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Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes

Rotating Radio Transients (RRATs) are neutron stars that emit sporadic radio bursts. We detected 1955 single pulses from RRAT J1913+1330 using the 19-beam receiver of the Five-hundred-meter Aperture Spherical Radio Telescope (FAST). These pulses were detected in 19 distinct clusters, with 49.4% of them occurring sequentially with a waiting time of one rotation period. The energy distribution of these individual pulses exhibited a wide range, spanning three orders of magnitude, reminiscent of repeating fast radio bursts (FRBs). Furthermore, we observed abrupt variations in pulse profile, width, peak flux, and fluence between adjacent sequential pulses. These findings suggest that this RRAT could be interpreted as pulsars with extreme pulse-to-pulse modulation. The presence of sequential pulse trains during active phases, along with significant pulse variations in profile, fluence, flux, and width, should be intrinsic to a subset of RRATs. Our results indicate that J1913+1330 represents a peculiar source that shares certain properties with populations of nulling pulsars, giant pulses, and FRBs from different perspectives. The dramatic pulse-to-pulse variation observed in J1913+1330 could be attributed to unstable pair creation above the polar cap region and the variation of the site where streaming pairs emit coherently. Exploring a larger sample of RRATs exhibiting similar properties to J1913+1330 has the potential to significantly advance our understanding of pulsars, RRATs, and FRBs., 12 pages, 10 figures, 1 table

Dynamic mesoscale flow channels move across the open field line regions of the polar caps, and then enter the nightside plasma sheet, where they can lead to important space weather disturbances, such as streamers, substorms, and omega bands. We find that the polar cap structures leading to disturbances can have long durations (at least ~1½ to 2 hours), and one flow structure can lead to more than one disturbance as it moves azimuthally within the polar cap. Examples using 630 nm auroral and radar observations indicate that the motion of flow channels within the polar cap may be significantly controlled by the IMF By. This motion appears to possibly be a critical factor in determining when and where a particular disturbance within the nightside auroral oval will be triggered. Also, potentially important is the occasional dramatic azimuthal turning of a flow channel, leading to azimuthal broadening of flow channel contact with the auroral oval and of a subsequent substorm onset. Of additional importance for future understanding of disturbances resulting from polar cap flow channels will be determining conditions along nightside auroral oval field lines (plasma sheet) that interact with an incoming flow polar-cap flow channel to give a particular disturbance. Additionally interesting will be consideration of the generality of geomagnetic disturbances being related to their connections with incoming polar cap flow channels, including the location, time, and type of disturbances, and also whether the duration of the disturbances appears to be related to the duration of an incoming flow channel.&nbsp

ESSnuSB is a design study for an experiment to measure the CP violation in the leptonic sector at the second neutrino oscillation maximum using a neutrino beam driven by the uniquely powerful ESS linear accelerator. The reduced impact of systematic errors on sensitivity at the second maximum allows for a very precise measurement of the CP violating parameter. This review describes the fundamental advantages of measurement at the 2nd maximum, the necessary upgrades to the ESS linac in order to produce a neutrino beam, the near and far detector complexes, the expected physics reach of the proposed ESSnuSB experiment, concluding with the near future developments aimed at the project realization., Comment: 19 pages, 11 figures; Corrected minor error in alphabetical ordering of the authors: the author list is now fully alphabetical w.r.t. author surnames as was intended. Corrected an incorrect affiliation for two authors per their request

Guobo Xie,1 Yanjia Zhong,2 Shuo Yang,3 Yang Zou4 1Cardiology Department, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Endocrinology Department, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Cardiology Department, Dean County People’s Hospital, Jiujiang, Jiangxi, People’s Republic of China; 4From the Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Yang Zou Email jxyxyzy@163.comPurpose: Remnant cholesterol (RC) is the cholesterol of triglyceride-rich lipoproteins, which has a high degree of atherogenic effect. To date, epidemiological evidence supports that higher RC levels lead to a greater risk of adverse cardiovascular events in patients with diabetes, but the nature of the association between RC levels and diabetes risk remains unclear. This study was designed to assess the association of RC with the risk of new-onset diabetes and to investigate whether there is a causal relationship between the two.Patients and Methods: The subjects included 15,464 individuals of the general population who participated in a health examination. Subjects were quartered according to the RC quartile, and the Cox proportional hazard model was used to assess the independent association between RC and new-onset diabetes.Results: During an average observation period of 6.13 years, 2.41% of the subjects were diagnosed with new-onset diabetes. Kaplan–Meier analysis showed that the 13-year cumulative diabetes rates corresponding to the RC quartile were 8.62%, 2.49%, 12.78%, and 17.91%. Multivariate Cox regression analysis indicated that higher RC levels were independently associated with an increased risk of new-onset diabetes (HR: 2.44, 95% CI: 1.50– 3.89). Additionally, according to the results of receiver operating characteristic curve analysis, RC had the largest area under the curve (0.7314) compared to traditional lipid parameters in predicting new-onset diabetes.Conclusion: These results indicated that RC is an important independent predictor of new-onset diabetes in the general population.Keywords: diabetes, remnant cholesterol, independent predictor, cohort study

Yulin Zou, Zudong Meng Department of Dermatology, Renmin Hospital, Hubei University of Medicine, Shiyan City, People’s Republic of ChinaCorrespondence: Zudong Meng Email zylmch1007@hbmu.edu.cnAbstract: The COVID-19 pandemic has posed a serious problem for drug anti-viral efficacy in combatting the cytokine storm triggered by SARS-CoV-2. From dermato-epidemiological studies conducted on psoriatic and other rheumatological patients, IL-17 inhibitors seem to attenuate or even prevent the cytokine storm and thus ICU referral. Furthermore, both in-vivo and in-vitro experiments suggest that IL-17 plays a key role in SARS-CoV-2 infection progression. Due to this evidence, we decided to summarize the literature findings on IL-17 inhibitors and COVID-19, maintaining psoriasis as the referral disease to better understand the extent of drug effects on the immune system.Keywords: biologics, COVID-19, psoriasis, therapy, IL-17

Shunxin Zhu,1 Caixiu Zeng,2 Yan Zou,1 Yanjiao Hu,1 Canfang Tang,1 Chunmei Liu2 1Clinical Laboratory, The Maternity & Child Health Care Hospital of Xiangtan City, Xiangtan City, Hunan Province, 411100, People’s Republic of China; 2Department of Pediatrics, The Maternity & Child Health Care Hospital of Xiangtan City, Xiangtan City, Hunan Province, 411100, People’s Republic of ChinaCorrespondence: Shunxin ZhuClinical Laboratory, The Maternity & Child Health Care Hospital of Xiangtan City, Xiangtan City, Hunan Province, 411100, People’s Republic of ChinaTel +86- 18975221633Email zhushunxin349@126.comBackground: Bacterial, viral, and bacterial and viral co-infections generally lead to inflammatory-related diseases. The aim of this study is to assess the clinical diagnostic values of serum amyloid A (SAA), procalcitonin (PCT), C-reactive protein (CRP), and interleukin (IL)-6 in children with bacterial, viral, or co-infections.Methods: A total of 181 children with infection symptoms (bacterial infection (Bac group), n = 46; viral infection (Vir group), n = 7; co-infections (Bac + Vir group), n = 128) were enrolled in our hospital from December 2019 to April 2020. Meanwhile, 42 healthy children without any infections were used as the controls. Venous blood samples were collected and the levels of serum SAA, PCT, CRP, and IL-6 were determined by immunoluminometric assay under an IMMAGE® analyzer. The diagnostic values of these biomarkers were assessed using the receiver operating characteristic (ROC) curves.Results: The results indicated that IL-6 level was increased in three infection groups compared to the controls. Both SAA and CRP were significantly elevated in Vir and Bac + Vir groups. High level of PCT was observed in Bac and Bac + Vir goups. In addition, PCT (0.9281, 95% CI = 0.8645– 0.9916) alone is an effective method for identifying bacterial infections. SAA in combination with CRP may distinguish co-infection from bacterial infection. Simultaneous positive of SAA, PCT, IL-6, and CRP can discriminate co-infection from the healthy controls.Conclusion: In a word, the levels of serum SAA, PCT, CRP, and IL-6 are increased to varying degrees in different infection situations. Our findings may provide early diagnosis for patients with different infections.Keywords: bacterial infection, viral infection, co-infection, combined biomarkers, diagnostic accuracy

Zuyi Ma,1,2,&ast; Zhenchong Li,1,3,&ast; Shujie Wang,1,4,&ast; Qi Zhou,5,6,&ast; Zuguang Ma,7 Chunsheng Liu,1,2 Bowen Huang,8 Zehao Zheng,1,2 LinLing Yang,9 Yiping Zou,1,2 Chuanzhao Zhang,1,3,4 Shanzhou Huang,1,3,4 Baohua Hou1,3,4 1Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2Shantou University of Medical College, Shantou, 515000, People’s Republic of China; 3South China University of Technology School of Medicine, Guangzhou, 51000, People’s Republic of China; 4The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 5Department of General Surgery, Hui Ya Hospital of the First Affiliated Hospital, Sun Yat-Sen University, Huizhou, 516081, People’s Republic of China; 6Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, People’s Republic of China; 7Sanshui Disease Prevention Cure Station, Foshan, 528100, People’s Republic of China; 8Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of China; 9Guangzhou Medical University, Guangzhou, 511436, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shanzhou Huang; Baohua Hou Tel +86 13928842869; +86 13609006510Email hshanzh@163.com; hbh1000@126.comBackground: Recent evidence has shown that Solute Carrier Family 39 Member 10 (SLC39A10) promoted tumor progression in several cancer types. The study intended to explore the expression and function of SLC39A10 in hepatocellular carcinoma (HCC).Methods: Multiple bioinformatics analyses were used to evaluate SLC39A10 expression and potential role in HCC. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to confirm SLC39A10 expression. Intro studies were performed to assess the effects of SLC39A10 on HCC cells proliferation and migration. Furthermore, flow cytometry was conducted to identify its specific function in apoptosis of HCC.Results: SLC39A10 was significantly over-expressed in HCC samples from both bioinformatic databases and our cohort. Survival analyses suggested patients with high expression of SLC39A10 had poor overall survival and disease-free survival (P-value < 0.01). Further, the expression of SLC39A10 was positively correlated with tumor-infiltrating lymphocytes and some immune checkpoints like CTLA4, TIM3 and TGFB1. In HCC cell lines, SLC39A10 knockdown inhibited cells proliferation and migration, but promoted apoptosis.Conclusion: An increased SLC39A10 expression was found and served as an unfavorable indicator of survival in HCC. Further studies suggested SLC39A10 promotes tumor aggressiveness and may provide a novel target for HCC therapy.Keywords: Solute Carrier Family 39 Member 10, hepatocellular carcinoma, immune infiltration, prognosis, cancer aggressiveness

