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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Provenance of Upper Jurassic in North Yellow Sea Basin， Eastern North China Craton

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Journal of Earth Science 2024年

作者： Haitian Yu Zhongjie Xu Rihui Cheng Duo Wan Dan Gao Zhen Zhang College of Earth Sciences， Jilin University 2. Key Laboratory of Mineral Resources Evaluation in Northeast asia， Ministry of Natural Resources College of Palaeontology， Shenyang Normal University Guangzhou Marine geological Survey

Base on the detrital zircon U-Pb dating data， this paper discusses the provenance and constructs source-to-sink system of the Upper Jurassic in the North Yellow Sea Basin (NYSB)， Eastern North China Craton (ENCC). In addition， to avoid the bias of detrital zircon ages caused by variations in zircon fertility， we gather 1709 whole rock zirconium content values (ppm) from granitic rocks with different ages in the North China Craton (NCC). Base on mean Zr content of granitic rocks in each age， these granitic rocks can be divided into four groups: Group A consists of Jurassic， Group B consists of Paleozoic， Neo-Mesoproterozoic and Neoarchean， Group C consists of Early Cretaceous and Triassic， and Group D consists of Paleoproterozoic. This research assigns these groups zircon fertility factors (ZFF) of 1， 1.4， 1.8 and 2.2. The U-Pb age of detrital zircons from Late Jurassic sediments corrected by ZFF are statistically analyzed (K-S test， Similarity， Cross-correlation， Linkeness， Multidimensional scaling). And combining with palaeocurrent and palaeogeography， we construct two source-to-sink systems: 1) Jiaodong Uplift and Sulu Orogenic belt as the source area and the North Yellow Sea Basin as the sink area; 2) Liaodong Peninsula as the source area and the North Yellow Sea Basin as the sink area.

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Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4028-4044页

作者： Chris Chun-Yiu Chan Qian Guo Jasper Fuk-Woo Chan Kaiming Tang Jian-Piao Cai Kenn Ka-Heng Chik Yixin Huang Mei Dai Bo Qin Chon Phin Ong Allen Wing-Ho Chu Wan-Mui Chan Jonathan Daniel Ip Lei Wen Jessica Oi-Ling Tsang Tong-Yun Wang Yubin Xie Zhenzhi Qin Jianli Cao Zi-Wei Ye Hin Chu Kelvin Kai-Wang To Xing-Yi ge Tao Ni Dong-Yan Jin Sheng Cui Kwok-Yung Yuen Shuofeng Yuan State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for InfectionDepartment of MicrobiologySchool of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China Department of Infectious Diseases and Microbiology the University of Hong Kong-Shenzhen HospitalShenzhen 518000China Centre for Virology Vaccinology and TherapeuticsHong Kong Science and Technology ParkHong Kong SAR 999077China Academician Workstation of Hainan Province Hainan Medical University-the University of Hong Kong Joint Laboratory of Tropical Infectious DiseasesHaikou 571100China School of Biomedical Sciences Li Ka Shing Faculty of Medicinethe University of Hong KongPokfulamHong Kong SAR 999077China NHC Key Laboratory of systems Biology of Pathogens Institute of Pathogen Biology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China College of Biology Hunan Provincial Key Laboratory of Medical VirologyHunan UniversityChangsha 410082China

There are only eight approved small molecule antiviral drugs for treating *** them,four are nucleotide analogues(remdesivir,JT001,molnupiravir,and azvudine),while the other four are protease inhibitors(nirmatrelvir,ensitrelvir,leritrelvir,and simnotrelvir-ritonavir).Antiviral resistance,unfavourable drug‒drug interaction,and toxicity have been reported in previous *** there is a dearth of new treatment options for *** this work,a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 *** compound,designated 172,demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of *** studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease(3CLpro)by binding to an allosteric site and reduces 3CLpro dimerization.A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in *** vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 ***,this study identified an alternative druggable site on the SARS-CoV-23CLpro,proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases.

关键词： SARS-CoV-2 High throughput screening Broad-spectrum antiviral treatment 3CLpro inhibitor Allosteric-site inhibitor Animal models Chemical genetics Reverse genetics

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3D coarse-grained DPM simulation of the MIP reaction-regeneration loop

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Particuology 2024年第6期89卷 57-66页

作者： Yanhao Ye Shuai Zhang Ji Xu Wei ge State Key Laboratory of Mesoscience and Engineering(formerly State Key Laboratory of Multiphase Complex systems) Institute of Process EngineeringChinese Academy of SciencesBeijing100190China School of Chemical Engineering University of Chinese Academy of SciencesBeijing100049China

The reactor-regenerator loop is the core facility of the maximizing iso-paraffin(MIP)*** the discrete particle method(DPM)simulation can provide detailed information at the particle scale,it has been unable to simulate such a complex loop system due to limitations of coarse-grained(CG)models,computing software,and *** this study,a newly proposed soft-shell CG-DPM model with a CG ratio of up to 800 is used to simulate a 3.5 Mt/a industrial-scale MIP reactor-regenerator *** solid fraction distribution obtained is found to agree well with in-situ *** properties including the distribution of solid fraction,gas and solid velocity,standard derivation of solid fraction with time,temporal distribution of the flow field,and particle residence time distribution are measured in the simulation,which are meaningful to better design and operate such systems in the future.

