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  • 简介:BackgroundStudyhasshownthatratbonemesenchymalstemcells(MSCs)canbedifferentiatedintoendothelialcellsbyVEGFandb-FGFinvitro.OurpreviousresearchfoundthatafterratboneMSCstreatedbyVEGFandb-FGFgainedthephenotypicandfunctionalfeaturesofendothelialcelllines,withsomedifferencesfromendothelialcelllinesregardtothestabilityandself-replicating.ThisstudywastoexploretheeffectofNotchsignalingonthefunctionsofMSCsdifferentiatedendothelialcells.MethodsRatboneMSCswerecultivatedandtreatedbyVEGF165andb-FGFfor2weekstoinduceendothelialcelldifferentiation.ThegeneofVEGF165wasimportedintodifferentiatedendothelialcells.ThereceptorofNotch1andtheligandofNotchsignalingJagged1weredetectedbyRT-PCRbeforeandafterthetransfection.γ-secretaseinhibitorwasusedtoblockNotchpathway,Cellmigrationabilitywasdetectedbyscarificationtest.Cellswereinoculatedonsemisolidgeltostudytheirabilityofcapillary-likestructureformation.ResultsAftertransfection,VEGF165mRNAwasdetectedonthedifferentiatedendothelialcells.TheexpressionofJagged1’smRNAwasupregulated(1.08±0.01comparedto1.01±0.02,P<0.01)andtherewasnochangeabouttheNotch1.Cellsmigrationabilitywasenhanced[numberofcellsonthescratchedarea:44.95±3.14comparedto41.61±1.42,P<0.05]andtheabilityofformingcapillary-likestructureonsemisolidgelwasnotchanged.Theγ-secretaseinhibitorL-685,458furtherenhancedtheabilitiesofcellmigration[numberofcellsonthescratchedarea:50.28±2.76comparedto44.95±3.14,P<0.05])andcapillary-likestructureformationonsemisolidgel(cellsclassification:4.00±0.63comparedto3.00±0.63,P<0.05).ConclusionsInhibitionofNotchsignalingcanenhancethefunctionsoftheendothelialcellsdifferentiatedfromratMSCs.

  • 标签: 骨髓间充质干细胞 血管内皮细胞 细胞分化 细胞功能 信号增强 NOTCH信号途径
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  • 简介:AbstractObjective:Pancreatic cancer (PC) is a highly lethal malignancy with an immunosuppressive environment. Yet, current immune checkpoint inhibitor monotherapies have shown limited efficacy in PC, prompting the need for combination therapies. Herein, we hypothesized that combinations of Notch signaling inhibitor and anti-ligand programmed death-ligand 1 (PD-L1) antibody immunotherapy would show synergistic efficacy.Methods:The baseline expression of PD-L1 and HES1 was measured in PC cell lines, single-cell RNA-seq data of PC (GSA: CRA001160), and cBioPortal databases. In an in vitro study, MIA PaCa2 and SW1990 were used to explore the mechanism between Notch signaling and PD-L1. To study the effects in vivo, a subcutaneous tumor model was established using Pan02 cells treated with either anti-PD-L1 monoclonal antibody and/or Notch inhibitor DAPT. The study performed involving human samples was approved by the Ethics Committee of Peking Union Medical College Hospital (approval No. S-K460, approval date: April 23, 2018). Animal studies were approved by the Animal Research Ethics Committee of Peking Union Medical College Hospital (approval No. XHDW-2019-049, approval date: November 28, 2019).Results:The Notch signaling inhibitor upregulated PD-L1 expression in PC tumor cells both in vitro and in vivo. Notch effector HES1 knockdown produced PD-L1 upregulation in both MIA PaCa2 and SW1990 cells. Combined DAPT and anti-PD-L1 antibody treatment of Pan02 subcutaneous tumor model resulted in significantly reduced tumor weights compared to that with monotherapy, as well as significantly reduced Ki67 than that in the monotherapy group and control group. Flow cytometry analysis revealed significantly increased CD8+ T cell infiltration in tumors of the combination group compared with those of the monotherapy group.Conclusion:Notch signaling blockade might enhance the antitumor effect of anti-PD-L1 therapy in PC.