Chih-Jung Chang,1,2,&ast; Hai-Qing Wang,3,&ast; Jing Zhang,3 Ying Zou,3 Yi-Hua Zhang,3 Jia-Wen Chen,3 Chun-Bing Chen,2,4– 7 Wen-Hung Chung,1,2,4– 6,8,9 Chao Ji3 1Medical Research Center and Xiamen Chang Gung Allergology Consortium, Xiamen Chang Gung Hospital, Xiamen, Fujian, People’s Republic of China; 2Department of Dermatology and Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, Taiwan; 3Department of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan; 7Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; 8Department of Dermatology, Xiamen Chang Gung Hospital, Xiamen, Fujian, People’s Republic of China; 9School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen-Hung ChungDepartment of Dermatology and Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and Keelung, TaiwanTel +886-3-3281200 ext. 8494Email wenhungchung@yahoo.comChao JiDepartment of Dermatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaTel +86-18651619908Email jichaofy@fjmu.edu.cnBackground: Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder characterized by a T helper 2 (Th2) immune response phenotype. Extracellular vesicles (EVs) are a heterogeneous family of cell-derived membranous structures, which transport cellular components such as DNA and proteins, and are involved in multiple physiological and pathological processes. Increasing evidence has shown that EVs secretion took part in the pathogenesis of AD. However, the proteomic studies of plasma-derived EVs in AD patients have not been reported.Objective: In this study, we investigated the diversity of plasma EVs collected from AD patients and healthy individuals and suggested that the candidates for uniquely or differentially expressed proteins in plasma EVs could be a diagnostic marker in AD.Methods: The plasma EVs were collected from 12 patients with moderate-to-severe AD and 13 healthy subjects. Proteomic analysis was performed by using a comprehensive nanoLC‑MS/MS method.Results: Proteomic analysis revealed that a total of 1478 proteins in plasma EVs were found to be common proteins in AD, whereas a total of 1597 proteins in plasma EVs were found to be common proteins in HC. Eighty-six proteins in plasma EVs showed more than 2.5-fold up-regulation, while a total of 225 proteins in plasma EVs showed less than 1/2.5-fold down-regulation with a significant difference (p < 0.05) among AD compared with HC. The candidates for differentially expressed proteins in plasma EVs have been described as a connectivity PPI network related to several KEGG pathways, including pathways in platelet activation, complement, and so on.Conclusion: SLP-76 tyrosine phosphoprotein (SLP76) involved in platelet activation may significantly contribute to the pathogenesis of AD. We will further verify the role of SLP67 in AD via animal and cell experiments to provide a promising therapeutic or diagnostic target.Keywords: atopic dermatitis, extracellular vesicle, plasma, proteomic profiling

Dingtao Hu,1,&ast; Nana Meng,2,&ast; Xiaoqi Lou,1 Zhen Li,3 Ying Teng,3 Bizhi Tu,4 Yanfeng Zou,3 Fang Wang1 1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Quality Management Office, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 4Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang WangDepartment of Oncology, The First Affiliated Hospital of Anhui Medical University, 218Jixi Road, Hefei, 230022, Anhui, People’s Republic of ChinaTel +86055162923615Fax +86055162923615Email wangfangahmu@163.comYanfeng ZouDepartment of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, No. 81, Meishan Road, Shushan District, Hefei, 230032, Anhui, People’s Republic of ChinaEmail zouyanfeng2015@163.comBackground: Numerous studies on the E2F transcription factors have led to increasing insights that E2Fs could be an important driver of the formation and progression of many human cancers. Little is known about the function of distinct E2Fs in chromophobe renal cell carcinoma (chRCC).Methods: We utilized the UALCAN, GEPIA, Cancer Genome Atlas (TCGA) database, cBioPortal, Metascape, STRING, Cytoscape, GeneMANIA, TIMER, TISIDB, GSCALite, and MEXPRESS databases to investigate the transcription level, genetic alteration, methylation, and biological function of E2Fs in chRCC patients, and its association with the occurrence, progress, prognosis, and immune cell infiltration in patients with chRCC.Results: We found that E2F1/2/4/7/8 were more expressed in chRCC tissues than in normal tissues, while the expression of E2F5/6 was lower in the former than in the latter, and the expression levels of E2F1/2/4/5/6//7/8 were also associated with the histological parameters of chRCC, including T-stage and N-stage. Higher expression of E2F1/2/7/8 was found to be significantly correlated with worse overall survival (OS) in chRCC patients. Cox regression and time-dependent ROC analysis further suggested that E2F1/2 could be the potential independent biomarkers for chRCC prognosis. Besides, a moderate mutation rate of E2Fs (34%) was noticed in chRCC, and the genetic mutations in E2Fs were associated with poor survival of chRCC patients. We noticed that the expression of E2Fs was statistically correlated with the immune cell infiltration in chRCC. Moreover, we also found that the expression of E2F1 was significantly correlated with tumor-infiltrating lymphocytes and immunomodulators, E2F7 expression was associated with MHC molecules, and the expression of E2F1/8 was correlated to their methylation levels.Conclusion: Our results provide novel insights for selecting the prognostic biomarkers for chRCC and suggest that E2F1/2 could act as potential prognostic biomarkers for the survival of chRCC patients. However, more in-depth experiments are required to identify the underlying mechanisms and verify the clinical value of E2F1/2 in the prognosis of chRCC.Keywords: chromophobe renal cell carcinoma, E2Fs, prognosis, UALCAN, GEPIA

Yao Zou,1,2 Owais M Bhat,2 Xinxu Yuan,2 Guangbi Li,2 Dandan Huang,2 Yi Guo,1,3 Dan Zhou,1,3 Pin-Lan Li2 1Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; 3School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of ChinaCorrespondence: Pin-Lan LiDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, 1220 East Broad Street, Richmond, VA, 23298-0613, USATel +1 804-828-4793Fax +1 804-828-4794Email pin-lan.li@vcuhealth.orgDan ZhouResearch Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel/Fax +86 22-59596211Email acuzhoudan@163.comBackground: Exosomes have been reported to mediate activation of the inflammatory response by secretion of inflammasome products such as IL-1β or IL-18 and that changes in exosomes production or secretion may be a therapeutic target for treatment of a variety of different chronic diseases. The present study tested the hypothesis that exosome-mediated release of NLRP3 inflammasome products instigates the inflammatory response in the lung during emphysema, a type of chronic obstructive pulmonary disease (COPD) and that electroacupuncture (EA) may attenuate emphysema by inhibition of NLRP3 inflammasome activation and consequent inflammation.Methods: The COPD mice model was developed by injecting porcine pancreatic elastase (PPE) via puncture tracheotomy and instillation. EA (4 Hz/20 Hz, 1 to 3 mA) was applied to the bilateral BL13 and ST36 for 30 min, once every other day for 2 weeks. Micro computed tomography (micro-CT) was performed to measure lung function. Histopathological changes in the lungs were displayed by HE staining.Results: In a mouse model of porcine pancreatic elastase (PPE)-induced emphysema, the lung tissue was found to display several key features of emphysema, including alveolar septal thickening, enlarged alveoli, interstitial edema, and inflammatory cells infiltration. Lungs of mice receiving PPE exhibited substantially increased low attenuation area (LAA) in micro-CT images. The colocalization of NLRP3 vs ASC or caspase-1 detected by confocal microscopy was shown to increase in both bronchial and alveolar walls, indicating the increased formation of NLRP3 inflammasomes. IL-1β, a prototype NLRP3 inflammasome activating product, was also found to have increased in the lung during emphysema, which was colocalized with CD63 (an exosome marker), an indicative of inflammatory exosome formation. By nanoparticle tracking analysis (NTA), IL-1β-containing exosomes were shown to significantly increase in the bronchoalveolar lavage (BAL) from mice with emphysema. Therapeutically, IL-1β production in the lung during emphysema was significantly reduced by EA at the acupoint Feishu (BL13) and Zusanli (ST36), accompanied by decreased colocalization of NLRP3 vs ASC or caspase-1. Increased exosome release into BAL during emphysema was shown to be significantly attenuated in EA-treated mice compared to their controls. However, EA of non-specific BL23 together with ST36 acupoint had no effects on NLRP3 inflammasome activation, exosome release and associated lung pathology during emphysema.Conclusion: NLRP3 inflammasome activation in concert with increased release of exosomes containing IL-1β or other inflammasome products contributes to the development of lung inflammation and injury during PPE-induced emphysema and that EA of lung-specific acupoints attenuates inflammasome activation and exosome release, thereby reducing inflammatory response in the lung of mice with emphysema.Keywords: chronic lung disease, inflammation, acupoints, exosome

Hongjie Qian,1,2 Qian Chen,1,2 Liyu Liang,1,2 Yang Zou,1,2 Huahua Pu,1,2 Liang Xin,1,2 Rong Song,1,2 Tingting Li,1,2 Huijuan Zhu,1,2 Yu Wang,3 Guanghui Tian,4 Jingshan Shen,2,3 Hualiang Jiang,2,3 Chen Yu,1,2 Zhen Wang,2,3 Jingying Jia1,2 1Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, 200031, People’s Republic of China; 3CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China; 4Vigonvita Life Science Co., Ltd., Suzhou, 215123, People’s Republic of ChinaCorrespondence: Jingying JiaShanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, 200031, People’s Republic of ChinaTel/Fax +86 21 54030254Email jyjia@shxh-centerlab.comZhen WangShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Pudong, Shanghai, 201203, People’s Republic of ChinaTel +86 21 20231000Fax +86 21 20231962Email wangzhen@simm.ac.cnPurpose: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.Methods: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.Results: In Part I, AUC and Cmax were proved to be linear within the 5– 30 mg dose range. T1/2 of TPN171H was 8.02– 10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination.Conclusion: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.Keywords: TPN171H, PDE5 inhibitor, safety, pharmacokinetics, food effect, healthy subjects

