FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2103402823> ?p ?o ?g. }

• W2103402823 endingPage "157" @default.
• W2103402823 startingPage "155" @default.
• W2103402823 abstract "HomeCirculation ResearchVol. 100, No. 2Endothelial Cell Protein C Receptor Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEndothelial Cell Protein C ReceptorRole Beyond Endothelium? Meenakshisundaram Thiyagarajan, Tong Cheng and Berislav V. Zlokovic Meenakshisundaram ThiyagarajanMeenakshisundaram Thiyagarajan From the Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research (M.T., T.C., B.V.Z.), Department of Neurosurgery, University of Rochester Medical Center, NY. Search for more papers by this author , Tong ChengTong Cheng From the Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research (M.T., T.C., B.V.Z.), Department of Neurosurgery, University of Rochester Medical Center, NY. Search for more papers by this author and Berislav V. ZlokovicBerislav V. Zlokovic From the Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research (M.T., T.C., B.V.Z.), Department of Neurosurgery, University of Rochester Medical Center, NY. Search for more papers by this author Originally published2 Feb 2007https://doi.org/10.1161/01.RES.0000258167.48227.84Circulation Research. 2007;100:155–157Endothelial cell protein C receptor (EPCR) is a type 1 transmembrane glycoprotein with homology to the major histocompatibility complex (MHC)-class 1/CD1 family of molecules.1 EPCR was isolated and cloned as an endothelial cell-specific, high selectivity and high affinity binding protein for protein C (PC) and activated PC (APC).1 EPCR binds PC on the endothelial surface and presents it to the thrombin:thrombomodulin (TM) complex for activation (Figure 1). Thrombin bound to TM proteolytically activates PC and generates APC which exerts independent anticoagulant and cellular activities.2 The APC anticoagulant pathway is mediated by proteolytic inactivation of blood coagulation Factors Va and VIIIa with the contribution of several cofactors, including protein S, high density lipoproteins, phosphatidylserine, cardiolipin, and glucosylceramide to name a few. The APC cellular pathway on endothelium requires EPCR and the protease activated receptor-1 (PAR-1)3 which mediates APC’s cytoprotective effects, including alterations in gene expression profiles, antiapoptotic activity, antiinflammatory activity and protection of endothelial barriers4–10 (Figure 1). EPCR also regulates endogenous physiologic activation of PC by thrombin which is linked to PAR-1-dependent APC protective autocrine signaling in endothelium.11Download figureDownload PowerPointFigure 1. EPCR binds protein C (PC) on endothelium and presents it to TM (thrombomodulin)-thrombin complex for activation by thrombin. Activated PC (APC) dissociates from EPCR and TM-thrombin complexes and inactivates coagulation factors Va and VIIIa into inactive forms Vi and VIIIi promoting anticoagulation. APC bound to EPCR activates the protease activated receptor-1 (PAR-1) which binds the Gq and Gi proteins to activate phosophlipase(s) (PLC) in SMCs and endothelium resulting in IP3 (inositol triphosphate)-mediated release of intracellular [Ca2+]i, activation of mitogen-activated kinases ERK1/2 and stimulation of DNA synthesis.22 In injured endothelium, EPCR-APC-mediated PAR-1 activation blocks mitochondria-mediated apoptotic pathway (eg, inhibition of p53 and Bax, activation of antiapoptotic Bcl-2 gene, blockade of caspase-9), and death receptor-mediated pathway through inhibition of caspase-8. Whether the same antiapoptotic signaling exists in injured SMCs is unknown. Soluble form of EPCR (sEPCR) binds APC/PC and forms complexes with proteinase-3 (PR3) which binds to Mac-1 on leukocytes and activates antiinflammatory signaling. EPCR-APC–dependent PAR-1 activation in leukocytes and endothelium blocks the expression of proinflammatory genes by preventing nuclear translocation of nuclear factor-κB (NF-κB). EPCR translocates itself from the plasma membrane to the nucleus and may internalize APC into injured vascular cells, but the physiological importance of EPCR internalization alone and/or of its ligands remains at present elusive.EPCR signaling can decrease inflammation. APC binding to EPCR rescues baboons from E. coli sepsis.12 EPCR has also cardioprotective role in lipopolyscharide-induced endotoxemia in mice.14 In addition to the cell-surface EPCR, soluble EPCR lacking the transmembrane helix of native EPCR interacts with the integrin CD11b/CD18 (Mac-1) (αMβ2) (CR3) on leukocytes (Figure 1), suggesting that binding