  • 标签: DAPT Notch signaling blockade Pancreatic cancer PD-L1 immune checkpoint PD-L1 upregulation
  • 简介:信号变换器的七个成员和抄写(STAT)的使活跃之物抄写因素的家庭被特定的酷氨酸残余的磷酸化响应许多不同cytokines和生长因素激活。STAT1和STAT3基因是激活的STAT的特定的目标1和3分别地,响应干扰素(STAT1)或ligands导致这些unphosphorylatedSTAT(U-STATs)的层次的大增加那活跃gp130,例如IL-6(STAT3)。由从那些不同的新奇机制的U-STATs开车基因表示由phosphorylatedSTAT(P-STAT)使用了暗淡ers。在这评论,我们在基因表示的抄写和规定讨论U-STATs的角色。

  • 标签: 细胞科学 转录因子 IL-6 磷酸化作用
  • 简介:Nanometer-scaleAuquantumdotshavebeenassembledonSiO2bycontrollingthereactionofrawmatedaistoformacitrateAusolandanaminosilane/dithiol-treatedpatternedSiwafer.Thedetailedformationmechanismhasbeenstudied.Threegoldcolloidalparticles(-15nm),alignedinachaintoformaone-dimensionalcurrentpath,wasbridgedacrossan80-nmgapbetweensourceanddrainmetalelectrodes,ThedeviceexhibitedaCoulombblockadeeffectat33K.

  • 标签: 量子点 二氧化硅基片 库仑阻断效应 单电子传输
  • 简介:Informationsharinginprocurementoccursinrichandvariedindustrycontextsinwhichmanagerialdecisionsaremadeandorganizationalstrategyisformulated.Weexplorehowinformationsharingoughttoworkinprocurementcontextsmatinvolveinvestmentsininter-organizationalinformationsystems(IOS)andcollaborativeplanning,forecastingandreplenishment(CPFR)practices.Howandunderwhatcircumstancesdoesafirmthatplaystheroleofasupplychainbuyerdecidetoshareinformationonkeyvariables,suchaspoint-of-saleconsumerdemanddatawithitssupplier,upthesupplychain?Thisisakeyissuethatcrossestheboundarybetweensupplychainmanagementandinformationsystems(IS)management.Theanswersthatweprovidearebasedonouruseofagame-theoreticsignalingmodelofbuyerandsupplierstrategyinthepresenceofuncertaintiesaboutfinalconsumerdemand.Wealsoexploretheconnectionbetweenoperationalcoststhatareassociatedwiththefirm'sinformationsharingandinformationwithholdingstrategies.Ourresultsprovidenormativeguidancetosupplychainbuyersabouthowtointerpretdifferentdemanduncertaintyscenariostoimprovetheirdecisionsandgeneratehighvalue.FromtheISmanagementperspective,weshowtheimpactsonthefirmofdifferentinformationsharingapproachesthataremadepossiblebypresentdaytechnologies.

  • 标签: 供应链管理 信息共享 信号模型 不确定性理论 管理决策 信息系统
  • 简介:AbstractBackground:Cerebral cavernous malformations (CCMs), a major neurosurgical condition, characterized by abnormally dilated intracranial capillaries, result in increased susceptibility to stroke. KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) have been identified as causes of CCMs in which at least one of them is disrupted in most familial cases. Our goal is to identify potential biomarkers and genetic modifiers of CCMs, using a global comparative omics approach across several in vitro studies and multiple in vivo animal models. We hypothesize that through analysis of the CSC utilizing various omics, we can identify potential biomarkers and genetic modifiers, by systemically evaluating effectors and binding partners of the CSC as well as second layer interactors.Methods:We utilize a comparative omics approach analyzing multiple CCMs deficient animal models across nine independent studies at the genomic, transcriptomic, and proteomic levels to dissect alterations in various signaling cascades.Results:Our analysis revealed a large set of genes that were validated across multiple independent studies, suggesting an important role for these identified genes in CCM pathogenesis.Conclusion:This is currently one of the largest comparative omics analysis of CCM deficiencies across multiple models, allowing us to investigate global alterations among multiple signaling cascades involved in both angiogenic and non-angiogenic events and to also identify potential biomarker candidates of CCMs, which can be used for new therapeutic strategies.