Context. Exoplanets with orbital periods of less than one day are known as ultra-short period (USP) planets. They are relatively rare products of planetary formation and evolution processes, but especially favourable for characterisation with current planet detection methods. At the time of writing, 125 USP planets have already been confirmed. Aims. Our aim is to validate the planetary nature of two new transiting planet candidates around M dwarfs announced by the NASA Transiting Exoplanet Survey Satellite (TESS), registered as TESS Objects of Interest (TOIs) TOI-1442.01 and TOI-2445.01. Methods. We used TESS data, ground-based photometric light curves, and Subaru/IRD spectrograph radial velocity (RV) measurements to validate both planetary candidates and to establish their physical properties. Results. TOI-1442 b is a validated exoplanet with an orbital period of $P$=0.4090682+/-0.0000004 d, a radius of $R_p$=1.15+/-0.06$R_{\oplus}$, and equilibrium temperature of $T_{p,eq}$=1357$_{-42}^{+49}$K. TOI-2445 b is also validated with an orbital period of $P$=0.3711286+/-0.0000004 d, a radius of $R_p$= 1.33+/-0.09$R_{\oplus}$, and equilibrium temperature of $T_{p,eq}$=1330$_{-56}^{+61}$K. Their physical properties align with current empirical trends and formation theories of USP planets. Based on the RV measurements, we set 3$\sigma$ upper mass limits of 8$M_{\oplus}$ and 20$M_{\oplus}$, thus confirming the non-stellar, sub-Jovian nature of both transiting objects. More RV measurements will be needed to constrain the planetary masses and mean densities, and the predicted presence of outer planetary companions. These targets extend the small sample of USP planets orbiting around M dwarfs up to 21 members. They are also among the 20 most suitable terrestrial planets for atmospheric characterisation via secondary eclipse with the JWST, according to a widespread emission spectroscopy metric., Comment: Published in A&A, 18 pages, 6 tables, 8 figures

Xiangtian Ling,1 Xinqi Ma,1 Xielan Kuang,1 Yuxiu Zou,1 Han Zhang,1 Han Tang,1 Han Du,1 Binbin Zhu,1 Hao Huang,1 Qing Xia,1 Minghao Chen,1 Danyi Mao,1 Dongli Chen,1 Huangxuan Shen,1,2 Jianhua Yan1 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of China; 2Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Huangxuan Shen; Jianhua YanZhongshan Ophthalmic Center, Sun Yat-Sen University, 54 Xianlie Road, Guangzhou, 510060, People’s Republic of ChinaTel +8620-8733-5261; +8620-8733-0484Fax +8620-8733-3271Email shenhx@mail.sysu.edu.cn; yanjh2011@126.comPurpose: To assess the cellular and molecular effects of lidocaine on muscles/myoblasts.Methods: Cultured myogenic precursor (C2C12) cells were treated with varying concentrations of lidocaine.Results: Cell viability of C2C12 cells was inhibited by lidocaine in a concentration-dependent manner, with concentrations ≥ 0.08%, producing a dramatic reduction in cell viability. These ≥ 0.08% concentrations of lidocaine arrested cell cycles of C2C12 cells in the G0/G1 phase. Moreover, lidocaine inhibited cell migration and myogenic processes in C2C12 cells at low concentrations. Results from QRT-PCR assays revealed that following treatment with lidocaine, Notch1, Notch2, Hes1, Csl and Dll4 all showed higher levels of expression, while no changes were observed in Mmal1, Hey1, Dll1 and Jag1.Conclusion: This work provides the first description of the effects of lidocaine upon the regeneration of muscles and maintenance of satellite cells at the cellular and molecular levels. In specific, we found that the Dll4-Notch-Csl-Hes1 axis was up-regulated suggesting that the Notch signaling pathway was involved in producing these effects of lidocaine. These findings provide a new and important foundation for future investigations into the effects of drug therapies in muscle diseases.Keywords: local anesthetics, C2C12 cells, myogenic differentiation, strabismus, Notch signaling pathway

Yaru Zou,1,2,* Dong Mei,1,* Jinjie Yuan,1,2 Jiaqi Han,1 Jiamin Xu,1 Ning Sun,1 Huan He,1 Changqing Yang,2 Libo Zhao1 1Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China*These authors contributed equally to this workCorrespondence: Libo ZhaoClinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of ChinaTel +86-010-59617018Email libozhao2011@163.comBackground: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP.Methods: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice.Results: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity.Conclusion: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.Keywords: 6-mercaptopurine, nanomedicines, Jurkat cells, acute lymphoblastic leukemia, ALL, bioavailability

Mingyue Xue,1,2 Xiaoping Yang,3 Yuan Zou,3 Tao Liu,3 Yinxia Su,3 Cheng Li,4 Hua Yao,3 Shuxia Wang3 1Hospital of Traditional Chinese Medicine Affiliated to the Fourth Clinical Medical College of Xinjiang Medical University, Urumqi 830011, People’s Republic of China; 2College of Public Health, Xinjiang Medical University, Urumqi, Xinjiang 830011, People’s Republic of China; 3Health Management Institute, Xinjiang Medical University, Urumqi 830011, People’s Republic of China; 4The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, People’s Republic of ChinaCorrespondence: Hua Yao; Shuxia Wang Email yaohua01@sina.com; 2724443591@qq.comBackground: High prevalence of non-alcoholic fatty liver disease (NAFLD) occurs in type 2 diabetes mellitus (T2DM), and about 13% of diabetic patients eventually die of liver cirrhosis or liver cancer. The purpose of our research was to develop a non-invasive predictive model of NAFLD in adults with T2DM.Patients and Methods: Adult patients diagnosed with T2DM during physical examination in 2018 in Urumqi were recruited, in total 40,921 cases. We chose questionnaire and physical measurement variables to build a simple, low-cost model. Variables were selected by the least absolute shrinkage and selection operator regression (LASSO). The features chosen by LASSO were used to build the nomogram prediction model of NAFLD. The receiver operating curve (ROC) and calibration were used for model validation.Results: Determinants in the nomogram included age, ethnicity, sex, exercise, smoking, dietary ratio, heart rate, systolic blood pressure (SBP), BMI, waist circumference, and atherosclerotic vascular disease (ASCVD). The area under ROC of developing group and validation group was 0.756 (95% confidence interval 0.750– 0.761) and 0.755 (95% confidence interval 0.746– 0.763), respectively, and the P values of the two calibration curves were 0.694 and 0.950, suggesting that the nomogram had good disease recognition ability and calibration.Conclusion: A nomogram constructed with accuracy can calculate the possibility of NAFLD in adults with T2DM. If validated externally, this tool could be utilized as a non-invasive method to diagnose non-alcoholic fatty liver in adults with T2DM.Keywords: type 2 diabetes mellitus, non-alcoholic fatty liver disease, screening tool, nomogram

Binbin Deng,1,* Jianyong Deng,1,* Xuan Yi,1 Yeqing Zou,2 Chen Li1 1Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen LiDepartment of Orthopedics, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi Province 330006, People’s Republic of ChinaEmail tanzikoulc@163.comYeqing ZouJiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi Province 330006, People’s Republic of ChinaEmail zouyeqing3366@163.comBackground: Osteosarcoma (OS) is a malignant bone tumour that exhibits a high mortality. While tumours thrive in a state of malnutrition, the mechanism by which OS cells adapt to metabolic stress through metabolic reprogramming remains unclear.Methods: We analysed the expression of ROCK2 in osteosarcoma tissues by RT-qPCR and Western blot. Cell proliferation were analysed using CCK8, EdU and colony formation assays. The level of cell glycolysis was detected by glucose-6 phosphate, glucose consumption, lactate production and ATP levels.Results: Herein, our study showed that ROCK2 expression in OS tissues was higher than in adjacent tissues. Functional assays have demonstrated that ROCK2 contributes to the growth of OS cells by inducing aerobic glycolysis. The current study revealed that ROCK2 knockdown decreased the levels of mitochondrial hexokinase II (HKII). And also indicated that ROCK2 served as a key enzyme in glycolysis and that it served an important role in tumour growth. A significant positive correlation was identified between the mRNA and protein expressions of ROCK2 and HKII, further demonstrating that ROCK2-induced glycolysis and proliferation was dependent on HKII expression in OS cells. Mechanistically, ROCK2 promotes HKII expression by activating the phospho-PI3K/AKT signalling pathway.Conclusion: Taken together, the results of the current study linked the two drivers of OS growth and aerobic glycolysis and identified a new mechanism of ROCK2 control in OS.Keywords: ROCK2, HKII, osteosarcoma, proliferation, glycolysis

Xin-ping Yu,1 Lei Wang,1 Hai-yang Yu,2 Yu-wei Zou,3 Chang Wang,1 Jin-wen Jiao,1 Hao Hong,4 Shuai Zhang2 1Department of Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 2Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 3Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 4Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, People’s Republic of ChinaCorrespondence: Shuai ZhangDepartment of Radiology, The Affiliated Hospital of Qingdao University, NO. 1677 Wutaishan Road, Huangdao District, Shandong Province 266000, People’s Republic of ChinaTel +86 18661804638Email zhangshuai19860302@163.comObjective: To investigate whether multidetector computed tomography (MDCT)-based radiomics features can discriminate between serous borderline ovarian tumors (SBOTs) and serous malignant ovarian tumors (SMOTs).Patients and Methods: Eighty patients with SBOTs and 102 patients with SMOTs, confirmed by pathology (training set: n = 127; validation set: n = 55) from December 2017 to June 2020, were enrolled in this study. The interclass correlation coefficient (ICC) and least absolute shrinkage and selection operator (LASSO) regression were applied to select radiomics parameters derived from MDCT images on the arterial phase (AP), venous phase (VP), and equilibrium phase (EP). Receiver operating characteristic (ROC) analysis of each selected parameter was carried out. Heat maps were created to illustrate the distribution of the radiomics parameters. Three models incorporating selected radiomics parameters generated by support vector machine (SVM) classifiers in each phase were analyzed by ROC and compared using the DeLong test.Results: The most predictive features selected by ICC and LASSO regression between SBOTs and SMOTs included 9 radiomics parameters on AP, VP, and EP each. Three models on AP, VP, and EP incorporating the selected features generated by SVM classifiers produced AUCs of 0.80 (accuracy, 0.75; sensitivity, 0.74; specificity, 0.75), 0.86 (accuracy, 0.78; sensitivity, 0.80; specificity, 0.75), and 0.73 (accuracy, 0.69; sensitivity, 0.71; specificity, 0.67), respectively. There were no significant differences in the AUCs among the three models (AP vs. VP, P = 0.199; AP vs. EP, P = 0.260; VP vs. EP, P = 0.793).Conclusion: MDCT-based radiomics features could be used as biomarkers for the differentiation of SBOTs and SMOTs.Keywords: ovarian tumors, multidetector computed tomography; MDCT, radiomics