关键词： Discrete particle method Coarse-grain Maximizing iso-paraffins Full-loop Reaction-regeneration system

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Dietary supplementation with calcitriol or quercetin improved eggshell and bone quality by modulating calcium metabolism

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Animal Nutrition 2024年第3期18卷 340-355页

作者： Yu Fu Jianmin Zhou Martine SchroyenJing Lin Haijun Zhang Shugeng Wu Guanghai Qi Jing Wang Key Laboratory of Feed Biotechnology Laboratory of Quality&Safety Risk Assessment for Animal Products on Feed Hazards(Beijing)Ministry of Agriculture and Rural AffairsInstitute of Feed ResearchChinese Academy of Agricultural SciencesBeijing 100081China Precision Livestock and Nutrition Laboratory TERRA Teaching and Research CentreGembloux Agro-Bio TechUniversity of LiègeB-5030 GemblouxBelgium

This study was aimed to investigate the effects of dietary calcitriol or quercetin supplementation on eggshell and bone quality of laying *** trial 1,72 Hy-Line Brown layers(80-week-old)with weak-shelled strength(25 to 30 N)were assigned into 4 dietary treatments with 6 replicates of 3 birds and fed a basal diet(4%calcium level)or basal diets supplemented with 0.5%calcium,5μg/kg calcitriol or 500 mg/kg quercetin for 4 *** trial 2,360 Hy-Line Brown layers(60-week-old)were divided into 3 groups with 8 replicates of 15 birds:control group(basal diet),calcitriol group(basal diet+5μg/kg calcitriol),and quercetin group(basal diet+500 mg/kg quercetin).This trial lasted for 12 *** results showed that dietary calcitriol or quercetin improved eggshell quality in both trials(Pgen receptor alpha(ERα)at 18.5 h PO(P<0.05),but down-regulated the uterine caspase 3(CASP3)relative mRNA expression level at 8.5 h PO(P<0.05).Meanwhile,the femoral relative mRNA expression levels of tartrate-resistant acid phosphatase(TRAP)(up-regulated at 8.5 and 18.5 h PO)and alkaline phosphatase(ALP)(up-regulated at 8.5 h PO but down-regulated at 18.5 h PO)were also affected by calcitriol or quercetin supplementation(P<0.05).Compared to the calcitriol,quercetin increased hen-day egg production and femoral medullary bone volume/bone tissue volume but reduced femoral stiffness(P<0.05),which were accompanied by increased relative mRNA expression levels

关键词： Uterine calcium transport Bone remodeling Eggshell quality Bone quality Calcitriol Quercetin

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Energy budget of cold and hot gas-solid fluidized beds through CFD-DEM simulations

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Particuology 2024年第6期89卷 153-171页

作者： Lei Bi Yunpeng Jiao Chunjiang Liu Jianhua Chen Wei ge School of Chemical Engineering and Technology Tianjin UniversityTianjin 300072China State Key Laboratory of Multiphase Complex systems Institute of Process EngineeringChinese Academy of SciencesBeijing100190China School of Chemical Engineering University of Chinese Academy of SciencesBeijing 100049China

Direct energy budget is carried out for both cold and hot flow in gas–solid fluidization ***,the energy paths are proposed from thermodynamic *** consumption means total power input to the specific system,and it can be decomposed into energy retention and energy *** retention is the variation of accumulated mechanical energy in the system,and energy dissipation is the energy converted to heat by irreversible *** based on the Computational Fluid Dynamics-Discrete Element Method(CFD-DEM)framework,different energy terms are quantified from the specific flow elements of fluid cells and particles as well as their interactions with the *** order to clarify the energy budget,it is important to identify which system is studied:the particle-fluid system or the particle *** the cold flow,the total energy consumption of the particle sub-system can well indicate the onset of bubbling and turbulent,while the variation of local energy consumption terms can reflect the evolution of heterogeneous *** the hot flow,different heat transfer mechanisms are analyzed and the solver is modified to reproduce the experimental *** impact of the heat transfer mechanisms and heat production on energy consumption is also *** proposed budget method has proven to be energy-conservative and easy to conduct,and it is hopeful to be applied to other multiphase flow systems.

