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A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

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Acta Pharmaceutica Sinica B 2024年第1期14卷 207-222页

作者： Hongrui Zhu Yamin Gao Liyun Liu Mengyu tao Xiao Lin Yijia Cheng Yaoyao Shen haitao xue Li Guan Huimin Zhao Li Liu Shuping Wang Fan Yang Yongjun Zhou Hongze Liao Fan Sun Houwen Lin Research Center for Marine Drugs Department of PharmacyRen Ji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Oncology Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Institute of Marine Drugs Guangxi University of Chinese MedicineNanning 530200China State Key Laboratory of New Drug and Pharmaceutical Process Shanghai Professional and Technical Ser-vice Center for Biological Material Drug-ability EvaluationShanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 200437China Institute of Marine Biomedicine Shenzhen PolytechnicShenzhen 518055China

Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

关键词： Colorectal cancer TNKSeUSP25 interaction Multi-drug resistance TNKS overexpression Wnt pathway Apoptosis Neoantimycin analog

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Developing a diagnostic model for predicting prostate cancer: a retrospective study based on Chinese multicenter clinical data

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Asian Journal of Andrology 2024年第1期26卷 34-40页

作者： Chang-Ming Wang Lei Yuan xue-Han Liu Shu-Qiu Chen hai-Feng Wang Qi-Fei Dong Bin Zhang Ming-Shuo Huang Zhi-Yong Zhang Jun Xiao tao tao Department of Urology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Radiology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Core Facility Center for Medical Sciences The First Affiliated Hospital of USTcDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Urology Affiliated Zhongda Hospital of Southeast UniversityNanjing 210009China Department of Urology Shanghai East HospitalTongji University School of MedicineShanghai 200120China Department of Urology Shanghai Changhai HospitalSecond Military Medical UniversityShanghai 200000China Department of Urology Affiliated Anhui Provincial Hospital of Anhui Medical UniversityHefei 230001China

The overdiagnosis of prostate cancer(PCa)caused by nonspecific elevation serum prostate-specific antigen(PSA)and the overtreatment of indolent PCa have become a global problem that needs to be solved urgently.We aimed to construct a prediction model and provide a risk stratification system to reduce unnecessary biopsies.In this retrospective study,clinical data of 1807 patients from three Chinese hospitals were used.The final model was built using stepwise logistic regression analysis.The apparent performance of the model was assessed by receiver operating characteristic curves,calibration plots,and decision curve analysis.Finally,a risk stratification system of clinically significant prostate cancer(csPCa)was created,and diagnosis-free survival analyses were performed.Following multivariable screening and evaluation of the diagnostic performances,a final diagnostic model comprised of the PSA density and Prostate Imaging-Reporting and Data System(PI-RADS)score was established.Model validation in the development cohort and two external cohorts showed excellent discrimination and calibration.Finally,we created a risk stratification system using risk thresholds of 0.05 and 0.60 as the cut-off values.The follow-up results indicated that the diagnosis-free survival rate for csPCa at 12 months and 24 months postoperatively was 99.7%and 99.4%,respectively,for patients with a risk threshold below O.05 after the initial negative prostate biopsy,which was significantly better than patients with higher risk.Our diagnostic model and risk stratification system can achieve a personalized risk calculation of csPCa.It provides a standardized tool for Chinese patients and physicians when considering thenecessity of prostatebiopsy.

关键词： nomogram prostate biopsy prostate cancer Prostate Imaging-Reporting and Data System prostate-specific antigen density

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Yemazhui(Herba Eupatorii Lindleyani)ameliorates lipopolysaccharide-induced acute lung injury via modulation of the toll-like receptor 4/nuclear factor kappa-B/nod-like receptor family pyrin domain-containing 3 protein signaling pathway and intestinal flor

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Journal of Traditional Chinese Medicine 2024年第2期44卷 303-314页

作者： REN Li hai Yang YANG xue LUO Xianqin Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases College of Traditional Chinese MedicineChongqing Medical UniversityChongqing 400016China College of Basic Medicine Chongqing Medical UniversityChongqing 400016China