Ling Hu,* Ting Li,* Yi Zou, Xiao-Ling Yin, Hui Gan Department of Endocrinology, The Third Affiliated Hospital of Nanchang University, Nanchang 330000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling HuDepartment of Endocrinology, The Third Affiliated Hospital of Nanchang University, No. 128 of Xiangshan North Road, Donghu District, Nanchang 330000, People’s Republic of ChinaTel +86 13970075119Email drhu_hl1172@163.comObjective: This study aimed to explore the clinical value of the fracture risk assessment tool (FRAX) in the fracture risk prediction of Chinese patients after replacing rheumatoid arthritis (RA) with type 2 diabetes mellitus (T2DM) in the FRAX algorithm.Methods: A total of 1,047 patients with T2DM from the Endocrinology Department of the Third Affiliated Hospital of Nanchang University were enrolled in this study. Dual-energy X-ray absorptiometry (DXA) was then used to detect their bone density. RA in the FRAX algorithm was replaced with T2DM, and the new RA-adjusted FRAX was used to assess the fracture risk of the patients.Results: The sensitivity, specificity, and Youden’s index of the RA-adjusted FRAX to the treatment opinions on T2DM-associated hip fractures were 0.4761, 0.9642, and 0.4403, respectively, while the sensitivity, specificity, and Youden’s index of RA-adjusted FRAX to the treatment opinions on T2DM-associated major bone osteoporotic fractures were 0.0080, 1.0000, 0.0080, respectively. The DXA and RA-adjusted FRAX both showed acceptable consistency in the treatment recommendations for hip fractures in patients with T2DM (κ = 0.49) but had poor consistency in treatment recommendations for major bone osteoporotic fractures (κ = 0.010). The body mass index (BMI) scores, femoral neck-bone mineral densities, and number of males in the same treatment opinion group were significantly higher than in the different treatment opinions group (P < 0.001).Conclusion: RA-adjusted FRAX is a useful clinical tool for evaluation of hip fracture risk for Chinese patients with T2DM, and the accuracy of fracture risk prediction for male patients with T2DM and patients with T2DM with high BMI scores or high femoral neck-bone mineral density is higher.Keywords: type 2 diabetes mellitus, FRAX, fracture risk, bone mineral density, osteoporosis

Qing Tu,1,* Yabing Zhu,1,* Yuan Yuan,1,* Long Guo,1 Lu Liu,2 Liangfang Yao,1 Yun Zou,1 Jinbao Li,1 Feng Chen1 1Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China; 2School of Anesthesiology, Weifang Medical University, Weifang 261053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinbao Li; Feng ChenDepartment of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaEmail lijinbaoshanghai@163.com; smmuchenfeng@163.comIntroduction: Severe inflammatory response leads to poor prognosis of acute lung injury (ALI), the role of gypenosides (GPs) on ALI is not fully clear. The study aimed at investigating the effects of GPs on ALI.Methods: We firstly established LPS-induced ALI mice model. Then, we tested whether GPs contributed to alleviate inflammatory response and lung injury of ALI in vivo. In order to identify specific mechanisms of the phenomenon, we conducted a bioinformatic analysis of LPS-induced ALI mice based on GEO database to identify hub differentially expressed genes (DEGs). PPI network of the DEGs was used to find hub-genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted based on the DAVID database to identify which pathways the genes enriched. Then, we tested whether GPs inhibited lung injury and inflammatory response via the enriched pathways. We also tested whether GPs inhibited the apoptosis of endothelial and epithelial cells secondary to severe inflammation.Results: We found GPs significantly alleviated lung injury and improved the survival rate of LPS-induced ALI mice in vivo. Bioinformatic analysis identified 20 hub-genes from DEGs, they were mainly enriched in NF-κB and TNF-α pathways. GPs could reduce the lung injury and inflammatory response via inhibiting NF-κB and TNF-α pathways in vivo. Our results indicated that GPs also inhibited inflammatory response of epithelial and endothelial cells via NF-κB and TNF-α pathways in vitro. Severe inflammatory response could also lead to apoptosis of endothelial and epithelial cells. Our results indicated that GPs effectively inhibited the apoptosis of endothelial and epithelial cells.Conclusion: Our study suggested GPs contributed to alleviated lung injury in vivo and inhibited inflammation and apoptosis of endothelial and epithelial cells in vitro, providing novel strategies for the prevention and therapy for ALI.Keywords: gypenosides, lipopolysaccharide, acute lung injury, inflammatory response, apoptosis

We demonstrate the first practical real-time dual-channel fiber-THz-fiber 2 * 2 MIMO seamless integration system with a record net data rate of 2 * 103.125 Gb/s at 385 GHz and 435 GHz over two spans of 20 km SSMF and 3 m wireless link., This paper has been accepted by ECOC 2022

Yi Zou,1 Ling Hu,1 Wenjun Zou,2 Honglin Li3 1Department of Endocrinology, The Third Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2General Surgery, Nanchang Third Hospital, Nanchang, People’s Republic of China; 3Department of Biochemistry, Medical College of Georgia, Augusta, GA, USACorrespondence: Ling HuDepartment of Endocrinology, The Third Affiliated Hospital of Nanchang University, No. 128 Xiangshan North Road, Nanchang 330000, Jiangxi Province, People’s Republic of ChinaTel +86 791-88862350Email hul@medmail.com.cnBackground: Leptin, an adipokine, has effects on the cardiovascular system with both protective and harmful role. This study aimed to assess the relationship between leptin and 3-month prognosis in ischemic stroke patients with type 2 diabetes.Patients and Methods: As a prospective single-center observational study, we collected consecutive first-ever acute ischemia stroke with type 2 diabetes mellitus from February 2019 to February 2020. Serum samples were obtained at admission, and leptin serum levels were tested by the ELISA method. Logistic regression models were used to assess leptin’s prognostic value to predict the functional outcome and mortality within three months.Results: Finally, two hundred and eleven patients were included, and the mean leptin serum level was 16.8 (SD. 6.9) ng/mL. At admission, 53.6% of those included patients (N=113) were defined as severe stroke (NIH Stroke Scale [NIHSS]> 5). In multivariable models adjusted for other factors, leptin levels< 11.6ng/mL (lowest quartile, Q1) related to severe stroke and the risk increased 175% (odds ratios [OR] =2.75; 95% confidence interval [CI]=2.13– 3.38; P=0.002). Serum leptin levels on admission in patients with poor outcomes and nonsurvivors were significantly reduced (P< 0.001 and P< 0.001). Leptin levels < 11.6ng/mL (lowest quartile, Q1) related to a higher risk of poor functional impairment (OR=5.13; 95% CI =3.25– 6.86; P< 0.001) and mortality (OR=3.19; 95% CI =2.03– 4.25; P< 0.001).Conclusion: The data shows that leptin serum level is a useful prognostic biomarker in ischemic stroke patients with type 2 diabetes, and this relationship is negative.Keywords: leptin, adipokine, ischemic stroke, type 2 diabetes, prognosis

Yanling Meng,1 Wenyang Li,1 Ying Zou,1 Ye Yao,1 Hong Huang,1 Jianjun Sun,1 Xiaomeng Li,1 Shu Guo,2 Xilong Zhang,3 Wei Wang1 1Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 3Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China C orrespondence: Wei Wang Email wwbycmu@126.comBackground: Obstructive sleep apnea (OSA) is characterized by repetitive episodes of upper airway collapse during sleep. The contraction of upper airway dilator muscles plays a crucial role in maintaining UA patency. Chronic intermittent hypoxia (CIH) is the most important pathophysiological process of OSA. Exposure to CIH induced not only the damage of dilator muscles but also the plasticity of the muscles. This study aimed to dynamically assess the influence of CIH on the upper airway.Methods: The experiments were performed on 44 rats. They were randomly divided into a normoxia (NO) group (n=22) and CIH group (n=22). In each group (n=6, respectively), EMG, transcranial magnetic stimulation (TMS) response, and critical pressure (Pcrit) value were recorded on day 0 (the day before exposure), and the 7th, 14th, 21st, and 28th day of air/CIH exposure. For each group, 16 rats were used for transmission electron microscopy observations on day 0, and the 7th, 14th and 28th day of air/CIH exposure (n=4 for every time point).Results: Compared to the NO group at the same point, the CIH group showed a damaged ultrastructure of genioglossus, increased activity of genioglossus corticomotor area, and increased Pcrit of the upper airway from the 7th to the 28th day of CIH. Increased EMG activity occurred at the 14th day of CIH and lasted for 2 weeks.Conclusion: The elevated genioglossus corticomotor excitability in response to the CIH could not counterbalance the damage effect of CIH on upper airway dilator muscles, which ultimately increased the collapsibility of the upper airway.Keywords: chronic intermittent hypoxia, ultrastructure, transcranial magnetic stimulation, upper airway critical pressure, electromyogram

