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Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression

Research 2024年第3期2023卷 35-50页

作者： June Li Danielle Karakas Feng Xue Yingyu Chen Guangheng Zhu Yeni H.Yucel Sonya A.MacParland Haibo Zhang John W.Semple John Freedman Qizhen Shi heyu ni Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada Toronto Platelet Immunobiology Group TorontoONCanada Keenan Research Centre for Biomedical Science of St.Michael's Hospital TorontoONCanada Canadian Blood Services Centre for Innovation TorontoONCanada Departments of Pediatrics Medical College of WisconsinMilwaukeeWIUSA Blood Research Institute Versiti WisconsinMilwaukeeWIUSA Departments of Ophthalmology and Vision Sciences Medicine University of TorontoTorontoONCanada Faculty of Engineering and Architectural Science Ryerson UniversityTorontoONCanada Multi-Organ Transplant Program Toronto General Hospital Research InstituteTorontoONCanada Department of Immunology University of TorontoTorontoONCanada Critical Care Medicine Department ofAnesthesiology and PainUniversity of TorontoTorontoONCanada Department of Physiology University of TorontoTorontoONCanada Department of Pharmacology University of TorontoTorontoONCanada. Division of Hematology and Transfusion Medicine Lund UniversityLundSweden clinical Immunology and Transfusion Medicine Ofice of Medical ServicesRegion SkaneLundSweden Department of Medicine University of TorontoTorontoONCanada Children's Research Institute Children's WisconsinWauwatosaWIUSA Midwest Athletes Against Childhood Cancer Fund Research Center MilwaukeeWIUSA.

Platelets are small, versatile blood cells that are critical for hemostasis/thrombosis. Local platelet accumulation is a known contributor to proinflammation in various disease states. However, the anti-inflammatory/immunosuppressive potential of platelets has been poorly explored. Here, we uncovered, unexpectedly, desialylated platelets (dPLTs) down-regulated immune responses against both platelet-associated and -independent antigen challenges. Utilizing multispectral photoacoustic tomography, we tracked dPLT trafficking to gut vasculature and an exclusive Kupffer cell-mediated dPLT clearance in the liver, a process that we identified to be synergistically dependent on platelet glycoprotein Ibα and hepatic Ashwell–Morell receptor. Mechanistically, Kupffer cell clearance of dPLT potentiated a systemic immunosuppressive state with increased anti-inflammatory cytokines and circulating CD4+ regulatory T cells, abolishable by Kupffer cell depletion. Last, in a clinically relevant model of hemophilia A, presensitization with dPLT attenuated anti-factor VIII antibody production after factor VIII ( infusion. As platelet desialylation commonly occurs in daily-aged and activated platelets, these findings open new avenues toward understanding immune homeostasis and potentiate the therapeutic potential of dPLT and engineered dPLT transfusions in controlling autoimmune and alloimmune diseases.

关键词： Platelet transfusion homeostasis

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SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance:Implications for Antibody Therapy and Vaccinations against COVID-19

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Research 2024年第3期2023卷 1-15页

作者： Xiaoying Ma Jady Liang Guangheng Zhu Preeti Bhoria Aron A.Shoara Daniel T.MacKeigan Christopher J.Khoury Sladjana Slavkovicl Lisha Lin Danielle Karakas Ziyan Chen Viktor Prifti Zhenze Liu Chuanbin Shen Yuchong Li Cheng Zhang Jiayu Dou Zack Rousseau Jiamin Zhang Tiffany ni Xi Lei Pingguo Chen Xiaoyu Wu Hamed Shaykhalishahi Samira Mubareka Kim AConnelly Haibo Zhang Ori Rotstein heyu ni Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada Department of Laboratory Medicine Keenan Research Centre for Biomedical Science of St.Michael’s HospitalTorontoONCanada Toronto Platelet Immunobiology Group TorontoONCanada Department of Physiology University of TorontoTorontoONCanada CCOA Therapeutics Inc. TorontoONCanada Canadian Blood Services Centre for Innovation TorontoONCanada The State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina Department of Laboratory Medicine The Second Affliated Hospital of Guangzhou University of Chinese MedicineGuangzhouChina Advanced Pharmaceutics&Drug Delivery Laboratory Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoONCanada Department of Medical Microbiology and Infectious Disease Sunnybrook Health Science CentreToronto ONCanada Department of Medicine University of TorontoTorontoONCanada Division of Cardiology.St.Michael's Hospital TorontoONCanada Department of Anesthesiology and Pain Medicine and Division of Critical Care Medicine University of TorontoTorontoONCanada interdepartmental Division of Critical Care Medicine University of TorontoTorontoONCanada Department of Surgery University of Toronto TorontoONCanada.

