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Complement activation by phospholipids: the interplay of factor H and C1q

Protein & Cell 2010年第11期1卷 1033-1049页

作者： Lee Aun Tan bingbin Yu Francis CJ sim Uday Kishore robert b sim MRC Immunochemistry Unit Department of BiochemistryUniversity of OxfordSouth Parks RdOxford OX13QUUK Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK Centre for Infection Immunity and Disease MechanismsBiosciencesSchool of Health Sciences and Social CareBrunel UniversityUxbridge UB83PH West LondonUK Present address Department of Immunology Faculty of MedicineImperial College LondonHammersmith HospitalDu Cane RoadLondon W120NNUK Present address School of Life Sciences and Engineering Biology BuildingTsinghua UniversityBeijing 100084China

Complement proteins in blood recognize charged *** anionic phospholipid(aPL)cardiolipin binds both complement proteins C1q and factor H.C1q is an activator of the complement classical pathway,while factor H is an inhibitor of the alternative *** examine opposing effects of C1q and factor H on complement activation by aPL,we surveyed C1q and factor H binding,and complement activation by aPL,either coated on microtitre plates or in *** C1q and factor H bound to all aPL tested,and competed directly with each other for *** the aPL activated the complement classical pathway,but negligibly the alternative pathway,consistent with accepted roles of C1q and factor ***,in this system,factor H,by competing directly with C1q for binding to aPL,acts as a direct regulator of the complement classical *** regulatory mechanism is distinct from its action on the alternative *** of classical pathway activation by factor H was confirmed by measuring C4 activation by aPL in human sera in which the C1q:factor H molar ratio was adjusted over a wide *** factor H,which is regarded as a down-regulator only of the alternative pathway,has a distinct role in downregulating activation of the classical complement pathway by aPL.A factor H homologue,β2-glycoprotein-1,also strongly inhibits C1q binding to *** globular domains of C1q A,b and C chains bound aPL similarly to native C1q,confirming that C1q binds aPL via its globular heads.

关键词： complement regulation classical pathway C1q factor H anionic phospholipid

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Surface-bound myeloperoxidase is a ligand for recognition of late apoptotic neutrophils by human lung surfactant proteins A and D

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Protein & Cell 2010年第6期1卷 563-572页

作者： Anne Jäkel Howard Clark Kenneth b.M.Reid robert b.sim Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK University of Southampton School of MedicineDivision of Infection Inflammation&ImmunitySouthampton General HospitalSouthampton SO166YDUK MRC Immunochemistry Unit Department of BiochemistryUniversity of OxfordSouth Parks RoadOxford OX13QUUK

Surfactant proteins A(SP-A)and D(SP-D),both members of the collectin family,play a well established role in apoptotic cell recognition and *** in vitro data show that SP-A and SP-D interact with apoptotic neutrophils in a distinct ***-A and SP-D bind in a Ca^(2+)-dependent manner to viable and early apoptotic neutrophils whereas the much greater interaction with late apoptotic neutrophils is Ca^(2+)-*** surface molecules on the apoptotic target cells responsible for these interactions had not been identified and this study was done to find candidate target ***(MPO),a specific intracellular defense molecule of neutrophils that becomes exposed on the outside of the cell upon apoptosis,was identified by affinity purification,mass-spectrometry and western blotting as a novel binding molecule for SP-A and *** confirm its role in recognition,it was shown that purified immobilised MPO binds SP-A and SP-D,and that MPO is surface-exposed on late apoptotic ***-A and SP-D inhibit binding of an anti-MPO monoclonal Ab to late apoptotic *** microscopy confirmed that anti-MPO mAb and SP-A/SP-D colocalise on late apoptotic *** was identified as a further potential ligand for SP-A,and neutrophil defensin as a target for both proteins.

关键词： SP-A SP-D myeloperoxidase neutrophils flow cytometry mass spectrometry

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Interactions of complement proteins C1q and factor H with lipid A and Escherichia coli:further evidence that factor H regulates the classical complement pathway

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Protein & Cell 2011年第4期2卷 320-332页

作者： Lee Aun Tan Andrew C.Yang Uday Kishore robert b.sim Medical Research Council Immunochemistry Unit Department of BiochemistryUniversity of OxfordSouth Parks RoadOxford OX13QUUK Present address:Department of Immunology Faculty of MedicineImperial College LondonHammersmith HospitalDu Cane RoadLondon W120NNUK St Peter’s College New Inn Hall St.Oxford OX12DLUK Present address:SUNY Downstate College of Medicine 450 Clarkson Avenue BrooklynNY 11203USA Weatherall Institute of Molecular Medicine John Radcliffe HospitalUniversity of OxfordHeadingtonOxford OX39DSUK Present address:Center for Infection Immunity and Disease MechanismsBiosciencesSchool of Health Sciences and Social CareBrunel UniversityUxbridge UB83PH West LondonUK Present address:Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK

Proteins of the complement system are known to interact with many charged *** recently characterized binding of C1q and factor H to immobilized and liposomal anionic *** H inhibited C1q binding to anionic phospholipids,suggesting a role for factor H in regulating activation of the complement classical pathway by anionic *** extend this finding,we examined interactions of C1q and factor H with lipid A,a well-characterized activator of the classical *** report that C1q and factor H both bind to immobilized lipid A,lipid A liposomes and intact Escherichia coli *** H competes with C1q for binding to these ***,increasing the factor H:C1q molar ratio in serum diminished C4b fixation,indicating that factor H diminishes classical pathway *** recombinant forms of the Cterminal,globular heads of C1q A,b and C chains bound to lipid A and *** in a manner qualitatively similar to native C1q,confirming that C1q interacts with these targets via its globular head *** observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain *** is distinct from its role as an alternative pathway *** suggest that under physiological conditions,factor H may serve as a downregulator of bacterially-driven inflammatory responses,thereby finetuning and balancing the inflammatory response in infections with Gram-negative bacteria.

关键词： complement lipid A bacteria factor H C1q

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Identification of four novel DC-SIGN ligands on Mycobacterium bovis bCG

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Protein & Cell 2010年第9期1卷 859-870页

作者： Maria V.Carroll robert b.sim Fabiana bigi Anne Jäkel Robin Antrobus Daniel A.Mitchell Department of Pharmacology University of OxfordMansfield RoadOxford OX13QTUK Institute of biotechnology CICVyA-INTALos Reseros y Las Cabañas1712 CastelarArgentina Cambridge Institute of Medical Research Addenbrooke’s HospitalHills RoadCambridge CB20XYUK CSRI-UHCW Walsgrave Campus University of WarwickCoventryCV22DXUK

Dendritic-cell-specific intercellular adhesion molecule-3-grabbing non-integrin(DC-SIGN;CD209)has an important role in mediating adherence of Mycobacteria species,including *** and *** bCG to human dendritic cells and macrophages,in which these bacteria can survive ***-SIGN is a C-type lectin,and interactions with mycobacterial cells are believed to occur via mannosylated structures on the mycobacterial *** studies suggest more varied modes of binding to multiple mycobacterial *** we identify,by affinity chromatography and mass-spectrometry,four novel ligands of *** bCG that bind to *** novel ligands are chaperone protein DnaK,60 kDa chaperonin-1(Cpn60.1),glyceraldehyde-3 phosphate dehydrogenase(GAPDH)and lipoprotein *** published work strongly suggests that these are on the cell *** these ligands,lprG appears to bind DC-SIGN via typical proteinglycan interactions,but DnaK and Cpn60.1 binding do not show evidence of carbohydrate-dependent *** was also identified as a ligand for DC-SIGNR(L-SIGN;CD299)and the *** orthologue of lprG has been found previously to interact with human toll-like receptor ***,these findings offer new targets for combating mycobacterial adhesion and within-host survival,and reinforce the role of DCSIGN as an important host ligand in mycobacterial infection.

关键词： DC-SIGN Mycobacteria lectins

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Specific interaction of hepatitis C virus glycoproteins with mannan binding lectin inhibits virus entry

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Protein & Cell 2010年第7期1卷 664-674页

作者： Kristelle S.brown Michael J.Keogh Ania M.Owsianka Richard Adair Arvind H.Patel James N.Arnold Jonathan K.ball robert b.sim Alexander W.Tarr Timothy P.Hickling Institute of Infection Immunity and InflammationSchool of Molecular Medical SciencesThe University of NottinghamQueen’s Medical CentreNottinghamNG72UHUK The Medical Research Council-University of Glasgow Centre for Virus Research University of GlasgowChurch StreetGlasgowG115JRUK MRC Immunochemistry Unit Department of BiochemistryUniversity of OxfordOX13QUUK Present address:Vitrology biotech 5 South AvenueClydebank Business ParkGlasgowG812LGUK Present address:Pfizer Technologies Ltd. Ramsgate RoadSandwichKentCT139NJUK