Qingqing Wu,1,2 Xiaodong Wang,3 Qian Chen,1,2 Yang Zou,1,2 Xiaoyan Xu,1,2 Tingting Li,1,2 Chen Yu,1,2 Fu Zhu,1,2 Kanyin E Zhang,4 Jingying Jia,1,2 Yanmei Liu1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Changzhou Siyao Pharmaceuticals Co., Ltd, Jiangsu, People’s Republic of China; 4ViaClinical Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Yanmei LiuCenter Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, People’s Republic of ChinaTel/Fax +86-21-54030254Email ymliu@shxh-centerlab.comPurpose: To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design.Methods: A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (SWR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations.Results: Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of Cmax (SWR> 0.294), while ABE method was used to evaluate the bioequivalence of AUC0-t and AUC0-∞. The geometric mean ratio (GMR) of the test/reference for Cmax was 99.52%, and the 95% upper confidence bound was < 0. For AUC0-t and AUC0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%– 108.21%, 96.28%– 107.88%, respectively. Under fed conditions, the SWR value of Cmax, AUC0-t and AUC0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for Cmax, AUC0-t and AUC0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all < 0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient.Conclusion: In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China.NMPA Registration No: CTR20181422.Keywords: valsartan, bioequivalence, replicate, pharmacokinetics, safety

Siyuan He,1,2,* Yuzhen Zou,1,2,* Mengling Zhan,1,2,* Qi Guo,1,2 Yongjie Zhang,1,2 Zhemin Zhang,1 Bing Li,1 Shaoyan Zhang,1 Haiqing Chu1,3 1Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China; 2Tongji University School of Medicine, Shanghai 200092, People’s Republic of China; 3Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiqing Chu; Shaoyan ZhangDepartment of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People’s Republic of ChinaTel/ Fax +86 21 6511 5006Email chu_haiqing@126.com; zhangshaoyan000@163.comPurpose: Imipenem is one of the very few effective options for treating Mycobacterium abscessus (M. abscessus) infections; the development of imipenem resistance is a major health concern.Materials and Methods: The susceptibility of 194 clinical M. abscessus isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit M. abscessus growth was also assessed.Results: M. abscessus exhibited an elevated resistance to imipenem (MIC50 = 16 mg/L, MIC90 = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC50 (from 16 to 4 mg/L) and MIC90 (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward M. abscessus. Similarly, EDTA (a potent MBLs inhibitor) promoted the anti-M. abscessus activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates.Conclusion: These findings demonstrate that TPEN can reduce the resistance of M. abscessus to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.Keywords: Mycobacterium abscessus, TPEN, imipenem resistance, metallo-β-lactamases

Yi-feng Zou,1,2,* Yu-ming Rong,3,* Ze-xian Chen,1,2,* Zhi-hong Shen,4 Xi Chen,1,2 Ying-xin Tan,1,2 Jing-rong Weng,1,2 Xiao-ming Huang,2,5 Xu-tao Lin2,6 1Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 2Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Very Important Person Region, Cancer Center of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of General Surgery, Jieyang Hospital of Traditional Chinese Medicine, Jieyang, Guangdong, People’s Republic of China; 5Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 6Department of Gastrointestinal Endoscopy, Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu-tao Lin; Xiao-ming Huang Email linxt23@mail.sysu.edu.cn; jackytom2008@126.comBackground: Huaier extract has been a part of traditional Chinese medicine (TCM) for roughly 1600 years and may serve as a potential anti-cancer drug as it is associated with good efficacy and low toxicity. Individuals with inflammatory bowel disease (IBD) are at a higher chance of being diagnosed with colorectal cancer (CRC) and as Huaier extract may potentially influence tumorigenesis, we set out to determine the effect of Huaier extract on colitis-associated CRC.Methods: The CRC mouse model, established through azoxymethane (AOM) and dextran sulfate sodium (DSS), was administered Huaier extract. Weight loss, colon length, tumor number and tumor size were evaluated macroscopically. Pro-inflammatory cytokine expression and STAT3 phosphorylation were assessed in the colon using ELISA, Western blot and/or immunohistochemistry.Results: Huaier extract improved the severity of colitis-associated tumorigenesis compared with control group, with attenuated weight loss and longer colons. Tumor number, size and load were drastically decreased in mice treated with Huaier. Histological assessment suggested that Huaier could decrease histological injury of the colon tissue. Additionally, Huaier extract treatment led to reduced pro-inflammatory cytokine levels (TNF-α, IL-6, IFN-γ and IL-1β) and a decrease of STAT3 phosphorylation in colon tissue. Additionally, present findings demonstrated that Huaier extract inhibited cell proliferation and induced apoptosis in CRC cells HCT116 and HCT8. The migration and invasion of CRC cells were markedly inhibited upon exposure to Huaier treatment. The apoptosis-associated protein levels (P53, Bax, Bcl-2, pro-caspase-3 and cleavage caspase-3) showed significant differences after the administration of Huaier extract in HCT116 and HCT8 cells. In vivo, the administration of Huaier extract to mice inhibited tumor growth and yielded a similar profile of apoptotic proteins expression p53, Bcl-2, pro-caspase-3 and cleaved caspase-3 while no significant differences in Bax were observed. Moreover, the ratio of TUNEL-positive/apoptotic cells was markedly increased in the Huaier-treated mice.Conclusion: Huaier extract may reduce the IBD-associated tumor development by suppressing pro-inflammatory cytokine levels and STAT3 stimulation.Keywords: colorectal cancer, Huaier extract, colitis, traditional Chinese medicine

Jun Zhou,1 Ruilian Zhe,1 Xiaohui Guo,1 Yuying Chen,1 Yan Zou,2 Li Zhou,1 Zhijian Wang3 1Department of Obstetrics, Shenzhen People’s Hospital, Shenzhen 518000, People’s Republic of China; 2Emergency Department of Shenzhen Maternal and Child Health Hospital, Shenzhen 518000, People’s Republic of China; 3Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510510, People’s Republic of ChinaCorrespondence: Zhijian WangDepartment of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Number 1838, North Guangzhou Avenue, Guangzhou, Guangdong 510515, People’s Republic of ChinaEmail wangzhijian2020@yeah.netBackground: Gestational diabetes mellitus (GDM) is a disorder of glucose metabolism that occurs or is found for the first time during pregnancy. GDM is very harmful and urgently needs drug treatment to improve pregnancy outcome. PPARδ is involved in a variety of biological processes related to glycolipid metabolism in the body, suggesting that it may be closely related to insulin resistance and impaired glucose tolerance. The role of PPARδ agonist GW501516 in gestational diabetes has not been studied.Methods: Firstly, the rat model of GDM was established. Then, fasting blood-glucose (FGB), fasting insulin (FINS), HOMA-islet resistance index (HOMA-IR) and insulin sensitivity index (ISI) of GDM rats treated with GW501516 were measured on day 3, day 10 and day 17. Glucose tolerance test was performed on the 20th day of gestation to measure glucose tolerance in rats. The expression of PPARδ and Angptl8 in islet tissues of rats was detected by Western blot and immunohistochemistry (IHC). Histopathological changes of islet were detected by HE stain; apoptosis rate of islet cells was detected by Tunel; and expression of apoptosis-related proteins in the cells was detected by Western blot. The biochemical kits were used to detect the expression of lipid metabolism-related factors in blood of GDM rats after the PPARδ agonist GW501516 treatment. Finally, the expression of SREBP-1c and GLUT2 in islet tissues was detected by RT-qPCR and IHC.Results: The PPARδ agonist GW501516 decreased the expression of FGB, FINS and HOMA-IR in GDM rats, and we found that GW501516 decreased ISI in GDM rats. GW501516 increased glucose tolerance in GDM rats too. In GDM rats, the expression of PPARδ in islet decreased and the expression of Angptl8 increased, which was reversed by GW501516. In addition, we also found that GW501516 can improve the damaged islet tissue of GDM rats, reduce the apoptosis rate of islet cells and inhibit the expression of lipid metabolism-related factors in the blood. Finally, we found that GW501516 inhibited the expression of SREBP-1c and promoted the expression of GLUT2 in the islet tissue.Conclusion: The PPARδ agonist GW501516 could improve the blood glucose level, damaged islet tissue and increase the insulin content in the rats with GDM, possibly by regulating the SREBP-1c/GLUT2 pathway. Our study provided a new basis for clinical treatment of GDM in pregnant women with PPARδ agonist GW501516.Keywords: PPARδ, GW501516, gestational diabetes mellitus, GDM, SREBP-1c/GLUT2 pathway

Xia Tian,* Meng Liu,* Xiaodong Huang, Qingxi Zhu, Weijie Liu, Wei Chen, Yanli Zou, Yishan Cai, Shasha Huang, Aifang Chen, Ting Zhan, Min Huang, Xiaoli Chen, Zheng Han, Jie Tan Department of Gastroenterology, Tongren Hospital of Wuhan University (Wuhan Third Hospital), Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zheng Han; Jie Tan Email 422435466@qq.com; 549774892@qq.comBackground: Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear.Materials and Methods: In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot.Results: We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling.Conclusion: These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.Keywords: colon cancer, noscapine, mitochondrial damage, PTEN, PI3K/mTOR