The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health *** cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia(VITT)are both associated with thrombosis and thrombocytopenia;however,the underlying mechanisms remain inadequately *** infection and vaccination utilize the spike protein receptor-binding domain(RBD)of *** found that intravenous injection of recombinant RBD caused significant platelet clearance in *** investigation revealed the RBD could bind platelets,cause platelet activation,and potentiate platelet aggregation,which was exacerbated in the Delta and Kappa *** RBD–platelet interaction was partially dependent on theβ3 integrin as binding was significantly reduced inβ3−/−***,RBD binding to human and mouse platelets was significantly reduced with relatedαIIbβ3 antagonists and mutation of the RGD(arginine-glycine-aspartate)integrin binding motif to RGE(arginine-glycine-glutamate).We developed anti-RBD polyclonal and several monoclonal antibodies(mAbs)and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation,aggregation,and clearance in vivo,and SARS-CoV-2 infection and replication in Vero E6 *** data show that the RBD can bind platelets partially thoughαIIbβ3 and induce platelet activation and clearance,which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and *** newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.

关键词： Antibody diagnosis vaccine

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Platelets in Thrombosis and Atherosclerosis

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中国动脉硬化杂志 2009年第7期17卷 577-578页

作者： heyu ni Canadian Blood Services and St. Michael' s Hospital Associate Professor Department of Laboratory Medicine and Pathobiology Department of Medicine and Department of Physiology University of Toronto

Platelets are anucleate cells generated from megakaryocytes in the bone marrow. After being released into the blood,platelets play essential roles in hemostasis and preserving vessel wall integrity. However,the processes of platelet adhesion,activation,and aggregation at the site of vascular injury may also cause vessel occlusion,and lead to thrombotic diseases.

关键词：血小板骨髓细胞预防措施血管阻塞

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Platelets in hemostasis and thrombosis:Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis

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The Journal of Biomedical Research 2015年第6期29卷 437-444页

作者： Yan Hou Naadiya Carrim Yiming Wang Reid C.Gallant Alexandra Marshall heyu ni Department of Laboratory Medicine Keenan Research Centre for Biomedical ScienceLi Ka Shing Knowledge InstituteSt.Michael's Hospital and Toronto Platelet Immunobiology Group Jilin Provincial Center for Disease Control and Prevention Department of Laboratory Medicine and Pathobiology University of Toronto Canadian Blood Services Department of Medicine and Department of Physiology University of Toronto

Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. Although platelet genera- tion, maturation, and clearance are still not fully understood, significant progress has been made in the last 1-2 dec- ades. In blood circulation, platelets can quickly adhere and aggregate at sites of vascular injury, forming the platelet plug （i.e. the first wave of hemostasis）. Activated platelets can also provide negatively charged phosphatidylserine- rich membrane surface that enhances cell-based thrombin generation, which facilitates blood coagulation （i.e. the second wave of hemostasis）. Platelets therefore play central roles in hemostasis. However, the same process of hemostasis may also cause thrombosis and vessel occlusion, which are the most common mechanisms leading to heart attack and stroke following ruptured atherosclerotic lesions. In this review, we will introduce the classical mechanisms and newly discovered pathways of platelets in hemostasis and thrombosis, including fibrinogen-inde- pendent platelet aggregation and thrombosis, and the plasma fibronectin-mediated ＂protein wave＂ of hemostasis that precedes the classical first wave of hemostasis. Furthermore, we briefly discuss the roles of platelets in inflam- marion and atherosclerosis and the potential strategies to control atherothrombosis.