Mannan-binding lectin(MbL)is a soluble innate immune protein that binds to glycosylated *** acts as an opsonin and activates complement,contributing to the destruction and clearance of infecting *** C virus(HCV)encodes two envelope glycoproteins E1 and E2,expressed as non-covalent E1/E2 heterodimers in the viral envelope.E1 and E2 are potential ligands for *** we describe an analysis of the interaction between HCV and MbL using recombinant soluble E2 ectodomain fragment,the full-length E1/E2 heterodimer,expressed in vitro,and assess the effect of this interaction on virus entry.A binding assay using antibody capture of full length E1/E2 heterodimers was used to demonstrate calcium dependent,saturating binding of MbL to HCV *** with various saccharides further confirmed that the interaction was via the lectin domain of *** binds to E1/E2 representing a broad range of virus *** was shown to neutralize the entry into Huh-7 cells of HCV pseudoparticles(HCVpp)bearing E1/E2 from a wide range of *** were neutralized to varying *** was also shown to neutralize an authentic cell culture infectious virus,strain JFH-1(HCVcc).Furthermore,binding of MbL to E1/E2 was able to activate the complement system via MbL-associated serine protease *** conclusion,MbL interacts directly with HCV glycoproteins,which are present on the surface of the virion,resulting in neutralization of HCV particles.

关键词： hepatitis C virus neutralization mannose binding lectin chronic viral infection

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Analysis of a passive ankle exoskeleton for reduction of metabolic costs during walking

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Defence Technology（防务技术） 2024年第7期37卷 62-68页

作者： Luís Quinto Pedro Pinheiro Sergio b.Goncalves Ivo Roupa Paula simoes Miguel Tavares da Silva CINAMIL Academia MilitarInstituto Universitario MilitarLisbonPortugal IDMEC Instituto Superior TecnicoUniversidade de LisboaLisbonPortugal

Modern conflicts demand substantial physical and psychological exertion,often resulting in fatigue and diminished combat or operational *** exoskeletons have been developed recently to address these challenges,presenting various limitations that affect their operational or everyday *** article evaluates the performance of a dual-purpose passive ankle exoskeleton developed for the reduction of metabolic costs during walking,seeking to identify a force element that could be applied to the target *** on the 6-min walk test,twenty-nine subjects participated in the study using three different force *** results indicate that it is possible to reduce metabolic expenditure while using the developed ***,the comfort and range of motion results verify the exoskeleton's suitability for use in uneven terrain and during extended ***,the choice of the force element should be tailored to each user,and the control system should be adjustable to optimise the exoskeleton's performance.

关键词： Ankle passive exoskeleton Metabolic cost reduction Dual-use exoskeleton Gait biomechanics

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Subpopulations of regulatory T cells are associated with subclinical atherosclerotic plaques,levels of LDL,and cardiorespiratory fitness in the elderly

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Journal of Sport and Health Science 2024年第3期13卷 288-296,I0002页

作者： Tim böttrich Pascal bauer Vincent Gröβer Magdalena Huber Hartmann Raifer Torsten Frech Svenja Nolte Theresa Dombrowski Franz Cemic Natascha Sommer robert Ringseis Klaus Eder Karsten Krüger Christopher Weyh Department of Exercise Physiology and Sports Therapy Institute of Sports ScienceJustus-Liebig-UniversityGiessen 35394Germany Department of Cardiology and Angiology Justus-Liebig-University GiessenGiessen 35392Germany Institute for Systems Immunology Center for Tumor und ImmunologyMarburg 35032Germany TH Mittelhessen Department of Computer ScienceUniversity of Applied Sciences GiessenGiessen 35390Germany Department of Internal Medicine Universities of Giessen and Marburg Lung Center(UGMLC)Member of the German Center for Lung Research(DZL)Giessen 35394Germany Excellence Cluster Cardio-Pulmonary Institute(CPI) Justus-Liebig UniversityGiessen 35394Germany Institute of Animal Nutrition and Nutrition Physiology Justus-Liebig-University GiessenGiessen 35390Germany

background:Atherosclerosis forms the pathological basis for the development of cardiovascular *** pathological processes initially develop without clinically relevant symptoms,the identification of early markers in the subclinical stage plays an important role for initiating early *** is evidence that regulatory T cells(Tregs)are involved in the development of ***,the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques(SAP).In addition,various lifestyle and risk factors,such as cardiorespiratory fitness,were investigated as associated ***:A cross-sectional study was performed in 79 participants(male:n=50;age=63.6±3.7 years;body mass index=24.9±3.1 kg/m2;mean±SD)who had no previous diagnosis of chronic disease and were not taking *** of the carotids to identify SAP,cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were ***,tests were conducted to assess blood lipids and determine glucose *** of Tregs and their subtypes(resting(rTregs)and effector/memory(mTregs))was performed by 8-chanel flow *** were categorized according to atherosclerotic plaque *** and logistic regression models were used to analyze associations between ***:SAP was detected in a total of 29 *** participants with plaque were older(64.8±3.6 years vs.62.9±3.5 years)and had higher peripheral systolic blood pressure(133.8±14.7 mmHg vs.125.8±10.9 mmHg).The participants with SAP were characterized by a lower percentage of rTregs(28.8%±10.7%vs.34.6%±10.7%)and a higher percentage of mTregs(40.3%±14.7%vs.30.0%±11.9%).Multiple logistic regression identified age(odds ratio(OR)=1.20(95%confidence interval(95%CI):1.011.42))and