of soluble EPCR to Mac-1 might regulate leukocytes adhesion.15 Proteinase-3 (PR3), a serine protease with elastase-like properties stored in granules of neutrophils, binds both Mac-1 and soluble EPCR which may be implicated in APC mediated signaling and activation of PC on leukocytes, because soluble EPCR:PR3 complexes bind both APC and PC.15Recent evidence indicates that EPCR is expressed on different cells beyond aortic endothelial cells. For example, EPCR is expressed on the surface of monocytes, CD56+ natural killer cells, neutrophils and eosinophils16–18, immature hematopoietic stem cells,19 brain capillary endothelial cells.13,20 EPCR is also expressed by embryonic giant trophoblast cells, and EPCR is critical for embryo development, because EPCR null mice die in mid-gestation.21 The study by Bretschneider et al, in the present issue of Circulation Research demonstrates functionally active EPCR in systemic vascular smooth muscle cells (SMCs).22 The data show that EPCR mediates APC signaling in SMCs, resulting in increases in intracellular [Ca2+]i, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK-1/2) and DNA synthesis (Figure 1). Along with EPCR, PAR-1 is also necessary to transduce APC signaling in SMCs.These findings are consistent with previous work demonstrating that both EPCR and PAR-1 are required for APC-mediated activation of ERK1/2 and [Ca2+]i signaling in systemic and cerebral capillary endothelial cells.5,20 These findings open a new chapter in biology of EPCR by demonstrating that EPCR can be expressed in cells which have different biological functions from endothelial and hematopoetic cells. In this context, it is of note that the microarray gene expression profiling of human cerebral SMCs and astrocytes have indicated the presence of EPCR mRNA and showed that the levels of EPCR transcripts in these brain cells were not altered by normal aging in humans or aging Alzheimer’s type (R. Zidovetski, N. Chow, B. Zlokovic, unpublished data, 2007). The exact role of EPCR and how its expression is regulated in nonendothelial cell types including systemic SMCs, primitive hematopoetic stem cells or cerebral SMCs, remain to be elucidated.A regulatory element 5.5 kb upstream to the human EPCR gene (hEPCR) translation start site is essential for driving hEPCR expression in endothelium and primitive hematopoetic cells which share a common precursor.23 It would be interesting to find out whether the same site in hEPCR is responsible for driving hEPCR expression in human SMCs.22 The present findings by Bretschneider et al22 raise not only a possibility that EPCR could play an important role in regulating the biology of vascular SMCs, but also suggest that its expression in SMCs might have implications for the pathogenesis of cardiovascular diseases such as atherosclerosis, and by extension, cerebral amyloid angiopathy in Alzheimer’s disease. EPCR may be a potential therapeutic target: novel EPCR agonists might modify cytoprotective APC/PC cellular pathways in injured or inflamed blood vessels.We still have much to learn about the role of EPCR beyond the endothelium, and perhaps in the endothelium itself. For example, Dr Esmon has suggested that EPCR appears to be able to translocate from the plasma membrane into the nucleus, a cellular trafficking pattern that is not observed with its Cys to Ser mutant.24 One may speculate that EPCR may internalize its endogenous ligands PC and APC into the cytoplasm and into the nucleus, which in turn could have important implications for regulation of gene expression and control of APC activity. Figure 2 a shows dense punctate staining of APC on the surface of brain endothelial normoxic cells, which is completely removed by pretreatment of cells with an antibody that blocks APC binding site on EPCR (Figure 2b),25 demonstrating that APC binding to the cell is highly EPCR-dependent, as suggested.1 On the other hand, Figure 2c shows that APC can be transported intracellularly and into the nucleus of brain endothelial cells under hypoxic conditions (Figure 2c), which is associated with cell protection and survival, as reported.13 This transport pattern, however, completely disappears if APC binding to EPCR is blocked (Figure 2d), and cells die as a result of APC unavailability, as shown by faint APC staining on cell debris. Thus, the role of EPCR-APC-PAR-1-dependent intracellular cytoprotective signaling and of EPCR-mediated intracellular trafficking and internalization of APC/PC in normal and injured vascular endothelial cells and SMCs, may open a new era in our understanding of EPCR