  • 标签: Cerebral cavernous malformation (CCM) CCM signaling complex (CSC) Angiogenesis Proteomics Transcriptomics Interactome Omics Comparative omics Biomarkers Genetic modifiers Systems biology
  • 简介:转变生长因素(TGF)-尾家庭成员是多功能的cytokines在细胞上得到他们的效果包括endothelial和墙壁的细胞,经由特定的类型我和类型IIserine/threoninekinase受体和细胞内部的Smad抄写因素。为表明小径部件的TGF-尾家庭的猛烈老鼠模型在合适的蛋黄囊angiogenesis揭示了他们的批评重要性。在人的基因研究在这些发信号的部件连接了变化到象世袭出血性的毛细管扩张,主要肺的高血压和Marfan症候群那样的特定的心血管的症候群。在这评论,我们在我们TGF-尾受体在脉管的生物学和疾病发信号的角色的理解的现在的最近的进展,并且讨论这怎么可以被申请治疗。

  • 标签: 血管发生 BMP Marfan综合症 肺部高血压 TGF-Β
  • 简介:Basedonanincompressiblemodel,byusingthelargestaintheory,thecontactofarubberwedgewitharigidnotchisanalyzedbytheasymptoticmethod.Theproblemistreatedasasymmetriccase,andthecontactsurfaceissmooth.Thestressandstrainfieldneartheapexoftherubberwedgeisshowntobesingular,andtheangulardistributionsofstressandstrainareobtained.Twoimportantparameterstandtareintroducedtoattaintheconclusions.TheresultshowsthatthesingularexponentorderofstressfieldisInr.

  • 标签: 不可压缩模型 橡胶楔 渐近线理论 刚性槽口 应变场 固体力学
  • 简介:摘要Notch信号通路在胚胎期细胞命运转归和成体组织稳态的维持中起重要作用。各种研究已经证明Notch信号通路在角膜损伤后修复及角膜生理性稳态的维持中有重大意义,角膜缘干细胞主要通过抑制Notch信号通路来抑制细胞的分化和增生;在角膜上皮早期修复阶段生理性下调促进细胞迁移和伤口覆盖,后期修复阶段生理性上调与防止角膜上皮细胞过度分层和维持细胞分化相关;角膜基质损伤后纤维化与Notch信号通路相关;角膜内皮损伤后转化生长因子-β(TGF-β)诱导的内皮-间质转化(EnMT)过程有Notch信号通路的直接参与;此外,Notch信号通路与14-3-3σ、表皮生长因子受体(EGFR)、Sirt6、微小RNA(miRNA)、基质金属蛋白酶(MMPs)在角膜上皮稳态维持、角膜上皮分化、角膜基质过度炎症反应、角膜新生血管生成等存在相互作用。本文就Notch信号通路在角膜各层损伤修复中的功能进行综述。

  • 标签: 角膜疾病 修复 再生 信号转导 Notch通路
  • 简介:Wnt/尾-catenin调整与肿瘤有关的细胞的功能开始和前进,房间增长,区别,幸存,和粘附。尾-Catenin独立的Wnt小径被建议了调整房间极性和移植,包括转移。在这评论,我们在肿瘤前进讨论catenin依赖的尾-和独立人士发信号小径的可能的角色,与他们Rho家庭GTPases,改变的细胞骨架,和与房间房间粘附和cilia/ciliogenesis的关系的规定上的一个重音。

  • 标签: Wnt信号通路 细胞骨架 潜在作用 肿瘤 区熔 细胞功能
  • 简介:Newneuronsaregeneratedandintegrateintoexistingcircuitrywithinthehippocampaldentategyrusandtheolfactorybulbofmostmammals(GageandTemple,2013).Neurogenesisinthehippocampuspersiststhroughadulthood,andwhileitsfunctionandimportanceremainsunclear,itappearstoberequiredintheformationofspecifictypesof

