nuclear factor kappa B (NF-κB) signaling besides inhibiting the epithelial–mesenchymal Transition (EMT). In addition, the rCNPs were less toxic on NCTC clone 929 (L929) fibroblasts in comparison to the Hep3B cells and possessed excellent hemocompatibility (less than 2% of hemolysis).Conclusion: The synthesized rCNPs were pH-responsive and possessed the physicochemical properties suitable for tumor targeting. The particles were effectively cytotoxic on Hep3B cells in comparison to normal cells and possessed excellent hemocompatibility. The very low hemolytic profile of rCNPs indicates that the drug could be administered intravenously for cancer therapy.Keywords: rCNPs, Hep3B, ROS, qPCR, mechanism

Jinyuan Ma,1,2,&ast; Zongguang Tai,1,2,&ast; Ying Li,1,2,&ast; Yang Li,3 Jiandong Wang,1,2 Tao Zhou,1,2 Min Shen,1,2 Rujuan Xin,1,2 Cuie Shen,1,2 Quangang Zhu,1,2 Zhongjian Chen1,2 1Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center for Topical Chinese Medicine, Shanghai, People’s Republic of China; 3CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Quangang Zhu; Zhongjian Chen, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai, 200443, People’s Republic of China, Tel/Fax +86 21 36803155 ; +86 21 36803007, Email qgzhu@126.com; aajian818@163.comPurpose: Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ).Methods: TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs).Results: Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process.Conclusion: The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.Keywords: photodynamic therapy, hypoxia activation, combination therapy, PDT enhancement

Chunkun Yang,1,&ast; Qinwei Zhu,2,&ast; Yanbo Chen,3,&ast; Kui Ji,2 Shuanghong Li,2 Qian Wu,1 Qingquan Pan,2 Jun Li1 1Department of Cardiology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Emergency, Weifang Hospital of Traditional Chinese Medicine, Weifang, Shandong, People’s Republic of China; 3Department of Arrhythmia, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China&ast;These authors contributed equally to this workThese authors contributed equally to this workCorrespondence: Jun Li, Email gamyylj@163.comAbstract: Cardiovascular diseases (CVDs) are the most common cause of death worldwide and has been the focus of research in the medical community. Curcumin is a polyphenolic compound extracted from the root of turmeric. Curcumin has been shown to have a variety of pharmacological properties over the past decades. Curcumin can significantly protect cardiomyocyte injury after ischemia and hypoxia, inhibit myocardial hypertrophy and fibrosis, improve ventricular remodeling, reduce drug-induced myocardial injury, improve diabetic cardiomyopathy(DCM), alleviate vascular endothelial dysfunction, inhibit foam cell formation, and reduce vascular smooth muscle cells(VSMCs) proliferation. Clinical studies have shown that curcumin has a protective effect on blood vessels. Toxicological studies have shown that curcumin is safe. But high doses of curcumin also have some side effects, such as liver damage and defects in embryonic heart development. This article reviews the mechanism of curcumin intervention on CVDs in recent years, in order to provide reference for the development of new drugs in the future.Keywords: curcumin, intima, endothelial cells, vascular smooth muscle cell, cardiovascular diseases, inflammation, apoptosis