Bi Wang,1,2,* Yaping Shen,3,* Yin Zou,4 Zhengjun Qi,4 Guijia Huang,4 Shan Xia,5 Rui Gao,6 Fenghu Li,5 Zhi Huang7 1Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Department of Paediatrics, Maternal and Child Health Hospital of Guiyang City, Guiyang, Guizhou, People’s Republic of China; 3Department of Interventional Radiology, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 4Department of Oncology, The Second Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 5Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 6Guiyang Customs Guizhou International Travel Healthcare Center, Guiyang, Guizhou, People’s Republic of China; 7Department of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fenghu LiDepartment of Gynecologic Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of ChinaEmail fenghuli19@163.comZhi HuangDepartment of Interventional Radiology, The Affiliated Hospital of Guizhou Medical University, Guiyang City, Guizhou Province, People’s Republic of ChinaEmail doctor@huangzhi.comBackground/Objective: Topoisomerases type IIA (TOP2A) was identified to present with a high-expression pattern in cervical cancer. However, TOP2A role in the progression of cervical cancer remains unknown. Here, we aimed to explore the effect and reveal the underlying mechanism of TOP2A in the migration, invasion and epithelial–mesenchymal transition (EMT) of cervical cancer.Materials and Methods: The expression profiles of TOP2A in 20 paired cervical cancer tissues and the paracancerous normal tissues were detected by using Western blotting assay. Transwell chambers were used to test cell migration and invasion abilities. Cell morphology and the expressions of E-cadherin and N-cadherin were detected to assess cell EMT. LY294002 was used to inhibit the activation of PI3K/AKT signaling.Results: Compared with the paracancerous normal tissues, TOP2A was overexpressed in 85% (17/20) cervical cancer tissues. Repression of TOP2A expression in SiHa cells significantly weakened cell migration and invasion abilities, reduced cell numbers in shuttle shape and increased E-cadherin expression while decreased E-cadherin expression. To the opposite, overexpression of TOP2A in Hela cells induced opposite results. In addition, the expression of p-AKT was increased when TOP2A was overexpressed in Hela cells, and p-AKT expression was decreased when TOP2A was silenced in SiHa cells. Moreover, suppression of the PI3K/AKT signaling with LY294002 treatment apparently rescued TOP2A-mediated promotions in cell migration, invasion and EMT in Hela cells.Conclusion: This study reveals that TOP2A is abnormally overexpressed in cervical cancer tissues, and TOP2A overexpression leads to cell migration, invasion and EMT via activating PI3K/AKT signaling.Keywords: topoisomerases type IIA, epithelial–mesenchymal transition, cell morphology, migration, PI3K/AKT signaling

Xi Chen,1,2 Yaping Huang,1 Dianyu Shi,2 Chuan Nie,3 Yiping Luo,4 Liangfen Guo,1 Yu Zou,1 Chun Xie5 1Department of Otorhinolaryngology, Guangdong Women and Children Hospital, Guang Zhou, Guangdong, 511400, People’s Republic of China; 2Department of Otorhinolaryngology, People’s Hospital of Longhua,Guangdong,People’s Republic of China; 3Department of Neonatology, Guangdong Women and Children Hospital, Guang Zhou 511400, Guangdong, People’s Republic of China; 4Department of Internal Medicine, Guangdong Women and Children Hospital, Guang Zhou 511400, Guangdong, People’s Republic of China; 5Department of Stomatology, People’s Hospital of Longhua, Shenzhen 518109, Guangdong, People’s Republic of ChinaCorrespondence: Yu Zou; Chun Xie Email Zouyu10291@163.com; xiechun2002@163.comBackground: Recently, long non-coding RNAs (lncRNAs) have been elucidated to play essential roles in cancers, and the recognition of lncRNA expression patterns in nasopharyngeal carcinoma (NPC) may be helpful for indicating novel mechanisms underlying NPC carcinogenesis. Herein, we conducted this study to probe into the function of lncRNA ZNF667-AS1 in NPC progression with the involvement of microRNA-1290 (miR-1290) and actin-binding LIM protein 1 (ABLIM1).Materials and Methods: In silico analysis screened differentially expressed genes and miRNAs in NPC and predicted potential mechanisms. ZNF667-AS1 expression was detected in NPC tissues and cells. The gain-and-loss function assays were performed to explore the effects of lncRNA ZNF667-AS1 and miR-1290 in NPC cell biological behaviors. In vivo experiments were further conducted to confirm the in vitro results.Results: In silico analysis predicted that ZNF667-AS1 was diminished in NPC, which may downregulate ABLIM1 through sponging miR-1290. ZNF667-AS1 was poorly expressed in NPC tissues and cells, and overexpression of ZNF667-AS1 inhibited growth of NPC cells. ZNF667-AS1 competitively bound with miR-1290, thereby upregulating ABLIM1. miR-1290 resulted in the promotion of NPC cell progression by suppressing ABLIM1. Overexpression of ZNF667-AS1 or suppression of miR-1290 inhibited tumorigenicity of NPC cells in vivo.Conclusion: This study highlights that lncRNA ZNF667-AS1 promotes ABLIM1 expression by sponging miR-1290 to suppress NPC cell progression.Keywords: nasopharyngeal carcinoma, lncRNA ZNF667-AS1, ABLIM1, microRNA-1290, competing endogenous RNA

Hui Cao, Guihua Pan, Shiqiang Tang, Ni Zhong, Huake Liu, Haizhi Zhou, Qin Peng, Yongbin Zou Department of Oncology, Chenzhou First People’s Hospital, Chenzhou, People’s Republic of ChinaCorrespondence: Yongbin ZouDepartment of Oncology, Chenzhou First People’s Hospital, 102 Luojiajing Road, Chenzhou 423000, People’s Republic of ChinaTel +86-13507357355 Email gjnzhu888@163.comObjective: Cervical carcinoma (CC) is a serious threat to women’s health and few effective therapeutic methods have been discovered. The purpose of this study is to explore the underlying mechanism of miR-145-5p in CC.Methods: Bioinformatics methods were employed to analyze the gene expression data of CC from TCGA database. qRT-PCR was used to detect the expression of miR-145-5p and KLF5 in CC cells, and Western blot was employed for the examination of KLF5 protein level. The targeted relationship between miR-145-5p and KLF5 was verified by a dual-luciferase reporter assay. Moreover, CCK-8, wound healing assay and transwell invasion assay were used to analyze the effects of miR-145-5p overexpression or KLF5 silencing on the proliferation, migration and invasion of CC cells.Results: miR-145-5p was shown to be down-regulated in CC tissues and cells, while KLF5 was up-regulated. miR-145-5p could bind to the complementary sequence within the wild type KLF5 3ʹUTR rather than the mutant one. In addition, miR-145-5p could effectively down-regulate KLF5, in turn inhibiting the proliferation, migration and invasion of CC cells.Conclusion: miR-145-5p regulates the proliferation, migration and invasion of CC cells by targeting KLF5.Keywords: cervical carcinoma, miR-145-5p, KLF5, proliferation, migration, invasion

Qi Guo,1,2 Jianhui Chen,1,2 Shaoyan Zhang,1 Yuzhen Zou,1,2 Yongjie Zhang,1,2 Dongdong Huang,1 Zhemin Zhang,1 Bing Li,1 Haiqing Chu1,3 1Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China; 2Tongji University School of Medicine, Shanghai 200092, People’s Republic of China; 3Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of ChinaCorrespondence: Haiqing Chu; Bing LiDepartment of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People’s Republic of ChinaTel/Fax +86 021 6511 5006Email chu_haiqing@126.com; libing044162@163.comPurpose: The emergence of clarithromycin resistance is a challenge in treating Mycobacterium abscessus infections. Known mechanisms that contribute to intrinsic clarithromycin resistance focus on rrl gene-related mutations, but resistant clinical isolates often exhibit an inconsistent rrl genotype.Patients and Methods: In this study, 194 clinical Mycobacterium abscessus isolates were collected from patients with lung infections and the whole genome of each isolate was sequenced. A comprehensive examination of the molecular mechanisms underlying intrinsic clarithromycin resistance was performed, combining MIC determination, comparative genome sequence analysis and qRT-PCR.Results: Of the 194 isolates, 13 (6.7%) were clarithromycin resistant; only seven of these harbored a rrl 2270/2271 mutation. The remaining six resistant isolates did not exhibit a specific resistance-associated mutation in the clarithromycin target-site genes, rrl, rplC, rplD and rplV, or in the rrl modification gene erm(41). qRT-PCR analysis showed that the increased expression of the efflux pump genes, MAB_2355c, MAB_1409c and MAB_1846, as well as their positive regulatory gene whiB7, consistently correlated with increased clarithromycin resistance. The presence of efflux pump inhibitors significantly decreased the MIC of clarithromycin for nonsusceptible isolates, especially the intrinsic resistant isolates that exhibited no rrl 2270/2271 mutation.Conclusion: These findings indicate that efflux pumps play a prominent role in the intrinsic resistance of M. abscessus to clarithromycin, complementing other known resistance mechanisms.Keywords: Mycobacterium abscessus, clarithromycin resistance, efflux pumps

In this Snowmass 2021 white paper, we summarise the Conceptual Design of the European Spallation Source neutrino Super Beam (ESSvSB) experiment and its synergies with the possible future muon based facilities, e.g. a Low Energy nuSTORM and the Muon Collider. The ESSvSB will benefit from the high power, 5 MW, of the European Spallation Source (ESS) LINAC in Lund-Sweden to produce the world most intense neutrino beam, enabling measurements to be made at the second oscillation maximum. Assuming a ten-year exposure, physics simulations show that the CP-invariance violation can be established with a significance of 5 sigma over more than 70% of all values of delta CP and with an error in the measurement of the delta CP angle of less than 8 degree for all values of delta CP. However, several technological and physics challenges must be further studied before achieving a final Technical Design. Measuring at the 2nd oscillation maximum necessitates a very intense neutrino beam with the appropriate energy. For this, the ESS proton beam LINAC, which is designed to produce the world's most intense neutron beam, will need to be upgraded to 10 MW power, 2.5 GeV energy and 28 Hz beam pulse repetition rate. An accumulator ring will be required for the compression of the ESS LINAC beam pulse from 2.86 ms to 1.3 mus. A high power target station facility will be needed to produce a well-focused intense (super) mu-neutrino beam. The physics performance of that neutrino Super Beam in conjunction with a megaton underground Water Cherenkov neutrino far detector installed at a distance of either 360 km or 540 km from the ESS, the baseline, has been evaluated., contribution to Snowmass 2021

Atoms with a highly excited electron, called Rydberg atoms, can form unusual types of molecular bonds. The bond differs from the well known ionic and covalent bonds not only by its binding mechanism, but also by its bond length ranging up to several micrometres. Here, we observe a new type of molecular ion based on the interaction between the ionic charge and a flipping induced dipole of a Rydberg atom with a bond length of several micrometres. We measure the vibrational spectrum and spatially resolve the bond length and the angular alignment of the molecule using a high-resolution ion microscope. As a consequence of the large bond length, the molecular dynamics is extremely slow. These results pave the way for future studies of spatio-temporal effects in molecular dynamics, e.g., beyond Born-Oppenheimer physics.

