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Virtual screening and optimization of typeⅡ inhibitors of JAK2 from a natural product library

中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： Dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of JAK2 using the DOLPHIN protocol.METHODS Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of JAK2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in silico.The novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for JAK2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral activity.RESULTS The top eleven highest-scoring compounds were generated from the initial high-throughput virtual screening.Amentoflavone 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological evaluation.In dose-response experiments,amentoflavone 1ainhibited JAK2 activity in a concentration dependent fashion with an IC50 value of 5μmol·L-1.As a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of 1a.The octyl(C8)analogue 1bdisplayed superior potency against JAK2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this study.Moreover,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of JAK2.CONCLUSION Amentoflavone 1ahas been identified as a JAK2 inhibitor by structure-based virtual screening of a natural product library.In silico optimization using the DOLPHIN model yielded analogues with enhanced potency against JAK2 activity and HCV activity in cellulo.Molecular modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of JAK2.

关键词： JAK2 natural products virtual screening structure-

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Meshing stiffness property and meshing status simulation of harmonic drive under transmission loading

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Frontiers of Mechanical Engineering 2022年第2期17卷 145-163页

作者： Xiaoxia CHEN Yunpeng YAO jingzhong XING School of Mechanical Engineering Tiangong UniversityTianjin 300387China Tianjin Key Laboratory of Modern Mechatronics Equipment Technology Tiangong UniversityTianjin 300387China

The multitooth meshing state of harmonic drive (HD) is an important basic characteristic of its high transformation precision and high bearing capacity. Meshing force distribution affects the load sharing of the tooth during meshing, and theoretical research remains insufficient at present. To calculate the spatial distributed meshing forces and loading backlashes along the axial direction, an iterative algorithm and finite element model (FEM) is proposed to investigate the meshing state under varied transmission loading. The displacement formulae of meshing point under tangential force are derived according to the torsion of the flexspline cylinder and the bending of the tooth. Based on the relationship of meshing forces and circumferential displacements, meshing forces and loading backlashes in three cross-sections are calculated with the algorithm under gradually increased rotation angles of circular spline, and the results are compared with FEM. Owing to the taper deformation of the cup-shaped flexspline, the smallest initial backlash and the earliest meshing point appear in the front cross-section far from the cup bottom, and then the teeth in the middle cross-section of the tooth rim enter the meshing and carry most of the loading. Theoretical and numerical research show that the flexibility is quite different for varied meshing points and tangential force amplitude because of the change of contact status between the flexspline and the wave generator. The meshing forces and torsional stiffness of the HD are nonlinear with the torsional angle.

关键词： harmonic drive meshing flexibility matrix meshing force loading backlash flexspline contact analysis

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Adaptive forgetting factor OS-ELM and bootstrap for time series prediction

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International Journal of Modeling, Simulation, and Scientific Computing 2017年第3期8卷 159-177页

作者： jingzhong Liu Hunan Institute of Technology School of MathematicsPhysics and Energy Engineering Hunan Hengyang 421101P.R.China

Online sequential extreme learning machine(OS-ELM)for single-hidden layer feedforward networks(SLFNs)is an effective machine learning algorithm.But OS-ELM has some underlying weaknesses of neglecting time series timeliness and being incapable to provide quantitative uncertainty for prediction.To overcome these shortcomings,a time series prediction method is presented based on the combination of OS-ELM with adaptive forgetting factor(AFF-OS-ELM)and bootstrap(B-AFF-OS-ELM).Firstly,adaptive forgetting factor is added into OS-ELM for adjusting the effective window length of training data during OS-ELM sequential learning phase.Secondly,the current bootstrap is developed to fit time series prediction online.Then associated with improved bootstrap,the proposed method can compute prediction interval as uncertainty information,meanwhile the improved bootstrap enhances prediction accuracy and stability of AFF-OS-ELM.Performances of B-AFF-OS-ELM are benchmarked with other traditional and improved OS-ELM on simulation and practical time series data.Results indicate the significant performances achieved by B-AFF-OS-ELM.

关键词： Online sequential extreme learning machine(OS-ELM) l2-regularization forecasting uncertainty prediction interval ensemble chaotic time series neural networks

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Tumor cell membrane-camouflaged responsive nanoparticles enable MRI-guided immuno-chemodynamic therapy of orthotopic osteosarcoma

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Bioactive Materials 2022年第11期7卷 221-233页

作者： Liwen Fu Weiying Zhang Xiaojun Zhou jingzhong Fu Chuanglong He State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of ChemistryChemical Engineering and BiotechnologyDonghua UniversityShanghai201620China Department of Thoracic Oncology Jiujiang Cancer HospitalJiangxi ProvinceChina Health Management Center Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinan250021China