Objectives: To determine the clinical course of fetal isolated non‐immune‐mediated second‐degree atrioventricular block (AVB) and the factors associated with spontaneous recovery in these cases. Methods: Fetuses with isolated non‐immune‐mediated second‐degree AVB were recruited prospectively between 2014 and 2022. These fetuses were divided into two groups: those which recovered spontaneously and those which did not. Maternal and fetal characteristics and intrauterine and postnatal outcomes were compared between the two groups. Results: The study cohort included 20 fetuses with isolated non‐immune‐mediated second‐degree AVB, diagnosed at a median gestational age of 22.0 (range, 17.0–35.0) weeks. In 12 fetuses, 1:1 atrioventricular conduction was restored spontaneously in utero and there was no recurrence during the postnatal follow‐up period. In the remaining eight fetuses, second‐degree AVB was maintained and, in six of these, the pregnancy was terminated on parental request. Of the two liveborn children who had persistent second‐degree AVB prenatally, one had progressed to complete AVB at the latest follow‐up, at the age of 34 months, but was asymptomatic, without heart enlargement or dysfunction. The other child progressed to complete AVB after delivery and was diagnosed with type‐2 long QT syndrome. This infant died aged 2 months. Fetuses in the group that recovered spontaneously had earlier gestational age at diagnosis (median, 20.0 (range, 17.0–26.0) vs 24.5 (range, 18.0–35.0) weeks; P = 0.004) and higher atrial rate at diagnosis (median, 147 (range, 130–160) vs 138 (range, 125–149) bpm; P = 0.006) in comparison with the group that did not recover spontaneously. The best cut‐off values for prediction of failure to recover spontaneously were 22.5 weeks' gestational age at diagnosis and 144 bpm atrial rate at diagnosis, with sensitivities of 87.5% and 75.0%, respectively, and specificities of 92.0% and 87.5%, respectively. Conclusions: The outcome of 60% of fetuses with isolated non‐immune‐mediated second‐degree AVB was favorable. Earlier gestational age and higher atrial rate at diagnosis were associated with spontaneous reversion to normal sinus rhythm. Prenatal genetic testing should be performed in cases with persistent AVB, to exclude heritable disorders including long QT syndrome. These findings provide important information for clinical management and prenatal counseling in these cases. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Resveratrol is converted to various metabolites by gut microbiota. Human and rat liver 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) are critical for glucocorticoid activation, while 11β-HSD2 in the kidney does the opposite reaction. It is still uncertain whether resveratrol and its analogues selectively inhibit 11β-HSD1. In this study, the inhibitory strength, mode of action, structure–activity relationship (SAR), and docking analysis of resveratrol analogues on human, rat, and mouse 11β-HSD1 and 11β-HSD2 were performed. The inhibitory strength of these chemicals on human 11β-HSD1 was dihydropinosylvin (6.91 μM) > lunularin (45.44 μM) > pinostilbene (46.82 μM) > resveratrol (171.1 μM) > pinosylvin (193.8 μM) > others. The inhibitory strength of inhibiting rat 11β-HSD1 was pinostilbene (9.67 μM) > lunularin (17.39 μM) > dihydropinosylvin (19.83 μM) > dihydroresveratrol (23.07 μM) > dihydroxystilbene (27.84 μM) > others and dihydropinosylvin (85.09 μM) and pinostilbene (>100 μM) inhibited mouse 11β-HSD1. All chemicals did not inhibit human, rat, and mouse 11β-HSD2. It was found that dihydropinosylvin, lunularin, and pinostilbene were competitive inhibitors of human 11β-HSD1 and that pinostilbene, lunularin, dihydropinosylvin, dihydropinosylvin and dihydroxystilbene were mixed inhibitors of rat 11β-HSD1. Docking analysis showed that they bind to the steroid-binding site of human and rat 11β-HSD1. In conclusion, resveratrol and its analogues can selectively inhibit human and rat 11β-HSD1, and mouse 11β-HSD1 is insensitive to the inhibition of resveratrol analogues. [ABSTRACT FROM AUTHOR]

There are significant differences in snow depth predictions among different earth system models, and many models underestimate snow depth, restricting their application. Here, major factors influencing snow depth changes in the Coupled Model Intercomparison Project Phase 6 (CMIP6) were identified and evaluated. Based on satellite‐derived snow depth and CMIP6 data, an ensemble learning model based on multiple deep learning methods (hereafter referred to as the Multi‐DL model) was developed to predict future snow depth. According to satellite observations and two Operation IceBridge products, the Multi‐DL model yielded root mean square errors of 7.48, 6.20, and 6.17 cm. A continuous decrease in snow depth was observed from 2002 to 2100, and the rate of decrease accelerated with increasing emissions. Under the highest emission scenario, the first snow‐free year occurred in 2047, within the same decade as the first ice‐free year (2056). The predicted warm season snow depth was sensitive to sea ice velocity, sea ice concentration (siconc), precipitation, sea surface temperature (tos) and albedo, while the predicted cold season snow depth was sensitive to tos, air temperature, and siconc. The above parameters introduce some snow depth uncertainty. This method provides new ideas for predicting snow depth, and the generated snow depth records can provide data support for formulating Arctic‐related policies. Plain Language Summary: Snow depth, a vital parameter of snowpack atop sea ice, is essential in the cryosphere. The rapid changes in snow depth on sea ice are attracting increasing amounts of attention to the changes in future snow depth. Multiple models have been used to predict a continuous decrease in snow depth. However, there are significant differences in snow depth predictions among different earth system models, and many models underestimate snow depth. Here, we propose a snow depth prediction model (i.e., the Multi‐DL model) based on multiple deep learning methods. The established model was evaluated using satellite‐derived snow depth data and two Operation IceBridge products. The results indicated that the model performed well in snow depth simulations. By using the Multi‐DL model and simulated data under four Coupled Model Intercomparison Project Phase 6 emission scenarios, snow depth was generated for four emission scenarios from 2015 to 2100. The results indicated that snow depth showed an accelerated decreasing trend under high‐emission scenarios, while the decrease in snow depth remained stable or was alleviated under low‐emission scenarios. Key Points: A novel ensemble learning model is developed for predicting snow depth over sea iceAn accelerated decline in snow depth is observed under the SSP3‐370 and SSP5‐585 scenariosWarm season snow depths are sensitive to sea ice velocity, sea ice concentration, precipitation, sea surface temperature, and albedo [ABSTRACT FROM AUTHOR]