关键词： platelets thrombosis and hemostasis integrin αIIbβ3 fibrinogen fibronectin

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Platelets and platelet alloantigens:Lessons from human patients and animal models of fetal and neonatal alloimmune thrombocytopenia

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Genes & Diseases 2015年第2期2卷 173-185页

作者： Brian Vadasz Pingguo Chen Issaka Yougbare Darko Zdravic June Li Conglei Li Naadiya Carrim heyu ni Toronto Platelet Immunobiology Group TorontoONCanada Department of Laboratory Medicine Keenan Research Centre for Biomedical ScienceSt.Michael’s HospitalTorontoONCanada Department of Laboratory Medicine and Pathobiology University of TorontoTorontoONCanada Canadian Blood Services TorontoONCanada Department of Physiology University of TorontoTorontoONCanada Department of Medicine University of TorontoTorontoONCanada

Platelets play critical roles in hemostasis and *** evidence indicates that they are versatile cells and also involved in many other physiological processes and disease *** and neonatal alloimmune thrombocytopenia(FNAIT)is a life threatening bleeding disorder caused by fetal platelet destruction by maternal alloantibodies developed during *** polymorphisms cause platelet surface protein incompatibilities between mother and fetus,and ultimately lead to maternal *** is the most common cause of intracranial hemorrhage in full-term infants and can also lead to intrauterine growth retardation and *** diagnosis,prevention and treatment of FNAIT is challenging due to insufficient knowledge of the disease and a lack of routine screening as well as its frequent occurrence in first *** the ethical difficulties in performing basic research on human fetuses and neonates,animal models are essential to improve our understanding of the pathogenesis and treatment of *** aim of this review is to provide an overview on platelets,hemostasis and thrombocytopenia with a focus on the advancements made in FNAIT by utilizing animal models.

关键词： Fetal and neonatal alloimmune thrombocytopenia Integrins and GPIb complex Platelets and platelet receptors Thrombosis and hemostasis and Animal models of human disease

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Recent progress in MnBi2nTe3n+1 intrinsic magnetic topological insulators: crystal growth, magnetism and chemical disorder

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National Science Review 2024年第2期11卷 65-80页

作者： Chaowei Hu Tiema Qian ni ni Department of Physics and Astronomy and California Nano Systems Institute University of California-Los Angeles

The search for magnetic topological materials has been at the forefront of condensed matter research for their potential to host exotic states such as axion insulators, magnetic Weyl semimetals, Chern insulators,etc. To date, the MnBi2nTe3n+1family is the only group of materials showcasing van der Waals-layered structures, intrinsic magnetism and non-trivial band topology without trivial bands at the Fermi level. The interplay between magnetism and band topology in this family has led to the proposal of various topological phenomena, including the quantum anomalous Hall effect, quantum spin Hall effect and quantum magnetoelectric effect. Among these, the quantum anomalous Hall effect has been experimentally observed at record-high temperatures, highlighting the unprecedented potential of this family of materials in fundamental science and technological innovation. In this paper, we provide a comprehensive review of the research progress in this intrinsic magnetic topological insulator family, with a focus on single-crystal growth, characterization of chemical disorder, manipulation of magnetism through chemical substitution and external pressure, and important questions that remain to be conclusively answered.

关键词： MnBi2Te4 magnetic topological insulator magnetism tuning antiferromagnetism ferromagnetism pressure chemical doping

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Regional features of pollen R-values in China

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Science China Earth Sciences 2024年第1期67卷 295-308页

作者： Jie XIA Jian ni College of Life Sciences Zhejiang Normal UniversityJinhua 321004China Jinhua Mountain Observation and Research Station for Subtropical Forest Ecosystems Jinhua 321004China

Establishing a quantitative relationship between modern pollen and vegetation remains a pivotal but intricate pursuit within the field of Quaternary *** R-value,a well-established and traditional metric characterized by its simplicity and direct applicability,serves to calibrate the nonlinear disparities between surface pollen and modern *** study entails the construction of a comprehensive pollen R-value dataset for China derived from R-values published between 1987 and *** dataset,compiled after rigorous screening,calibration,and standardization processes,encompasses 898 modern pollen sampling sites and 2115 pollen R-value data entries,encapsulating 152 pollen taxa spanning 65 families and 113 *** the extracted R-values yielded the following insights:(1)A macrospatial analysis validates previously established knowledge at a site-specific ***,pollen R-value variations across China are statistically *** two-thirds of pollen taxa exhibit underrepresentation(e.g.,Taxodiaceae,Corylus,nitraria,Tamarix,Cyperaceae,Poaceae,and Fabaceae),while the remaining one-third display overrepresentation(e.g.,Pinus,Picea,Betula,Ephedra,Chenopodiaceae,and Artemisia).The degree of underrepresentation surpasses that of overrepresentation,and the representation patterns of Castanea,Quercus,Polygonaceae,and Asteraceae are contingent upon vegetation types.(2)Pollen R-values follow distinct spatial distribution patterns within *** the woody vegetation region of eastern China,R-values progressively decline from north to south,correlating with rising temperatures and ***,in herbaceous vegetation regions of northern and western China,R-values decrease from east to west and from northeast to southwest,corresponding to increased ***,pollen R-values manifest variation contingent on pollen taxa,vegetation types,and climatic regions,even differing for the same taxa across varying