Osteosarcoma is a refractory bone disease in young people that needs the updating and development of effective treatment.Although nanotechnology is widely applied in cancer therapy,poor targeting and inadequate effi-ciency hinder its development.In this study,we prepared alendronate(ALD)/K7M2 cell membranes-coated hollow manganese dioxide(HMnO_(2))nanoparticles as a nanocarrier to load Ginsenoside Rh2(Rh2)for Mag-netic Resonance imaging(MRI)-guided immuno-chemodynamic combination osteosarcoma therapy.Subse-quently,the ALD and K7M2 cell membranes were successively modified on the surface of HMnO_(2) and loaded with Rh2.The tumor microenvironment(TME)-activated Rh2@HMnO_(2)-AM nanoparticles have good bone tumor-targeting and tumor-homing capabilities,excellent GSH-sensitive drug release profile and MRI capability,and attractive immuno-chemodynamic combined therapeutic efficiency.The Rh2@HMnO_(2)-AM nanoparticles can effectively trigger immunogenic cell death(ICD),activate CD4^(+)/CD8^(+)T cells in vivo,and upregulate BAX,BCL-2 and Caspase-3 in cellular level.Further results revealed that Rh2@HMnO_(2)-AM enhanced the secretion of IL-6,IFN-γand TNF-αin serum and inhibited the generation of FOXP3^(+)T cells(Tregs)in tumors.Moreover,the Rh2@HMnO_(2)-AM treatment significant restricted tumor growth in-situ tumor-bearing mice.Therefore,Rh2@HMnO_(2)-AM may serve as an effective and bio-friendly nanoparticle platform combined with immuno-therapy and chemodynamic therapy to provide a novel approach to osteosarcoma therapy.

关键词： Ginsenoside Rh2 Hollow manganese dioxide Magnetic resonance imaging Chemodynamic therapy Immunotherapy

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Fault detection for a class of linear systems with integral measurements

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Science China(Information Sciences) 2021年第3期64卷 207-216页

作者： Xiaoqiang ZHU Yang LIU jingzhong FANG Maiying ZHONG College of Electrical Engineering and Automation Shandong University of Science and Technology

This paper discusses the parity space-based fault detection(FD) method for a class of linear discrete-time systems with integral measurements. The integral measurements are functions of the system states over a given time window. We establish a novel parity relation to tackle integral measurements. The parameters of the FD unit are redesigned such that the generated residual signal is simultaneously decoupled from initial states, robust against disturbances, and sensitive to the faults. We employ the singular value decomposition algorithm to calculate parity space matrices. Finally, an experiment is presented to show the effectiveness of the proposed method.

关键词： fault detection linear discrete-time systems integral measurements parity space optimization problem

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Multi-source Data-driven Identification of Urban Functional Areas:A Case of Shenyang,China

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Chinese Geographical Science 2023年第1期33卷 21-35页

作者： XUE Bing XIAO Xiao LI jingzhong ZHAO Bingyu FU Bo Institute of Applied Ecology Chinese Academy of SciencesShenyang 110016China Key Lab for Environmental Computation and Sustainability of Liaoning Province Shenyang 110016China University of Chinese Academy of Sciences Beijing 100049China College of Urban Planning and Architecture Xuchang UniversityXuchang 461000China

Urban functional area(UFA)is a core scientific issue affecting urban sustainability.The current knowledge gap is mainly reflected in the lack of multi-scale quantitative interpretation methods from the perspective of human-land interaction.In this paper,based on multi-source big data include 250 m×250 m resolution cell phone data,1.81×105 Points of Interest(POI)data and administrative boundary data,we built a UFA identification method and demonstrated empirically in Shenyang City,China.We argue that the method we built can effectively identify multi-scale multi-type UFAs based on human activity and further reveal the spatial correlation between urban facilities and human activity.The empirical study suggests that the employment functional zones in Shenyang City are more concentrated in central cities than other single functional zones.There are more mix functional areas in the central city areas,while the planned industrial new cities need to develop comprehensive functions in Shenyang.UFAs have scale effects and human-land interaction patterns.We suggest that city decision makers should apply multi-sources big data to measure urban functional service in a more refined manner from a supply-demand perspective.

关键词： human-land relationship multi-source big data urban functional area identification method Shenyang City

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A raster-based typification method for multiscale visualization of building features considering distribution patterns

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International Journal of Digital Earth 2022年第1期15卷 249-275页

作者： Yilang Shen jingzhong Li Ziqi Wang Rong Zhao Lu Wang Institute of Geodesy and Geoinformation University of BonnBonnGermany School of Resource and Environment Sciences Wuhan UniversityWuhanPeople’s Republic of China Department of Computer Science and Technology Nanjing UniversityNanjingPeople’s Republic of China Wanke School of Public Health Tsinghua UniversityBeijingPeople’s Republic of China

In map multiscale visualization,typification is the process of replacing original objects,such as buildings,using a smaller number of objects while maintaining initial geometrical and distribution characteristics.During the past few decades,many vector-based methods for building typification have been developed,whereas raster-based methods have received less attention.In this paper,a new method for the typification of buildings with different distribution patterns called superpixel building typification(SUBT)is developed based on raster data.Using this method,buildings with different distribution patterns,such as linear,grid and irregular patterns,are first grouped by image connected component detection and superpixel analysis.Then,the new positions for building typification are determined by superpixel resegmentation.Finally,a new representation of the buildings is determined through analysis of the orientation and shape of the buildings in each superpixel.To test the proposed SUBT method,buildings from both cities and countrysides in China are applied to perform typification.The experimental results show that the proposed SUBT method can realize typification for buildings with linear,grid and irregular distributions while effectively maintaining the original distribution characteristics of the buildings.