Kinetochore scaffold 1 (KNL1) is indispensable for generating motile micro-tubule attachments and isolating chromosomes. KNL1 is highly expressed in multiple middle-route tissues and promotes tumor development. However, how it functions in non-small cell lung cancer (NSCLC) is unclear. Real-time quantitative PCR (RT-qPCR) and Western blotting (WB) were used to determine KNL1 expression in NSCLC tissues and cells. The sh-KNL1 or oe-KNL1 was transfected into NSCLC cells. The colony formation assay, cell counting kit-8 (CCK-8) assay, and flow cytometry were used to evaluate cell proliferation and apoptosis. A transwell assay was used to monitor invasion and migration. The CCK-8 assay was used to measure NSCLC cell sensitivity to chemotherapy drugs. WB confirmed the protein levels of apoptosis-related proteins, cell cycle-associated proteins, and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/nuclear factor kappaB (NF-κB) pathway. A PI3K/AKT/NF-κB pathway inhibitor was used to intervene in NSCLC cell transfection along with oe-KNL1, thus revealing the function of the pathway in carcinogenicity mediated by KNL1. In result KNL1 expression was substantially increased in NSCLC tissues and cells. High-level KNL1 expression is related to the poor prognosis of NSCLC patients. KNL1 silencing bolstered promoted NSCLC cell apoptosis and inhibited proliferation, cell cycle progression, invasion, and EMT, whereas KNL1 silencing had the opposite effect. KNL1 knockdown increased NSCLC cell sensitivity to chemical drugs. KNL1 promoted PI3K/AKT/NF-κB pathway activation, while PI3K/AKT/NF-κB pathway inhibition weakened the procancer effect mediated by KNL1 overexpression but had little influence on KNL1 levels. We conclude that KNL1 activates the PI3K/AKT/NF-κB pathway to increase NSCLC progression and attenuate NSCLC sensitivity to chemotherapy drugs. [ABSTRACT FROM AUTHOR]

Unique wool-ball shaped nanocrystalline CoS was synthesized using solvothermal method in which dopamine (DA) was added as carbon source to combine with the CoS. The DA in situ polymerized and coated on the CoS particle surfaces during the solvothermal process. N, S co-doped carbon-encapsulated CoS(Co9S8) were achieved after a post carbonization. In the composites, CoS(Co9S8) nanocrystals and carbon are tightly bound and embedded into the amorphous carbon layer to form a spherical core–shell structure. Hybrid counter electrodes (CEs) fabricated with the product have good conductivity, dispersion and stability due to the synergetic effect between carbon and nanocrystalline CoS(Co9S8). Charge transfer through the CE/electrolyte interfaces is improved by dopamine-carbon combination. In the optimal case, PCE of 8.82% of the dye-sensitized solar cells (DSSCs) with the hybrid CEs was achieved, which is close to that of the cell with Pt (8.86%) CE, and is a 41.12% increase compared with that of CoS CE cell with the structure of photoanode/N719/electrolyte (I−/I3−)/CE. Moreover, stability of the cells with the composite CEs was greatly improved. The results demonstrate that the as-prepared composites are promising alternatives to Pt-CEs for high-performance DSSCs. The reported preparation method will guide further developments in highly efficient carbon-based catalysts for electrochemistry and energy related applications. [ABSTRACT FROM AUTHOR]