关键词： Energy budget Gas-solid fluidization CFD-DEM Regime transition Heat transfer mechanism

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Soft coarse-grained particle model for particle-fluid systems

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Particuology 2024年第1期84卷 178-193页

作者： Yanhao Ye Ji Xu Wei ge State Key Laboratory of Multiphase Complex systems Institute of Process EngineeringChinese Academy of SciencesBeijing100190China School of Chemical Engineering University of Chinese Academy of SciencesBeijing100049China Innovation Academy for Green Manufacture Chinese Academy of SciencesBeijing100190China

By modeling a group of neighboring real particles as a single coarse-grained particle(CGP),discrete particle method(DPM)is now capable of simulating industrial-scale particle-fluid ***,a systematic approach to determine the CGP properties and develop their interaction models is still lacking,which casts uncertainty on the predictivity of the *** this study,collisions between predefined particle groups are analyzed to construct kernel functions for modeling the CGPs and then the model parameters are determined by equating the statistical properties of the CGPs and the real particles in the physical process *** approach is implemented for homogeneous cooling of granular gas,then demonstrated effective in simulating experimental fluidized beds.

关键词： Coarse-grain(CG) Discrete particle method(DPM) Fluidized bed Multi-scale simulation

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Theoretical study on the stability of nanobubbles and its verification in molecular dynamics simulation

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Particuology 2024年第4期87卷 99-105页

作者： Sheng Mi Chaofeng Hou Wei ge School of Chemical Engineering and Technology Tianjin UniversityTianjin300072China State Key Laboratory of Multiphase Complex systems Institute of Process EngineeringChinese Academy of SciencesBeijing.100190China School of Chemical Engineering University of Chinese Academy of SciencesBeijing100049China

The stability of vapor nanobubbles in bulk liquid was investigated theoretically and the critical bubble size was derived from macroscale thermodynamic equations,below which the system destabilizes with sharp drop in *** critical size was quantitatively verified in molecular dynamic simulation using the Lennard-Jones model of argon,where stronger attraction between the molecules at lower density is found to contribute most to the drop of system pressure and,as the Laplace pressure on the curved bubble interface fails to balance the pressure difference across the interface,the bubbles become *** theoretical model could be extended to other systems where reliable equations of state and interfacial tension are available.

关键词： Nanobubble Stability Phase diagram Critical size

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Health systems perspectives - infectious diseases of poverty

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Infectious Diseases of Poverty 2012年第1期1卷 107-109页

作者： Dale Huntington asia Pacific Observatory on Health systems and Policies WHO/WPROManilaPhilippines

The right to health as a fundamental human right is enshrined in the World Health Organization’s charter and has been reaffirmed in international agreements spanning *** new journal reminds us of the essential characteristic of poverty as a violent abuse of human *** context of poverty–its social,political and economic dimensions–remain in the reader’s mind as evidence is provided on technical solutions to managing the infectious diseases that afflict poor populations *** a health systems framework to a discussion on infectious diseases of poverty emerges from the papers in this journal’s first *** of the articles discuss treatments,indicating the importance of pharmaceuticals for neglected *** strategies to reach impoverished populations also figure within this first round of *** programs that provide diagnostics and treatment for infectious diseases to hard-to-reach rural and urban communities are needed clearly needed,and some good examples are discussed *** editions will explore other health system components,broadening the evidence base to increase understanding of effective and sustainable interventions to reduce the burden of infectious disease among the *** editors are to be congratulated on the release of this inaugural issue of the journal Infectious Diseases of *** look forward to reading subsequent editions.

关键词： journal poverty neglected

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Influence of transversal vibration on cutting performance and surface integrity during ultrasonic peening drilling of Al-Li alloys

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Chinese Journal of Aeronautics 2024年第10期37卷 493-507页

作者： Zhefei SUN Daxi geNG Hailin GUO Ende ge Entao ZHOU Zhilei FAN Fanxing MENG Xinggang JIANG Deyuan ZHANG School of Mechanical Engineering and Automation Beihang UniversityBeijing 100191China Institute of Bionic and Micro-Nano systems Beihang UniversityBeijing 100191China Inner Mongolia Metal Material Research Institute Ningbo 315103China Shanghai Aircraft Manufacturing Factory Commercial Aircraft Corporation of ChinaShanghai 201324China

Advanced hole-making process is of great importance to enhance the fatigue performance of Al-Li alloy part in aviation *** peening drilling(UPD),in which an ultrasonic transversal vibration is applied to the cutting tools,is a recently proposed hole-making method that integrates precision-machining and surface strengthening by single-shot *** the study,kinematics,material removal mechanism and strengthening mechanism for UPD of Al-Li alloy by helical fluted reamers are *** effect of transversal vibration on the cutting performance and surface integrity is studied through comparative experiments between UPD and conventional drilling(CD)of Al-Li alloy *** experimental results show that UPD exhibits superior cutting performance with a maximum reduction of 52.6%in thrust force and 52.3%in torque,respectively,compared to ***,narrower dimensional tolerance is obtained in UPD due to the reduced transversal force and improved machining ***,deeper plastic deformation,higher surface microhardness and residual compressive stress of machined holes are obtained by *** electron back-scattered diffraction(EBSD)analysis confirms that deeper machined affect area and grain refinement are realized in ***,the results indicate that UPD is a feasible method for achieving high-precision and strengthened holes for Al-Li alloy.

关键词： Al-Li alloy Ultrasonic transversal vibration Cutting tools Strengthening mechanism Surface integrity

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