  • 标签: 精神分裂症 神经元 海马齿状回 展望 信令 神经系统疾病
  • 简介:ThemolecularmechanismsforNF-κBsignalingtransductionandtranscriptionhavebeenthemostattractivesubjectsforbothbasicresearchandpharmaceuticalindustriesduetoitsimportantrolesinbothphysiologicalandpathogenesis,particularlythecloseassociationofdysregulatedNF-κBwithtumorgenesisandinflammation.SeveralnovelintracellularmoleculareventsthatregulateNF-κBactivityhavebeendescribedrecently,includingthediscoveryofanalternativesignalingpathwaythatappearsinducingaspecificsubsetgenesinvolvedinadoptiveimmuneresponse.Multi-levelandmulti-dimensionalregulationofNF-κBactivitybyphosphorylationandacetylationmodificationshaveunveiledandbecamethehottesttargetsforpotentiallytissuespecificmolecularinterventions.AnotheremergingmechanismforNF-κB-responsivegene'sregulationwhereNF-κBparticipatesthetranscriptionalregulationindependentofitscognateregulatorybindingsitewithinthetargetgene'spromoterbutfacilitatingthetransactionactivityofotherinvolvedtranscriptionfactors,thatimplicatedannoveltranscriptionalactivitiesforNF-κB.Thus,thecurrentreviewwillfocusontheserecentprogressesthathavebeenmadeonNF-κBsignalingtransductionandtranscription.Cellular&MolecularImmunology.2004;1(6):425-435.

  • 标签: 超前作用 NF-κB信号 转换信号 |
  • 简介:<正>ThesusceptibilityofprimaryBcellstoFas(APO-1,CD95)-mediatedapoptosisisregulatedbysignalsderivedfromadditionalsurfacereceptors.CD40engagementproducesupregulationofFasexpressionandinducesmarkedsensitivitytoFas-inducedcelldeath,whereasBcellantigenreceptor(BCR)engagementinhibitsFaskillingandtherebyproducesFas-resistance,eveninotherwisesusceptible,CD40-stimulatedtargets.BCRsignalingforinducibleFas-resistancedevelopsoveraperiodof12hoursanddependson

  • 标签: 初级B淋巴细胞 Fas介导细胞凋亡 耐受性 信号转导
  • 简介:AIMTodeterminetheroleofcorticotropinreleasingfactorreceptor(CRF2)inepithelialpermeabilityandenterocytecelldifferentiation.METHODSForthispurpose,weusedratSpragueDawleyandvariouscoloncarcinomacelllines(SW620,HCT8R,HT-29andCaco-2celllines).ExpressionofCRF2proteinwasanalyzedbyfluorescentimmunolabelinginnormalratcolonandthenbywesternblotindissociatedcolonicepithelialcellsandinthelysatesofcoloncarcinomacelllinesorduringtheearlydifferentiationofHT-29cells(tenfirstdays).ToassesstheimpactofCRF2signalingoncoloniccelldifferentiation,HT-29andCaco-2cellswereexposedtoUrocortin3recombinantproteins(Ucn3,100nmol/L).Insomeexperiments,cellswerepre-exposedtotheastressin2b(A2b)aCRF2antagonistinordertoinhibittheactionofUcn3.Intestinalcelldifferentiationwasfirstanalyzedbyfunctionalassays:thetrans-cellularpermeabilityandthepara-cellularpermeabilityweredeterminedbyDextran-FITCintakeandmeasureofthetransepithelialelectricalresistancerespectively.Morphologicalmodificationsassociatedtoepithelialdysfunctionwereanalyzedbyconfocalmicroscopyafterfluorescentlabelingofactin(phaloidin-TRITC)andintercellularadhesionproteinssuchasE-cadherin,p120ctn,occludinandZO-1.Theestablishmentofmatureadherensjunctions(AJ)wasmonitoredbyfollowingthedistributionofAJproteinsinlipidraftfractions,afterseparationofcelllysatesonsucrosegradients.Finally,themRNAandtheproteinexpressionlevelsofcharacteristicmarkersofintestinalepithelialcell(IEC)differentiationsuchasthetranscriptionalfactorkrüppel-likefactor4(KLF4)orthedipeptidylpeptidaseIV(DPPIV)wereperformedbyRT-PCRandwesternblotrespectively.ThespecificactivitiesofDPPIVandalkalinephosphatase(AP)enzymesweredeterminedbyacolorimetricmethod.RESULTSCRF2proteinispreferentiallyexpressedinundifferentiatedepithelialcellsfromthecryptsofcolonandinhumancoloncarcinoma

  • 标签: Urocortin3 结肠癌房间线 细胞间的粘附建筑群 房间渗透 上皮的房间区别 释放因素 2 的 Corticotrophin