biology, its physiological and pathological functions, and therapeutic opportunities for disorders of the cardiovascular system and cerebral circulation. Download figureDownload PowerPointFigure 2. Human brain endothelial cells were cultured under normoxic and hypoxic (< 1% oxygen, no glucose) conditions, as we described.10,13,20 Human plasma-derived APC (20 nM) was incubated with cells for 4 hour under either normoxic (A and B) or hypoxic (C and D) conditions in the absence (A and C) and presence (B and D) of an anti-EPCR antibody (RCR-252) which blocks APC binding site on EPCR.25 APC binding was detected by an APC/PC-specific antibody (C3), as described,11,13 using confocal microscopy. In normoxic cells, a punctate staining shows binding of APC to the plasma membrane (A) and complete displacement of APC binding by anti-EPCR antibody (B). In hypoxic cells, APC is internalized into the cytoplasm and nucleus which is associated with the cell survival (C). In contrast, anti-EPCR antibody prevents APC binding to hypoxic cells which is associated with loss of protection and cell death (D), as reported.13The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Berislav V. Zlokovic, MD, PhD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, New York 14642. E-mail [email protected] References 1 Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem. 1994; 269: 26486–26491.CrossrefMedlineGoogle Scholar2 Mosnier LO, Zlokovic BV, Griffin JH The cytoprotective protein C pathway. Blood. 2006. In press.Google Scholar3 Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991; 64: 1057–1068.CrossrefMedlineGoogle Scholar4 Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001; 276: 11199–11203.CrossrefMedlineGoogle Scholar5 Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002; 296: 1880–1882.CrossrefMedlineGoogle Scholar6 Riewald M, Ruf W. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. J Biol Chem. 2005; 280: 19808–19814.CrossrefMedlineGoogle Scholar7 Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW, O’Brien J, Gruber M, Zarini S, Murphy RC, Kuhn K, Richter D, Kast KR, Abraham E. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood. 2004; 104: 3878–3885.CrossrefMedlineGoogle Scholar8 Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR-1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood. 2005; 105: 3178–3184.CrossrefMedlineGoogle Scholar9 Finigan JH, Dudek SM, Singleton PA, Chiang ET, Jacobson JR, Camp SM, Ye SQ, Garcia JG. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J Biol Chem. 2005; 280: 17286–17293.CrossrefMedlineGoogle Scholar10 Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernandez JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006; 12: 1278–1285.CrossrefMedlineGoogle Scholar11 Feistritzer C, Schuepbach RA, Mosnier LO, Bush LA, Di Cera E, Griffin JH, Riewald M. Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem. 2006; 281: 20077–20084.CrossrefMedlineGoogle Scholar12 Taylor FB, Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang ACK, Laszik Z, Kosanke S, Peer G, Esmon CT. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000; 95: 1680–1686.CrossrefMedlineGoogle Scholar13 Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003; 9: 338–342.CrossrefMedlineGoogle Scholar14 Iwaki T, Cruz DT, Martin JA, Castellino FJ. A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse. Blood. 2005; 105: 2364–2371.CrossrefMedlineGoogle Scholar15 Kurosawa S, Esmon CT, Stearns-Kurosawa DJ. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol. 2000; 165: 4697–4703.CrossrefMedlineGoogle Scholar16 Stephenson DA, Toltl LJ, Beaudin S, Liaw PC. Modulation of monocyte function by activated protein C, a natural anticoagulant. J Immunol. 2006; 177: 2115–2122.CrossrefMedlineGoogle Scholar17 Galligan L, Livingstone W, Volkov Y, Hokamp K, Murphy C, Lawler M, Fukudome K, Smith O. Characterization of protein C receptor expression in monocytes. Br J Haematol. 2001; 115: 408–414.CrossrefMedlineGoogle Scholar18 Sturn DH, Kaneider NC, Feistritzer C, Djanani A, Fukudome K, Wiedermann CJ. Expression and function of the endothelial protein C receptor in human neutrophils. Blood. 2003; 102: 1499–1505.CrossrefMedlineGoogle Scholar19 Balazs AB, Fabian AJ, Esmon CT, Mulligan RC. Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood. 2006; 107: 2317–2321.CrossrefMedlineGoogle Scholar20 Domotor E, Benzakour O, Griffin JH, Yule D, Fukudome K, Zlokovic BV. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood. 2003; 101: 4797–4801.CrossrefMedlineGoogle Scholar21 Gu JM, Crawley JTB, Ferrell G, Zhang FJ, Li WH, Esmon NL, Esmon CT. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem. 2002; 277: 43335–43343.CrossrefMedlineGoogle Scholar22 Bretschneider E, Uzonyi B, Weber AA, Fischer JW, Pape R, Lotzer K, Schror K Human Vascular Smooth Muscle Cells Express Functionally Active Endothelial Cell Protein C Receptor. Circ Res. 2007; 100: 255–262.LinkGoogle Scholar23 Mollica LR, Crawley JT, Liu K, Rance JB, Cockerill PN, Follows GA, Landry JR, Wells DJ, Lane DA. Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene. Blood. 2006; 108: 1251–1259.CrossrefMedlineGoogle Scholar24 Esmon CT. The endothelial cell protein C receptor. Thromb Haemost. 2000; 83: 639–643.CrossrefMedlineGoogle Scholar25 Ye X, Fukudome K, Tsuneyoshi N, Satoh T, Tokunaga O, Sugawara K, Mizokami H, Kimoto M. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries. Biochem Biophys Res Commun. 1999; 259: 671–677.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Won T, Wood M, Hughes D, Talor M, Ma Z, Schneider J, Skinner J, Asady B, Goerlich E, Halushka M, Hays A, Kim D, Parikh C, Rosenberg A, Coppens I, Johns R, Gilotra N, Hooper J, Pekosz A and Čiháková D (2022) Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs, eBioMedicine, 10.1016/j.ebiom.2022.103812, 75, (103812), Online publication date: 1-Jan-2022. Gofrit S and Shavit-Stein E (2019) The neuro-glial coagulonome: the thrombin receptor and coagulation pathways as major players in neurological diseases, Neural Regeneration Research, 10.4103/1673-5374.262568, 14:12, (2043), . Negreva M, Georgiev S and Vitlianova K (2016) Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation, Clinical and Applied Thrombosis/Hemostasis, 10.1177/1076029616654262, 23:7, (793-799), Online publication date: 1-Oct-2017. Gera O, Shavit-Stein E, Bushi D, Harnof S, Shimon M, Weiss R, Golderman V, Dori A, Maggio N, Finegold K and Chapman J (2016) Thrombin and protein C pathway in peripheral nerve Schwann cells, Neuroscience, 10.1016/j.neuroscience.2016.10.034, 339, (587-598), Online publication date: 1-Dec-2016. Wang Q, Liu Q, Wang T, Yang H, Han Z and Zhang P (2015) Endothelial cell protein C receptor promotes MGC803 gastric cancer cells proliferation and migration by activating ERK1/2, Medical Oncology, 10.1007/s12032-015-0614-y, 32:5, Online publication date: 1-May-2015. Cayci F, Ekim M, Egin Y, Gökce H, Yalcinkaya F, Ozcakar B and Akar N (2013) An Analysis of the Levels of the Soluble Form of the Endothelial Protein C Receptor in Children with Henoch–Schönlein Purpura, Pediatric Hematology and Oncology, 10.3109/08880018.2013.860648, 32:2, (115-122), Online publication date: 17-Feb-2015. Genc K (2009) The involvement of Nrf2-mediated antioxidant defense in neurovascular protection by activated protein C, Bioscience Hypotheses, 10.1016/j.bihy.2008.09.007, 2:3, (188-189), Online publication date: 1-Jan-2009. Nayak R, Sen P, Ghosh S, Gopalakrishnan R, Esmon C, Pendurthi U and Rao L (2009) Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications, Blood, 10.1182/blood-2009-03-208900, 114:9, (1974-1986), Online publication date: 27-Aug-2009. Deane R, LaRue B, Sagare A, Castellino F, Zhong Z and Zlokovic B (2008) Endothelial Protein C Receptor-Assisted Transport of Activated Protein C across the Mouse Blood—Brain Barrier, Journal of Cerebral Blood Flow & Metabolism, 10.1038/jcbfm.2008.117, 29:1, (25-33), Online publication date: 1-Jan-2009. Orfanos S, Maniatis N and Kotanidou A (2008) The Effects of Activated Protein C on the Septic Endothelium Yearbook of Intensive Care and Emergency Medicine, 10.1007/978-3-540-77290-3_67, (721-729), . Orfanos S, Maniatis N and Kotanidou A The Effects of Activated Protein C on the Septic Endothelium Intensive Care Medicine, 10.1007/978-0-387-77383-4_67, (721-729) Wang Q, Tang Y, Wang T, Yang H, Wang X, Ma H and Zhang P (2018) EPCR promotes MGC803 human gastric cancer cell tumor angiogenesis in�vitro through activating ERK1/2 and AKT in a PAR1‑dependent manner, Oncology Letters, 10.3892/ol.2018.8869 Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, Thiyagarajan M, Deane R, Fernandez J, Lane S, Zlokovic A, Liu T, Griffin J, Chow N, Castellino F, Stojanovic K, Cleveland D and Zlokovic B (2009) Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells, Journal of Clinical Investigation, 10.1172/JCI38476 February 2, 2007Vol 100, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000258167.48227.84PMID: 17272817 Originally publishedFebruary 2, 2007 Keywordsprotease activated receptor-1endotheliumvascular smooth muscle cellsactivated protein Cendothelial protein C receptorPDF download Advertisement" @default.