OBJECTIVE:To investigate the impact of Yemazhui(Herba Eupatorii Lindleyani,HEL)against lipopolysaccharide(LPS)-induced acute lung injury(ALI)and explore its underlying mechanism in vivo.METHODS:The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatographyquadrupole time-of-flight mass spectrometry method.Then,HEL was found to suppress LPS-induced ALI in vivo.Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups:control,LPS,Dexamethasone(Dex),HEL low dose 6 g/kg(HEL-L),HEL medium dose 18 g/kg(HEL-M)and HEL high dose 54 g/kg(HEL-H)groups.The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model.Leukocyte counts,lung wet/dry weight ratio,as well as myeloperoxidase(MPO)activity were determined followed by the detection with hematoxylin and eosin staining,enzyme linked immunosorbent assay,quantitative real time polymerase chain reaction,western blotting,immunohistochemistry,and immunofluorescence.Besides,to explore the effect of HEL on ALI-mediated intestinal flora,we performed 16s rRNA sequencing analysis of intestinal contents.RESULTS:HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance.Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats,inhibited leukocytes exudation and MPO activity,and improved the pathological injury of lung tissue.In addition,HEL reduced the expression of tumor necrosis factoralpha,interleukin-1beta(IL-1β)and interleukin-6(IL-6)in bronchoalveolar lavage fluid and serum,and inhibited nuclear displacement of nuclear factor kappa-B p65(NF-κBp65).And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4(TLR4),myeloid differentiation factor 88,NF-κBp65,phosphorylated inhibitor kappa B alpha(phospho-IκBα),nod-like receptor family pyrin domain-containing 3 protein(NLRP3),IL-1β,and interleukin-18(IL-18)in lung tissue,and regulated intestinal flora disturbance.CONCLUSIONS:In summary,our findings revealed

关键词： Yemazhui(Herba Eupatorii Lindleyani) acute lung injury anti-inflammation toll-like receptor 4 nuclear factor kappa-B nod-like receptor family pyrin domain-containing 3 protein signal transduction gastrointestinal microbiome

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Study on theoretical model for electrical explosion resistivity of Al/Ni reactive multilayer foil

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Defence Technology（防务技术） 2024年第2期32卷 348-356页

作者： Zehao Wang tao Wang Pengfei xue Mingyu Li Qingxuan Zeng State Key Laboratory of Explosion Science and Technology Beijing Institute of TechnologyBeijing 100081China China Ship Development and Design Center Wuhan 430064China

Al/Ni reactive multilayer foil(RMF)possesses excellent comprehensive properties as a promising substitute for traditional Cu bridge.A theoretical resistivity model of Al/Ni RMF was developed to guide the optimization of EFIs.Al/Ni RMF with different bilayer thicknesses and bridge dimensions were prepared by MEMS technology and electrical explosion tests were carried out.According to physical and chemical reactions in bridge,the electrical explosion process was divided into 5 stages:heating of condensed bridge,vaporization and diffusion of Al layers,intermetallic combination reaction,intrinsic explosion,ionization of metal gases,which are obviously shown in measured voltage curve.Effects of interface and grain boundary scattering on the resistivity of film metal were considered.Focusing on variations of substance and state,the resistivity was developed as a function of temperature at each stage.Electrical explosion curves were calculated by this model at different bilayer thicknesses,bridge dimensions and capacitor voltages,which showed an excellent agreement with experimental ones.

关键词： Al/Ni reactive multilayer foil Electrical explosion Resistivity model Phase transition Calculation

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Increasing operational stability of journal bearing in hydraulic suspension micro-pump by herringbone grooved structure

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Science China(Technological Sciences) 2024年第3期67卷 853-862页

作者： HONG tao XING GuanYing ZUO HuaiYu xue Song LUO XiaoBing State Key Laboratory of Coal Combustion School of Energy and Power EngineeringHuazhong University of Science and TechnologyWuhan 430074China

The operational stability of radial journal bearings is the bottleneck that limits the reliability of hydraulic suspension micropump. Due to self-excited vibrations, the whirl amplitude of the plain journal bearing(PJB) is large at high rotational speeds,which will accelerate wear failure. It has been proven that employing herringbone grooved journal bearing(HGJB) is an effective method to reduce the whirl amplitude and improve operational stability. However, enhancing the stability of journal bearings in micro-pumps by herringbone grooved structures has rarely been studied, and its effect needs to be verified. We validated the mechanism of the stability improvement with the CFD method and compared the dynamic characteristics of HGJB and PJB by rotor dynamics evaluation and experiment. The experimental results show that under the same conditions the whirl amplitude of the HGJB decreases by 29.61% in the x direction and by 24.09% in the y direction compared with that of the PJB. This study reveals the effect of the herringbone grooved structure on the operational stability of bearings and may provide guidance for the reliability improvement of hydraulic suspension micro-pump.