关键词： Cardiorespiratory fitness Elderly Regulatory T cells Subclinical atherosclerosis

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The Sigma-1 Receptor as a Pharmacologic Chaperone: Energetics

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Journal of biosciences and Medicines 2024年第8期12卷 347-356页

作者： robert b. Raffa Joseph V. Pergolizzi Jr. School of Pharmacy (Emeritus) Temple University Philadelphia PA USA College of Pharmacy (Adjunct) University of Arizona Tucson AZ USA NEMA Research Naples FL USA

Initially thought to be an opioid receptor subtype, Sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis, and cell survival. These roles offer significant insight for understanding homeostasis of normal physiologic processes, and the pathophysiologic consequences of disruption of normal function. because of the broad nature of chaperone action, S1R agonists and antagonists represent potential drug discovery goals for the pharmacotherapeutic treatment of a variety of disorders that result from dysfunctional proteins. The present study summarizes the S1R as a pharmacologic chaperone crucial for protein folding and cellular homeostasis. Through literature review and thermodynamic analysis, it explores how S1R stabilizes target proteins, influencing neuroprotection and potential drug therapies. The binding of chaperones to target proteins is thermodynamically favorable, offering insights into treating diseases linked to protein misfolding.

关键词： Chaperone Sigma-1 Receptor Energetics Thermodynamics Isothermal Titration Microcalorimetry

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Advances in discovery of novel investigational agents for functional cure of chronic hepatitis b:A comprehensive review of phases II and III therapeutic agents

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World Journal of Hepatology 2024年第3期16卷 331-343页

作者： robert Lam Joseph K Lim Section of Digestive Diseases Yale University School of MedicineNew HavenCT 06520United States

Chronic hepatitis b virus(HbV)infection affects over 295 million people globally and an estimated 1.6 million people in the United *** is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver *** therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver ***,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver *** investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis b surface antigen(HbsAg)loss and suppression of HbV *** we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis b,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HbsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

关键词： Hepatitis b virus Treatment Clinical trials RNA interference Entry inhibitors Core inhibitors Immunomodulators

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Effects of soil metal(loid)s pollution on microbial activities and environmental risks in an abandoned chemical smelting site

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Journal of Environmental Sciences 2024年第9期143卷 60-70页

作者： Hao Li Jun Yao Jianli Liu Ning Min Geoffrey Sunahara Dongyang Men robert Duran School of Water Resources and Environment Research Center of Environmental Science and EngineeringChina University of Geosciences(Beijing)Beijing 100083China Department of Natural Resource Sciences McGill University21111Lakeshore DriveSte-Anne-de-BellevueQuebecH9X 3V9Canada Equipe Environnement et Microbiologie MELODY groupUniversitéde Pau et des Pays de l’AdourE2S-UPPAIPREM UMR CNRS 5254BP 115564013 Pau CedexFrance

Abandoned chemical smelting sites containing toxic substances can seriously threaten and pose a risk to the surrounding ecological *** samples were collected from different depths(0 to 13 m)and analyzed for metal(loid)s content and fractionation,as well as microbial *** potential ecological risk indices for the different soil depths(ordered from high to low)were:1 m(D-1)>surface(S-0)>5 m(D-5)>13 m(D-13)>9 m(D-9),ranging between 1840.65-13,089.62,and representing extremely high environmental risks,of which Cd(and probably not arsenic)contributed to the highest environmental risk.A modified combined pollution risk index(MCR)combining total content and mobile proportion of metal(loid)s,and relative toxicities,was used to evaluate the degree of contamination and potential environmental *** the near-surface samples(S-0 and D-1 layers),the MCR considered that As,Cd,Pb,Sb,and Zn achieved high and alarming degrees of contamination,whereas Fe,Mn,and Ti were negligible or low to moderate pollution *** microcalorimetry and enzymatic activity measurements of contaminated soil samples were used to assess the microbial metabolic activity *** analysis elucidated the relationship between metal(loid)s exchangeable fraction or content and microbial activity characteristics(pbial metabolic activity in the D-1 layer was low presumably due to heavy metal *** activity indicators and microcalorimetric growth rate(k)measurements were considered sensitive indicators to reflect the soil microbial activities in abandoned chemical smelting sites.

关键词： Abandoned chemical smelting sites Microbial activities Modified combined pollution risk Microcalorimetry Enzymatic activities

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