• W2103402823 created "2016-06-24" @default.
• W2103402823 creator A5017164865 @default.
• W2103402823 creator A5036566811 @default.
• W2103402823 creator A5039691328 @default.
• W2103402823 date "2007-02-02" @default.
• W2103402823 modified "2023-10-18" @default.
• W2103402823 title "Endothelial Cell Protein C Receptor" @default.
• W2103402823 cites W1508779802 @default.
• W2103402823 cites W1566872112 @default.
• W2103402823 cites W1570103822 @default.
• W2103402823 cites W172709144 @default.
• W2103402823 cites W1969909530 @default.
• W2103402823 cites W1984849676 @default.
• W2103402823 cites W1991830982 @default.
• W2103402823 cites W1992217074 @default.
• W2103402823 cites W1994292141 @default.
• W2103402823 cites W1999902547 @default.
• W2103402823 cites W2000985786 @default.
• W2103402823 cites W2020363094 @default.
• W2103402823 cites W2026106674 @default.
• W2103402823 cites W2040968233 @default.
• W2103402823 cites W2050569979 @default.
• W2103402823 cites W2054493150 @default.
• W2103402823 cites W2063908549 @default.
• W2103402823 cites W2065227956 @default.
• W2103402823 cites W2077392251 @default.
• W2103402823 cites W2081753893 @default.
• W2103402823 cites W2125418204 @default.
• W2103402823 cites W2140432387 @default.
• W2103402823 cites W2146884753 @default.
• W2103402823 cites W2147489014 @default.
• W2103402823 cites W60494188 @default.
• W2103402823 doi "https://doi.org/10.1161/01.res.0000258167.48227.84" @default.
• W2103402823 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17272817" @default.
• W2103402823 hasPublicationYear "2007" @default.
• W2103402823 type Work @default.
• W2103402823 sameAs 2103402823 @default.
• W2103402823 citedByCount "19" @default.
• W2103402823 countsByYear W21034028232013 @default.
• W2103402823 countsByYear W21034028232014 @default.
• W2103402823 countsByYear W21034028232015 @default.
• W2103402823 countsByYear W21034028232016 @default.
• W2103402823 countsByYear W21034028232017 @default.
• W2103402823 countsByYear W21034028232018 @default.
• W2103402823 countsByYear W21034028232019 @default.
• W2103402823 countsByYear W21034028232022 @default.
• W2103402823 crossrefType "journal-article" @default.
• W2103402823 hasAuthorship W2103402823A5017164865 @default.
• W2103402823 hasAuthorship W2103402823A5036566811 @default.
• W2103402823 hasAuthorship W2103402823A5039691328 @default.
• W2103402823 hasBestOaLocation W21034028231 @default.
• W2103402823 hasConcept C170493617 @default.
• W2103402823 hasConcept C185592680 @default.
• W2103402823 hasConcept C55493867 @default.
• W2103402823 hasConcept C86803240 @default.
• W2103402823 hasConcept C95444343 @default.
• W2103402823 hasConceptScore W2103402823C170493617 @default.
• W2103402823 hasConceptScore W2103402823C185592680 @default.
• W2103402823 hasConceptScore W2103402823C55493867 @default.
• W2103402823 hasConceptScore W2103402823C86803240 @default.
• W2103402823 hasConceptScore W2103402823C95444343 @default.
• W2103402823 hasIssue "2" @default.
• W2103402823 hasLocation W21034028231 @default.
• W2103402823 hasLocation W21034028232 @default.
• W2103402823 hasOpenAccess W2103402823 @default.
• W2103402823 hasPrimaryLocation W21034028231 @default.
• W2103402823 hasRelatedWork W1976229112 @default.
• W2103402823 hasRelatedWork W1984089825 @default.
• W2103402823 hasRelatedWork W2035184614 @default.
• W2103402823 hasRelatedWork W2041734989 @default.
• W2103402823 hasRelatedWork W2050316456 @default.
• W2103402823 hasRelatedWork W2078422320 @default.
• W2103402823 hasRelatedWork W2125589729 @default.
• W2103402823 hasRelatedWork W2142925367 @default.
• W2103402823 hasRelatedWork W2270573517 @default.
• W2103402823 hasRelatedWork W351849447 @default.
• W2103402823 hasVolume "100" @default.
• W2103402823 isParatext "false" @default.
• W2103402823 isRetracted "false" @default.
• W2103402823 magId "2103402823" @default.
• W2103402823 workType "article" @default.