关键词： journal bearing herringbone groove hydrodynamic effect micro-pump

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Media Power Measuring via Emotional Contagion

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Journal of Social Computing 2024年第1期5卷 15-35页

作者： xue Lin Hong Huang Zongya Li hai Jin National Engineering Research Center for Big Data Technology and System Services Computing Technology and System LabCluster and Grid Computing LabSchool of Computer Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China School of Journalism Huazhong University of Science and TechnologyWuhan 430074China

Media power,the impact that media have on public opinion and perspectives,plays a significant role in maintaining internal stability,exerting external influence,and shaping international dynamics for nations/regions.However,prior research has primarily concentrated on news content and reporting time,resulting in limitations in evaluating media power.To more accurately assess media power,we use news content,news reporting time,and news emotion simultaneously to explore the emotional contagion between media.We use emotional contagion to measure the mutual influence between media and regard the media with greater impact as having stronger media power.We propose a framework called Measuring Media Power via Emotional Contagion(MMPEC)to capture emotional contagion among media,enabling a more accurate assessment of media power at the media and national/regional levels.MMPEC also interprets experimental results through correlation and causality analyses,ensuring explainability.Case analyses confirm the higher accuracy of MMPEC compared to other baseline models,as demonstrated in the context of COVID-19-related news,yielding compelling and interesting insights.

关键词： explainability media power emotional contagion

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KLF4 Inhibits the Activation of Human Hepatic Stellate Cell In Vitro

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Current Medical Science 2024年第3期44卷 512-518页

作者： Xing-yu YANG Zhe CHEN Jun TAN Yin-kai xue hai ZHENG Department of Emergency Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Department of Thoracic Surgery The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an710061China Department of Thoracic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China

Objective Hepatic stellate cells(HSCs)play a crucial role in liver fibrosis.Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs.Kruppel-like factor 4(KLF4)plays a pivotal role in a wide array of physiological and pathological processes.This study aimed to investigate the effect of KLF4 on the proliferation,apoptosis and phenotype of quiescent HSCs Methods We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector,to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection.Cell proliferation was assessed using the CCK-8 assay.Flow cytometry was used to detect the cell cycle distribution and apoptosis rate.Western blotting was used to determine the levels of some quiescence and activation markers of HSCs Results Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1,which are quiescent HSC markers,while significantly decreased the levels of N-cadherin and a-SMA,known activated HSC markers.In contrast,cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced Conclusion KLF4 inhibits the proliferation and activation of human LX-2 HSCs.It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.

关键词： Kruppel-like factor 4 hepatic stellate cells LX-2 cells liver fibrosis

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High-throughput calculation-based rational design of Fe-doped MoS_(2) nanosheets for electrocatalytic p H-universal overall water splitting

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Journal of Energy Chemistry 2024年第4期91卷 194-202页

作者： Guangtong hai Xiangdong xue Zhenyu Wu Canyang Zhang Xin Liu Xiubing Huang Institute of Zhejiang University-Quzhou Zhejiang UniversityQuzhou 324000ZhejiangChina Beijing Key Laboratory of Membrane Materials and Engineering Department of Chemical EngineeringTsinghua UniversityBeijing 100084China Beijing Advanced Innovation Center for Materials Genome Engineering Beijing Key Laboratory of Function Materials for Molecule&Structure ConstructionSchool of Materials Science and EngineeringUniversity of Science and TechnologyBeijing 100083China CentreÉnergie Matériaux et Télécommunications(EMT) Institut national de la recherche scientifique(INRS)Varennes J3X1P7QuébecCanada