Diabetic retinopathy (DR) is a specific microvascular complication arising from diabetes, and its pathogenesis is notcompletely understood. tRNA-derived stress-induced RNAs (tiRNAs), a new type of small noncoding RNA generated by specific cleavage of tRNAs, has become a promising target forseveral diseases. However, the regulatory function of tiRNAs in DR and its detailed mechanism remain unknown. Here, we analyzed the tiRNA profiles of normal and DR retinal tissues. The expression level of tiRNA-Val was significantly upregulated in DR retinal tissues. Consistently, tiRNA-Val was upregulated in human retinal microvascular endothelial cells (HRMECs) under high glucose conditions. The overexpression of tiRNA-Val enhanced cell proliferation and inhibited cell apoptosis in HRMECs, but the knockdown of tiRNA-Val decreased cell proliferation and promoted cell apoptosis. Mechanistically, tiRNA-Val, derived from mature tRNA-Val with Ang cleavage, decreased Sirt1 expression level by interacting with sirt1 3’UTR, leading to the accumulation of Hif-1α, a key target for DR. In addition, subretinal injection of adeno-associated virus to knock down tiRNA-Val in DR mice ameliorated the symptoms of DR. Therefore, these data suggest that tiRNA-Val is a potential target in treating diabetic retinopathy.

Shipeng Wang,1,2,* Hui Gao,3,* Zewen Ru,1 Yanan Zou,1 Yilan Li,1 Wei Cao,4 Wei Meng,1 Jihe Li,5 Yuan Yao,1 Yanxiu Zhang,1 Xueyan Lang,1 Yao Zhang1,2 1Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, People’s Republic of China; 2Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150086, People’s Republic of China; 3Department of Cardiology, People’ Hospital of Xinzheng, Xinzheng, Henan Province 451150, People’s Republic of China; 4Department of Cardiology, Heilongjiang Provincial Hospital Affiliated to Harbin Institute of Technology, Harbin 150036, People’s Republic of China; 5Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shipeng WangDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Xuefu Road 246#, Nangang District, Harbin 150086, People’s Republic of ChinaTel +86 13654504286Fax +86 86296225Email guoyunqaz@126.comBackground: Sleep disorders (SDs) are usually associated with an increase in frequency of ventricular tachycardia (VT). However, the relationship between SDs and the prevalence of VT within the first week of acute myocardial infarction (AMI) remains unclear. This study aimed to evaluate their associations and potential mechanisms.Methods: This structured questionnaire-based cross-sectional study enrolled 303 patients with AMI from a hospital in northern China. Pittsburgh Sleep Quality Index (PSQI) was used to determine sleep quality of subjects. Heart rate variability (HRV) of patients was investigated by ambulatory electrocardiography recorders. Enzyme-linked immunosorbent assay was used to measure the plasma levels of catecholamine in a subgroup including 80 patients with AMI.Results: After adjusting to basic cardiovascular characteristics, results of multivariate logistic regression demonstrated that the global PSQI score and its main components were positively associated with VT prevalence in inpatients with AMI. There were significantly different HRV parameters interpreted as autonomic nerve activity in two groups of AMI patients with different sleep quality. In addition, we found the influence of sleep quality on plasma concentrations of adrenaline and norepinephrine in AMI patients.Conclusion: Sleep status was significantly associated with the initiation of VT within the first week of AMI, probably due to the effect of SDs on sympathetic nerve activity. Amelioration of sleep quality and sympathetic hyperactivity may be prospective strategy to curb arrhythmias after AMI.Keywords: ventricular tachycardia, acute myocardial infarction, sleep disorders, heart rate variability, catecholamine

Chunfa Qian,*,1Bin Wang,*,2Yuanjie Zou,*,1Yansong Zhang,*,1Xinhua Hu,*,1Wenbo Sun,*,1Hong Xiao,*,3Hongyi Liu,1 Lei Shi21Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2Department of Neurosurgery, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, People’s Republic of China; 3Department of Neuro-Psychiatric Institute, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing 210029, People’s Republic of China*These authors contributed equally to this workBackground: The presence of glioma stem cells (GSCs) is thought to be a key factor responsible for development of the incurable glioblastoma multiforme (GBM). GSCs are often displayed during chemotherapy resistance, except for demethoxycurcumin (DMC), a component of curcumin, which has been previously confirmed to inhibit GSCs proliferation and induce apoptosis.Purpose: The objective of this study was to identify the main mechanism underlying anti-GSCs resistance by DMC.Patients and methods: qRT-PCR was used to determine the expression of miR-145 in glioma patients and GSCs, and GSCs were transfected with miR-145 overexpressed vectors. Then, functional analyses (in vitro and in vivo) were performed to confirm the role of miR-145 and DMC in GSCs. Finally, related proteins were tested by immunohistochemistry and Western blot.Results: miR-145 was atypically low-expressed miRNA in GSCs, and could enhance GSC chemosensitivity to DMC both in vitro and in vivo. Upregulation of miR-145 in GSCs resulted in increased cell growth inhibition and apoptosis to DMC. Further research on the mechanism demonstrated that the combined effects of miR-145 and DMC were involved in the miR-145/SOX2-Wnt/β-catenin pathway. Overexpression of SOX2 reduced GSC resistance to growth inhibition by miR-145+DMC treatment.Conclusion:Our data strongly support an important role for miR-145 in enhancing GSC chemosensitivity to DMC by targeting the SOX2-Wnt/β-catenin axis.Keywords: glioma stem cells, miR-145, demethoxycurcumin, proliferation, apoptosis

Yiqun Huang, Yong Zou, Luhui Lin, Xudong Ma, Ruiji Zheng Department of Hematology, Zhangzhou Affiliated Hospital of Fujian Medical University, 363000 Zhangzhou, People’s Republic of China Background: miR-101 is reported to be associated with cell proliferation and apoptosis. However, it is unknown whether miR-101 expression affects cell proliferation and apoptosis in diffuse large B cell lymphoma (DLBCL). The aim of the present study was to investigate the expression of miR-101 and its effect on cell proliferation and apoptosis in DLBCL. Methods: miR-101 expression was detected in 30 cases of patients with DLBCL and normal lymph node by qRT-PCR. Then, miR-101 expression was up-regulated and down-regulated in Originated Cell Line-Large Lymphoma 8 (OCL-LY8) cell line, respectively. MTT and flow cytometry assay were used to evaluate the effect of miR-101 on cell proliferation and apoptosis, respectively. As KDM1A was confirmed to be as a specific target of miR-101 by TargetScanHuman, the relationship between MiR-101 and KDM1A was further investigated. Results: miR-101 expression in patients with DLBCL was significantly reduced compared those in normal lymph node (P

Yun Zou, Juan Zhou, Bin Xu, Wenzhi Li, Zhong WangDepartment of Urology and Andrology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of ChinaBackground: Sufficient supply of deoxyribonucleoside triphosphates (dNTPs) is required for the uncontrolled replication of cancers. The current study aimed to investigate the biological and clinical role of ribonucleotide reductase subunit M2 (RRM2), a key enzyme regulating the dNTP pool, in clear-cell renal cell carcinoma (ccRCC).Methods: The expression of RRM2 on disease progression and patient outcome was assessed in ccRCC. Then, the effect of RRM2 inhibition on renal cell carcinoma (RCC) growth using siRNA or Triapine, an RRM2-specific inhibitor, was characterized in RCC cell lines.Results: The expression of RRM2 was up-regulated in ccRCC tissues as compared to the normal tissues. Patients with high RRM2 expression tend to have advanced pT stages, high Fuhrman grades, and shortened overall survival (OS). RRM2-siRNAs or Triapine significantly inhibited the cell growth by inducing G0/G1 cell cycle arrest in RCC cells through the attenuation of dNTP pool.Conclusions: The current results provided evidence that RRM2 might act as a novel target for ccRCC, and exploration of nonnucleoside, reversible, small-molecule inhibitors against RRM2 could be promising.Keywords: clear-cell renal cell carcinoma, RRM2, targeted therapy

Limei Wang,1,2 Jin Pei,1 Zhongcheng Cong,1 Yifang Zou,1 Tianmeng Sun,3 Fionán Davitt,4,5 Adrià Garcia-Gil,4,5 Justin D Holmes,4,5 Caitriona M O’Driscoll,6 Kamil Rahme,4,7 Jianfeng Guo1 1School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China; 2Department of Pharmacy, The General Hospital of FAW, Changchun 130011, China; 3The First Hospital of Jilin University, Changchun 130021, China; 4School of Chemistry and the Tyndall National Institute, University College Cork, Cork, Ireland; 5CRANN, Trinity College Dublin, Dublin, Ireland; 6Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland; 7Department of Sciences, Faculty of Natural and Applied Science, Notre Dame University (Louaize), Zouk Mosbeh 1200, Lebanon Background: Gold nanorods (AuNRs), due to the optical and electronic properties namely the surface plasma resonance, have been developed to achieve the light-mediated photothermal therapy (PTT) for cancer. However, PTT alone may suffer from inefficient tumor killing. Recently, the combination of PTT and chemotherapy has been utilized to achieve synergistic anticancer effects. Methods: In this study, AuNRs capped with hexadecyltrimethylammonium bromide (CTAB), poly(acrylic acid) (PAA), and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of negatively charged anisamide-targeted PEGylated AuNRs (namely Au-CTAB-PAA-PEG-AA) for the combination of PTT and chemotherapy (termed as chemo-photothermal therapy [CPTT]). Epirubicin (EPI, an anthracycline drug) was efficiently loaded onto the surface of Au800-CTAB-PAA-PEG-AA via the electrostatic interaction forming Au800-CTAB-PAA-PEG-AA.EPI complex. Results: The resultant complex demonstrated pH-dependent drug release, facilitated nucleus trafficking of EPI, and induced antiproliferative effects in human prostate cancer PC-3 cells. When Au800-CTAB-PAA-PEG-AA.EPI complex was further stimulated with desired laser irradiation, the synergistic outcome was evident in PC-3 xenograft mice. Conclusion: These results demonstrate a promising strategy for clinical application of CPTT in cancer. Keywords: gold nanoparticles, non-viral drug delivery, chemotherapy, photothermal therapy, synergistic effect

A shortcoming of the RZ-SHAW model (A hybrid version of Root Zone Water Quality Model and The Simultaneous Heat and Water Model) is that it cannot simulate the plastic mulching technology which is widely used in arid areas. Our objectives in this study were to develop RZ-SHAW to include a new plastic module, and to evaluate the model's performance over three years of maize (Zea mays L.) production in China. A new plastic module was added to compute changes in the shortwave and longwave radiation transfer, turbulent heat and vapor transfer from the surface, and the energy and water balances in the system associated with a plastic mulch layer. The modified RZ-SHAW model can adequately simulate soil water (0.017 cm3 cm−3 ≤ RMSE ≤ 0.030 cm3 cm−3) and capture the evaporation reduction and transpiration increase under plastic mulch. The model overestimated the increased soil temperatures under plastic mulch (2.3 ℃ over the 100-cm profile) compared to the measured data (1.4 ℃). Overall, the revised RZ-SHAW model adequately simulated soil water and heat exchange under plastic mulch conditions. The modified RZ-SHAW model can be used as an effective decision tool for management optimization in plastic mulched cropland.