关键词： Pollen R-value Modern pollen-vegetation relationship Regional pattern Variability Paleovegetation reconstruction

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Theoretical optimization of micropillar arrays for structurally stable bioinspired dry adhesives

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Theoretical & Applied Mechanics Letters 2024年第2期14卷 124-129页

作者： Ke ni Zhengzhi Wang Department of Engineering Mechanics School of Civil EngineeringWuhan UniversityWuhan 430072China Wuhan University Shenzhen Research Institute Shenzhen 518108China

Inspired by the excellent adhesion performances of setae structure from organisms,micro/nano-pillar array has become one of the paradigms for adhesive *** micropillar arrays are composed of the resin pillars for adhesion and the substrate with different elastic modulus for *** stress singularity at the bi-material corner between the pillars and the substrate can induce the failure of the micropillar-substrate corner and further hinder the fabrication and application of micropillar arrays,yet the design for the stability of the micropillar array lacks systematical and quantitative *** this work,we develop a semi-analytical method to provide the full expressions for the stress distribution within the bi-material corner combining analytical derivations and numerical *** predictions for the stress within the singularity field can be obtained based on the full expressions of the *** good agreement between the predictions and the FEM results demonstrates the high reliability of our *** adopting the strain energy density factor approach,the stability of the pillar-substrate corner is assessed by predicting the failure at the *** the elastic mismatch between the pillar and substrate given in this paper,the stability can be improved by increasing the ratio of the shear modulus of the substrate to that of the *** study provides accurate predictions for the stress distribution at the bi-material corner and can guide the optimization of material combinations of the pillars and the substrate for more stable bioinspired dry adhesives.

关键词： Micropillar array Stability Bi-material corner Dry adhesive

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Oligomerization of drug transporters:Forms,functions,and mechanisms

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1924-1938页

作者： Chunxu ni Mei Hong College of Life Sciences South China Agricultural UniversityGuangzhou 510642China Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms South China Agricultural UniversityGuangzhou 510642China

Drug transporters are essential players in the transmembrane transport of a wide variety of clinical *** broad substrate spectra and versatile distribution pattern of these membrane proteins infer their pharmacological and clinical *** our accumulating knowledge on the three-dimensional structure of drug transporters,their oligomerization status has become a topic of intense study due to the possible functional roles carried out by such kind of post-translational modification(PTM).In-depth studies of oligomeric complexes formed among drug transporters as well as their interactions with other regulatory proteins can help us better understand the regulatory mechanisms of these membrane proteins,provide clues for the development of novel drugs,and improve the therapeutic *** this review,we describe different oligomerization forms as well as their structural basis of major drug transporters in the ATP-binding cassette and solute carrier superfamilies,summarize our current knowledge on the influence of oligomerization for protein expression level and transport function of these membrane proteins,and discuss the regulatory mechanisms of ***,we highlight the challenges associated with the current oligomerization studies and propose some thoughts on the pharmaceutical application of this important drug transporter PTM.

关键词： Drug development Drug transporters Oligomerization Protein expression Protein–protein interaction Regulatory mechanism Structural basis Transport function

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Aubry-Mather theory for contact Hamiltonian systems Ⅲ

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Science China Mathematics 2024年第11期67卷 2541-2570页

作者： Panrui ni Lin Wang Shanghai Center for Mathematical Sciences Fudan University School of Mathematics and Statistics Beijing Institute of Technology

By exploiting the contact Hamiltonian dynamics（T*M × R,Φ_t） around the Aubry set of contact Hamiltonian systems,we provide a relation among the Mather set,the Φ_t-recurrent set,the strongly static set,the Aubry set,the Ma?é set,and the Φ_t-non-wandering ***,we consider the strongly static set,as a new flow-invariant set between the Mather set and the Aubry set in the strictly increasing *** show that this set plays an essential role in the representation of certain minimal forward weak Kolmogorov-Arnold-Moser（KAM） solutions and the existence of transitive orbits around the Aubry set.

关键词： Aubry-Mather theory weak KAM theory contact Hamiltonian systems Hamilton-Jacobi equations

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