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Tau in Alzheimer’s Disease:Pathological Alterations and an Attractive Therapeutic Target

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Current Medical Science 2020年第6期40卷 1009-1021页

作者： Jian-lan GU fei liu Department of Biochemistry and Molecular Biology School of MedicineNantong UniversityNantong 226001China Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu Co-innovation Center of NeuroregenerationNantong 226001China Department of Neurochemistry Inge Grundke-Iqbal Research FloorNew York State Institute for Basic Research in Developmental DisabilitiesStaten IslandNY 10314USA

Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

关键词： Alzheimer’s disease tau protein hyperphosphorylation propagation of tau pathology

Research progress in pathogenic genes of hereditary non-syndromic mid-frequency deafness

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Frontiers of Medicine 2016年第2期10卷 137-142页

作者： Wenjun Xia fei liu Duan Ma Institute of Biomedical Sciences Fudan University Shanghai 200023 China Key Laboratory of Metabolism and Molecular Medicine Ministry of Education Department of Biochemistry and Molecular Biology Institute of Biomedical Sciences School of Basic MedicalSciences Fudan University Shanghai 200023 China

Hearing impairment is considered as the most prevalent impairment worldwide. Almost 600 million people in the world suffer from mild or moderate hearing impairment, an estimated 10% of the human population. Genetic factors play an important role in the pathogenesis of this disorder. Hereditary hearing loss is divided into syndromic hearing loss （associated with other anomalies） and non-syndromic hearing loss （not associated with other anomalies）. Approximately 80% of genetic deafness is non-syndromic. On the basis of the frequency of hearing loss, hereditary non-syndromic hearing loss can be divided into high-, mid-, low-, and total-frequency hearing loss. An audiometric finding of mid-frequency sensorineural hearing loss, or a ＂bowl-shaped＂ audiogram, is uncommon. Up to now, merely 7 loci have been linked to mid-frequency hearing loss. Only four genetic mid- frequency deafness genes, namely, DFNA10 （EYA4）, DFNA8/12 （TECTA）, DFNA13 （COLIIA2）, DFNA44 （CCDC50）, have been reported to date. This review summarizes the research progress of the four genes to draw attention to mid-frequency deafness genes.

关键词： hereditary non-syndromic hearing loss mid-frequency hearing loss deafiaess genes

The Uniqueness of Knieper Measure on Non-compact Rank 1 Manifolds of Non-positive Curvature

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Acta Mathematica Sinica,English Series 2021年第8期37卷 1219-1228页

作者： fei liu Fang WANG College of Mathematics and Systems Science Shandong University of Science and TechnologyQingdao 266590P.R.China School of Mathematical Sciences Capital Normal UniversityBeijing 100048P.R.China

We study the Knieper measures of the geodesic flows on non-compact rank 1 manifolds of non-positive curvature.We construct the Busemann density on the ideal boundary,and prove that if there is a Knieper measure on T^(1)M with finite total mass,then the Knieper measure is unique,up to a scalar multiple.Our result partially extends Paulin-Pollicott-Shapira’s work on the uniqueness of finite Gibbs measure of geodesic flows on negatively curved non-compact manifolds to non-compact manifolds of non-positive curvature.

关键词： Geodesic flows Patterson-Sullivan measure Knieper measure

Experimental investigation on the movement mechanism of top coal in steeply inclined ultra-thick coal seams

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Acta Mechanica Sinica 2021年第4期37卷 631-648,I0003页

作者： Jiachen Wang fei liu Zhaohui Wang School of Energy and Mining Engineering China University of Mining&TechnologyBeijing 100083China Coal Industry Engineering Research Center of Top-Coal Caving Mining Beijing 100083China

The pre-blasting zones have a significant influence on the coal broken and the recovery rate of the top coal caving mining.This paper explores the coal movement mechanism in the top coal with pre-blasting zones based on the geological parameters of Jiangcang No.1 mine in the western of China.The steeply inclined ultra-thick coal seam was mined by using the sublevel top-coal caving mining method.The geo-image process system(GIPS)software was used to track the mark points on the coal and roof.The support was used to record the load on the top of the support during the caving mining process.The results show that the horizontal coal is moved to the shield window and the vertical coal is moved downward in the first level,while that in the second level shows consistency for the integrity of the coal.The vertical displacements of the corresponding points in the first level are lairger than that in the second level.However,the load on the top of the support in the first level is smaller than that in the second level.It indicated that the pre-blasting zones will give a more loosen top-coal and a small degree of difficulty in the top coal caving.