Electrocatalytic water splitting is crucial for H2generation via hydrogen evolution reaction(HER)but subject to the sluggish dynamics of oxygen evolution reaction(OER).In this work,single Fe atomdoped MoS_(2)nanosheets(SFe-DMNs)were prepared based on the high-throughput density functional theory(DFT)calculation screening.Due to the synergistic effect between Fe atom and MoS_(2)and optimized intermediate binding energy,the SFe-DMNs could deliver outstanding activity for both HER and OER.When assembled into a two-electrode electrolytic cell,the SFe-DMNs could achieve the current density of 50 mA cm^(-2)at a low cell voltage of 1.55 V under neutral condition.These results not only confirmed the effectiveness of high-throughput screening,but also revealed the excellent activity and thus the potential applications in fuel cells of SFe-DMNs.

关键词： High-throughput calculation Overall water splitting Single atom doped catalyst Molybdenum disulfide nanosheet

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Tailoring sulfur-doped and nitrogen-defective carbon nitride nanosheets for efficient photo-controlled radical polymerizations

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Science China Chemistry 2024年第7期67卷 2325-2334页

作者： xue Li Meng Kai Xu Yuan Huang tao Cai Key Laboratory of Biomedical Polymers of Ministry of Education College of Chemistry and Molecular SciencesWuhan UniversityWuhan 430072China Wuhan University Shenzhen Research Institute Shenzhen 518057China

Despite the challenges that remain,the synergistic adjustment of various microstructures and photochemical parameters of graphitic carbon nitride(g-C_(3)N_(4))in photocatalytic reactions holds promises for improving catalytic efficiency and reducing energy consumption.Herein,sulfur-doped and nitrogen-defective g-C_(3)N_(4)(n-SC_(3)N_(x))nanosheets were designed and elaborately synthesized.The resultant n-SC_(3)N_(x)possessed a precisely defined 2D layer structure with extensive porosity and incremental specific surface area.Enhanced photoinduced electron transfer-reversible addition-fragmentation chain transfer(PET-RAFT)polymerization of vinyl monomers with low dispersity,excellent temporal control and high chain-end fidelity was achieved under mild blue light irradiation in a nondegassed system.Owing to their ultrathin nanostructures with nitrogen defects and sulfur dopants,n-SC_(3)N_(x)was capable of catalyzing RAFT polymerization in aqueous solutions at significantly accelerated rates,which were nearly 8 times faster compared to bulk g-C_(3)N_(4).The ease of separation and efficient reusability in subsequent polymerizations was enabled by the heterogeneous nature of n-SC_(3)N_(x).The appeal of this approach was illustrated by the fact that utilizing a reusable and metal-free photocatalyst in aqueous environments allowed for the synthesis of polymers with molecular weight up to 300 kg mol-1and a dispersity of 1.32.

关键词： graphitic carbon nitride nitrogen defects sulfur dopants PET-RAFT polymerization recyclability

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Ballistic performance of additive manufacturing 316l stainless steel projectiles based on topology optimization method

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Defence Technology（防务技术） 2024年第5期35卷 1-17页

作者： Hao xue tao Wang Xinyu Cui Yifan Wang Guangyan Huang State Key Laboratory of Explosion Science and Technology Beijing Institute of TechnologyBeijing 100081China

Material and structure made by additive manufacturing(AM)have received much attention lately due to their flexibility and ability to customize complex structures.This study first implements multiple objective topology optimization simulations based on a projectile perforation model,and a new topologic projectile is obtained.Then two types of 316L stainless steel projectiles(the solid and the topology)are printed in a selective laser melt(SLM)machine to evaluate the penetration performance of the projectiles by the ballistic test.The experiment results show that the dimensionless specific kinetic energy value of topologic projectiles is higher than that of solid projectiles,indicating the better penetration ability of the topologic projectiles.Finally,microscopic studies(scanning electron microscope and X-ray micro-CT)are performed on the remaining projectiles to investigate the failure mechanism of the internal structure of the topologic projectiles.An explicit dynamics simulation was also performed,and the failure locations of the residual topologic projectiles were in good agreement with the experimental results,which can better guide the design of new projectiles combining AM and topology optimization in the future.

关键词： Additive manufacturing Topology optimization Ballistic performance Projectile design

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