Background: Cyclophosphamide (CTX) is an alkylating agent used in the treatment of systemic lupus erythematosus (SLE) for its potent immunosuppression effect. Many aspects of the use of CTX in SLE have been previously studied. However, its relation to mortality in SLE had rarely been mentioned. Thus we investigate the effect of cyclophosphamide on organ involvements and the overall and cause-specific mortality of SLE patients.Methods: Information about CTX prescription were taken from medical records in the Jiangsu Lupus database that was set up to collect data from SLE patients since their first admission during 1999-2009 in Jiangsu province, China. Follow- up studies were carried out in 2010 and 2015 to check the survival status of the patients. Cox regression models were used to estimate hazard ratio (HR) and 95% CI. Kaplan-Meier model was used to assess the effect of CTX on mortality between organ involvements and non-involvements.Results: There were 221 deaths observed out of 2446 SLE patients. CTX users showed a lower mortality of SLE (8.4%) with adjusted HR (95% CI) of 0.74 (0.56-0.97), as compared to non-users. A decreased in overall mortality of SLE in low daily dosage of CTX, with adjusted HR (95% CI) of 0.54 (0.36-0.81) and a significant dose-response pattern (P = 0.004) between overall mortality of SLE and long-term use of CTX with adjusted HR (95% CI) 0.53 (0.35-0.80) were observed. In cause-specific mortality analyses, protective effective of CTX was found to be insignificant. However, CTX could eliminate the differences in mortality between organ involvement and non-involvement, including renal, neuropsychiatric, cardiopulmonary, gastrointestinal and hematological involvements.Conclusion: Low daily dosage and long-term use of CTX lowers the risk of overall mortality of SLE. CTX might improve the survival of patients with renal, neuropsychiatric, cardiopulmonary, gastrointestinal and hematological involvements.

Aim Our study aimed to establish a nomogram to predict the cancer-specific surviva (CSS) of patients with Glioma. Patients and methods Patients diagnosed with glioma between 2004 and 2016 were collected from the SEER database. On the basis of the logistic regression model, the nomogram was established, the C-index was used to evaluate the accuracy of the nomogram, and the Decision Curve Analysis was used to evaluate the clinical use of the nomogram. Results 2626 eligible patients were randomly divided into training group (n=1864) and verification group (n=762). Nomogram had better discrimination ability, the C index of the training cohort was 0.74, and the C index of the verification cohort was 0.736. This new predictive model has shown better discriminative ability and greater benefits in both training and validation cohorts to predict CSS in patients with Glioma.Conclusion A nomogram was constructed to predict the CSS of Glioma patients at 1, 3, and 5 years. The verification showed that the nomogram had better discrimination and calibration ability, indicating that the nomogram can be used to predict the CSS of Glioma patients and guide the treatment of Glioma patients.

Social cooperation is fundamentally important for group animals but rarely studied with mice because of their natural aggressiveness. In the present work, we induced pairs of mice to develop a mutualistic cooperative behavior in a non-divided chamber. Each mouse was first trained to learn to use a water dispenser by occupying a particular zone served as a switch to the dispenser. Two trained mice were then put into a chamber containing two separate zones jointly controlling two dispensers. We recorded the latency before each co-drinking, the number and cumulated time of co-drinking each day during the test. These parameters served as quantitative measurements of cooperative behavior in mice. The whole procedure includes preparation, training and testing phases, which take 15 days in total. This assay provides detailed procedures and analytical methods for investigators to characterize and quantify the mutualistic cooperative behavior. The use of mice as subjects allows convenient coupling to other behavior assays and is amiable to genetic manipulations for mechanistic study.

The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

The absolute electron capture cross sections for single and double charge exchanges between the highly charged ions O6+ and CO2, CH4, H2, N2, the dominant collision processes in the solar wind, have been measured in the energy from 7 keV*q (2.63 keV/u) to 52 keV*q (19.5 keV/u). These measurements were carried out in the new experimental instrument set up at Fudan University, and the error of cross sections for single and double charge exchanges at the 1{\sigma} confidence level are about 11% and 16%, respectively. Limited agreement is achieved with single electron capture results calculated by the classical over-barrier model. These cross sections data are useful for simulation ion-neutral processes in astrophysical environments and to improve the present theoretical model of fundamental atomic processes., Comment: 9 pages, 4 pages

In this paper, we present the physics performance of the ESSnuSB experiment in the standard three flavor scenario using the updated neutrino flux calculated specifically for the ESSnuSB configuration and updated migration matrices for the far detector. Taking conservative systematic uncertainties corresponding to a normalization error of $5\%$ for signal and $10\%$ for background, we find that there is $10\sigma$ $(13\sigma)$ CP violation discovery sensitivity for the baseline option of 540 km (360 km) at $\delta_{\rm CP} = \pm 90^\circ$. The corresponding fraction of $\delta_{\rm CP}$ for which CP violation can be discovered at more than $5 \sigma$ is $70\%$. Regarding CP precision measurements, the $1\sigma$ error associated with $\delta_{\rm CP} = 0^\circ$ is around $5^\circ$ and with $\delta_{\rm CP} = -90^\circ$ is around $14^\circ$ $(7^\circ)$ for the baseline option of 540 km (360 km). For hierarchy sensitivity, one can have $3\sigma$ sensitivity for 540 km baseline except $\delta_{\rm CP} = \pm 90^\circ$ and $5\sigma$ sensitivity for 360 km baseline for all values of $\delta_{\rm CP}$. The octant of $\theta_{23}$ can be determined at $3 \sigma$ for the values of: $\theta_{23} > 51^\circ$ ($\theta_{23} < 42^\circ$ and $\theta_{23} > 49^\circ$) for baseline of 540 km (360 km). Regarding measurement precision of the atmospheric mixing parameters, the allowed values at $3 \sigma$ are: $40^\circ < \theta_{23} < 52^\circ$ ($42^\circ < \theta_{23} < 51.5^\circ$) and $2.485 \times 10^{-3}$ eV$^2 < \Delta m^2_{31} < 2.545 \times 10^{-3}$ eV$^2$ ($2.49 \times 10^{-3}$ eV$^2 < \Delta m^2_{31} < 2.54 \times 10^{-3}$ eV$^2$) for the baseline of 540 km (360 km)., Comment: 13 pages, 8 figures, 3 tables. Changes: Text updated, this is a published version

Artificial Neural networks-based geometric shaping is proposed that includes Gray-like mappings. Over 0.2dB gain in GMI and BER improvement is achieved over a wide range of SNRs without requiring any presumed model for the channel.

Contains fulltext : 237518.pdf (Publisher’s version ) (Open Access) Mobile service innovation has gained much interest from governments, businesses, and researchers. The long-term success of mobile service innovations depends nowadays more and more on whether these service innovations allow consumers to co-create and experience value-in-use, and with this idea in mind innovators continue to design and redesign their complex service offerings. To support service innovators in improving their offerings, the overall research aim in this dissertation has been to answer the question: How do consumers co-create and experience value-in-use in mobile service constellations? I have addressed this question by conducting three studies: one systematic literature review and two empirical investigations, a qualitative and a quantitative one. First, the systematic literature review was conducted to obtain an in-depth overview of the value-in-use literature, and interpret insights from that literature for a contemporary service context (Chapter 2). Second, because social network platforms have been identified as important bases and facilitators of value-in-use co-creation in the digital economy, in the second study we aimed to develop a better understanding of 1) how value-in-use is co-created and experienced in practice, especially in complex mobile social network-based services 2) what roles social value and social capital play in the co-creation and experience of value-in-use on a social network-based mobile service platform and 3) which role complementarity among services plays in these processes (Chapter 3). Ultimately, while consumers expect convenient, enjoyable and seamless service experiences anywhere and anytime, many researchers consider value-in-use creation in mobile services to be dependent on the usage context. Therefore, an investigation into the role of the context in the value-in-use co-creation process was also conducted (Chapter 4). These analyses have been conducted using various methods (e.g., a systematic literature review, focus groups, and a field experiment). Radboud University, 12 oktober 2021 Promotores : Bloemer, J.M.M., Riel, A.C.R. van 152 p.

Toxic aggregated amyloid-β accumulation is a key pathogenic event in Alzheimer's disease (AD), which derives from amyloid precursor protein (APP) through sequential cleavage by BACE1 (β-site APP cleavage enzyme 1) and γ-secretase. Small interfering RNAs (siRNAs) show great promise for AD therapy by specific silencing of BACE1. However, lack of effective siRNA brain delivery approaches limits this strategy. Here, we developed a glycosylated "triple-interaction" stabilized polymeric siRNA nanomedicine (Gal-NP@siRNA) to target BACE1 in APP/PS1 transgenic AD mouse model. Gal-NP@siRNA exhibits superior blood stability and can efficiently penetrate the blood-brain barrier (BBB) via glycemia-controlled glucose transporter-1 (Glut1)-mediated transport, thereby ensuring that siRNAs decrease BACE1 expression and modify relative pathways. Noticeably, Gal-NP@siBACE1 administration restored the deterioration of cognitive capacity in AD mice without notable side effects. This "Trojan horse" strategy supports the utility of RNA interference therapy in neurodegenerative diseases.