关键词： Sublevel Top coal caving Pre-blasting Physical modeling Movement mechanism

Entropy-expansiveness of Geodesic Flows on Closed Manifolds without Conjugate Points

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Acta Mathematica Sinica,English Series 2016年第4期32卷 507-520页

作者： fei liu Fang WANG College of Mathematics and System Science Shandong University of Science and Technology Qingdao 266590 P. R. China School of Mathematical Sciences Capital Normal University Beijing 100048 P. R. China Beijing Center for Mathematics and Information Interdisciplinary Sciences (BCMIIS) Beijing 100048 P. R. China

In this article,we consider the entropy-expansiveness of geodesic flows on closed Riemannian manifolds without conjugate points.We prove that,if the manifold has no focal points,or if the manifold is bounded asymptote,then the geodesic flow is entropy-expansive.Moreover,for the compact oriented surfaces without conjugate points,we prove that the geodesic flows are entropy-expansive.We also give an estimation of distance between two positively asymptotic geodesics of an uniform visibility manifold.

关键词： Entropy-expansiveness geodesic flows manifolds without conjugate points

Compositional colored Petri net approach to multiscale modeling for systems biology

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International Journal of Modeling, Simulation, and Scientific Computing 2014年第4期5卷 106-122页

作者： fei liu Ming Yang Control and Simulation Center Harbin Institute of Technology West Dazhi Street 92 HarbinHeilongjiangP.R.China

Colored Petri nets have been demonstrated as a powerful tool for modeling multiscale systems biology.However,the construction of colored Petri nets for biological systems requires prior knowledge about colored Petri nets and is often error-prone and cum-bersome for biologists,especially when the communication between components and hierarchical organization of components in a multiscale model are an issue.To address this problem,an established way is to develop small components and then compose them into bigger models.In this paper,we present a compositional colored Petri net approach to aid automatic modeling of systems biology,and demonstrate it with two case stud-ies.We focus on the modeling of communication between components and hierarchical organization of components as they are key to build multiscale models.

关键词： Colored Petri nets compositional modeling multiscale modeling systems biology

Safety assessment of approximate segregated parallel operation on closely spaced parallel runways

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Chinese Journal of Aeronautics 2019年第2期32卷 463-476页

作者： fei liu Xinze liu Mingjiang MOU Zhiqiang WEI Air Traffic Management College Civil Aviation University of China

With the continuous growth of air traffic flow, some airports in China or other countries begin to construct Closely Spaced Parallel Runways(CSPR) to meet the capacity requirement of civil aviation. In this paper, the simulation and calculation method of flight trajectory is developed,as well as the collision risk calculation method and wake vortex encounter risk calculation method.New methods for departure and go-around procedures are proposed to achieve approximate segregated parallel operation in an attempt to obtain approximately the same results on closely spaced parallel runways as on widely spaced parallel runways. By comparing with the independent parallel departure and segregated parallel operation in ICAO Doc. 9643, it is found that the lateral separation between aircraft in this proposal is not less than the separations in the other two cases. Based on the simulation calculation of flight trajectories under different conditions, the probabilities of collision conflict and encountering wake vortex are lower than those in current operation plan.The proposed plan has no special requirements in pilot operation, control command procedures,airport facilities, or meteorological observation and prediction, so it is convenient to promote and implement at the airports with closely spaced parallel runways.

关键词： Air traffic control Air transportation Closely spaced parallel runways Segregated parallel operation Wake vortex encounter Wake vortex separation standards

The establishment of polypeptide PSMA-targeted chimericantigen receptor-engineered natural killer cells forcastration-resistant prostate cancer and the induction of ferroptosis-related cell death

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Cancer Communications 2022年第8期42卷 768-783页

作者： Liyuan Wu fei liu Le Yin Fangming Wang Hui Shi Qinxin Zhao feiya Yang Dong Chen Xiying Dong Yuchun Gu Nianzeng Xing State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Department of Urology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021P.R.China Molecular Pharmacology Laboratory Institute of Molecular MedicinePeking UniversityBeijing 100871P.R.China Translation Medicine Research Group Aston Medical SchoolAston UniversityBirminghamB47ETUnited Kingdom Research and Development Department Allife Medicine Inc.Beijing 100176P.R.China Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical SciencesBeijing 100730P.R.China Department of Urology Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical UniversityTaiyuanShanxi 030013P.R.China

Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited

关键词： CAR-NK92MI chimeric antigen receptors immunotherapy prostate-specific membrane antigen ferroptosis

Consensus Problem of Heterogeneous Multi-agent Systems with Time Delay under Fixed and Switching Topologies

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International Journal of Automation and computing 2014年第3期11卷 340-346页

作者： Ping-Ping Dai Cheng-Lin liu fei liu Key Laboratory of Advanced Process Control for Light Industry (Ministry of Education) Jiangnan University

Consensus problem is investigated for heterogeneous multi-agent systems composed of first-order agents and second-order agents in this paper. Leader-following consensus protocol is adopted to solve consensus problem of heterogeneous multi-agent systems with time-varying communication and input delays. By constructing Lyapunov-Krasovkii functional, sufficient consensus conditions in linear matrix inequality(LMI) form are obtained for the system under fixed interconnection topology. Moreover, consensus conditions are also obtained for the heterogeneous systems under switching topologies with time delays. Simulation examples are given to illustrate effectiveness of the results.

关键词： Consensus problem,heterogeneous multi-agent systems,switching topologies,communication delay,input delay.