关键词： Building visualization building distribution pattern superpixel segmentation map generalization

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Tooth Position and Deformation of Flexspline Assembled with Cam in Harmonic Drive Based on Force Analysis

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Chinese Journal of Mechanical Engineering 2021年第6期34卷 385-404页

作者： Yunpeng Yao Xiaoxia Chen jingzhong Xing Liteng Shi Yuqi Wang School of Mechanical Engineering Tiangong UniversityTianjin300387China Tianjin City Key Lab of Modern Mechatronics Equipment Technology Tianjin300387China

Deformation of the flexspline is the basis of analyzing tooth trajectory and designing tooth profile.Considering the tooth influence on the position of equivalent neutral layer,a piecewise method for calculating the deformation of flexspline assembled with a cam wave generator is presented in this paper.Firstly,a mechanic model of a ring of uniform thickness in contact with a rigid cam is established.The displacements of the ring inside and outside an unknown wrapping angle are determined by the geometric constraints of the cam profile and the equilibrium rela-tionship,respectively.Meanwhile,the wrapping angle is solved according to the boundary conditions.The assembly forces are derived to investigate the circumferential elongation and strain.Then,considering the tooth effects on the neutral layer of flexspline,the tooth is positioned on the equivalent neutral layer,which is the non-elongation layer within one gear pitch but offset from the geometric mid-layer.The equivalent neutral layer is positioned by the empirical formula of the offset ratio,which is summarized by the orthogonal simulation on finite element models of racks.Finally,finite element models of a ring-shaped and a cup-shaped flexspline assembled with elliptical cam are established to verify the effectiveness and accuracy of the piecewise method.The results show that,compared with the geometric method,the tooth positioning deviation calculated by the piecewise method can be reduced by about 70%with a more accurate deformation description from the geometric condition and mechanic condition inside and outside the wrapping angle.

关键词： Harmonic drive Deformation calculation Cam wave generator Force analysis Equivalent neutral layer

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Identification method and empirical study of urban industrial spatial relationship based on POI big data: a case of Shenyang City, China

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Geography and Sustainability 2020年第2期1卷 152-162页

作者： Bing Xue Xiao Xiao jingzhong Li Key Lab of Pollution Ecology and Environmental Engineering Institute of Applied EcologyChinese Academy of SciencesShenyang 110016China Key Lab for Environmental Computation and Sustainability of Liaoning Province Shenyang 110016China University of Chinese Academy of Sciences Beijing 100049China College of Urban Planning and Architecture Xuchang UniversityXuchang 461000China

The industrial spatial relationship is a cross-cutting subject of economic geography and geographical information science which has considerable significance to promote a sustainable planning and development of regional economic system.Taking Shenyang City as our study area and using the location information of manufacturing units and automobile sales outlets extracted from points of interest(POI),we investigated the spatial relationship between the two industries from integration,correlation and coordination perspective.Based on spatial statistical analyses,the equipment manufacturing industry and the automobile sales industry in Shenyang City showed a spatial complementary integration,weak spatial correlation,and coordination with scale dependence and spatial heterogeneity in 2018.This distribution characteristic is attributed to:1)local policy factors(i.e.,that industrial land should be located in the periphery of the city or outside the Second Ring Road),and 2)the economic factors(i.e.,that the degree of dependence of the equipment manufacturing industry and automobile sales industry were also influenced by external factors such as costs).These results improved the current industrial spatial relationship analysis by developing a new framework based on POI big data in order to accelerate a coordinated development between manufacturing and service industries and to promote the construction of industrial ecosystem.

关键词： Human-land relationship POI Space organization Industrial ecology

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A REVIEW AND PROSPECT OF READABLE MACHINE PROOFS FOR GEOMETRY THEOREMS

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Journal of Systems Science & Complexity 2012年第4期25卷 802-820页

作者： Jianguo JIANG jingzhong ZHANG School of Mathematics Liaoning Normal University Laboratory of Computer Reasoning and Trustworthy Compution University of Electronic Science and Technology of China Chengdu Institute of Computer Applications Chinese Academy of Sciences

在半世纪研究以后，在几何学证明的机械定理在自动化推理领域里成为了一个活跃研究话题。这评论在为包括搜索方法，没有坐标的方法，和正式逻辑方法的几何学定理产生可读的机器证明自动化上包含三条途径。关于这些途径的一些关键问题也... 详细信息

在半世纪研究以后，在几何学证明的机械定理在自动化推理领域里成为了一个活跃研究话题。这评论在为包括搜索方法，没有坐标的方法，和正式逻辑方法的几何学定理产生可读的机器证明自动化上包含三条途径。关于这些途径的一些关键问题也被讨论。而且，作者为几何学定理为可读的机器证明建议三个进一步的研究方向，包括几何学不平等，聪明的几何学软件和机器学习。

关键词：定理机器证明几何定理展望几何自动推理几何不等式自动生成搜索方法形式逻辑

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