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Volumn 181, Issue 12, 2008, Pages 8288-8297

Dendritic cell differentiation signals induce anti-inflammatory properties in human adult microglia

Author keywords

[No Author keywords available]

Indexed keywords

CD209 ANTIGEN; CYTOKINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 12P70; INTERLEUKIN 4; LIPOPOLYSACCHARIDE; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; AUTACOID; HLA ANTIGEN CLASS 1; HLA ANTIGEN CLASS 2;

EID: 58849147077     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.181.12.8288     Document Type: Article
Times cited : (37)

References (50)
  • 1
    • 16244417773 scopus 로고    scopus 로고
    • Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis
    • McMahon, E. J., S. L. Bailey, C. V. Castenada, H. Waldner, and S. D. Miller. 2005. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat. Med. 11: 335-339.
    • (2005) Nat. Med. , vol.11 , pp. 335-339
    • McMahon, E.J.1    Bailey, S.L.2    Castenada, C.V.3    Waldner, H.4    Miller, S.D.5
  • 2
    • 34249049841 scopus 로고    scopus 로고
    • Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis
    • Miller, S. D., E. J. McMahon, B. Schreiner, and S. L. Bailey. 2007. Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann. NY Acad. Sci. 1103: 179-191.
    • (2007) Ann. NY Acad. Sci. , vol.1103 , pp. 179-191
    • Miller, S.D.1    McMahon, E.J.2    Schreiner, B.3    Bailey, S.L.4
  • 3
    • 0033564675 scopus 로고    scopus 로고
    • Colonisation of the developing human brain and spinal cord by microglia: A review
    • DOI 10.1002/(SICI)1097-0029(19990615)45:6<359::AID-JEMT4>3.0.CO;2-D
    • Rezaie, P., and D. Male. 1999. Colonisation of the developing human brain and spinal cord by microglia: a review. Microsc. Res. Tech. 45: 359-382. (Pubitemid 29321051)
    • (1999) Microscopy Research and Technique , vol.45 , Issue.6 , pp. 359-382
    • Rezaie, P.1    Male, D.2
  • 4
    • 36448994709 scopus 로고    scopus 로고
    • Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
    • DOI 10.1038/nn2014, PII NN2014
    • Ajami, B., J. L. Bennett, C. Krieger, W. Tetzlaff, and F. M. Rossi. 2007. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10: 1538-1543. (Pubitemid 350175883)
    • (2007) Nature Neuroscience , vol.10 , Issue.12 , pp. 1538-1543
    • Ajami, B.1    Bennett, J.L.2    Krieger, C.3    Tetzlaff, W.4    Rossi, F.M.V.5
  • 5
    • 6944234040 scopus 로고    scopus 로고
    • Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia
    • Simard, A. R., and S. Rivest. 2004. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. FASEB J. 18: 998-1000.
    • (2004) FASEB J. , vol.18 , pp. 998-1000
    • Simard, A.R.1    Rivest, S.2
  • 7
    • 39749173780 scopus 로고    scopus 로고
    • The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells
    • Ifergan, I., H. Kebir, M. Bernard, K. Wosik, A. Dodelet-Devillers, R. Cayrol, N. Arbour, and A. Prat. 2008. The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 131: 785-799.
    • (2008) Brain , vol.131 , pp. 785-799
    • Ifergan, I.1    Kebir, H.2    Bernard, M.3    Wosik, K.4    Dodelet-Devillers, A.5    Cayrol, R.6    Arbour, N.7    Prat, A.8
  • 8
    • 34247506378 scopus 로고    scopus 로고
    • Duration, combination and timing: The signal integration model of dendritic cell activation
    • DOI 10.1016/j.it.2007.03.008, PII S1471490607000798
    • Macagno, A., G. Napolitani, A. Lanzavecchia, and F. Sallusto. 2007. Duration, combination and timing: the signal integration model of dendritic cell activation. Trends Immunol. 28: 227-233. (Pubitemid 46654873)
    • (2007) Trends in Immunology , vol.28 , Issue.5 , pp. 227-233
    • Macagno, A.1    Napolitani, G.2    Lanzavecchia, A.3    Sallusto, F.4
  • 9
    • 33846018916 scopus 로고    scopus 로고
    • GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis
    • Ponomarev, E. D., L. P. Shriver, K. Maresz, J. Pedras-Vasconcelos, D. Verthelyi, and B. N. Dittel. 2007. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178: 39-48.
    • (2007) J. Immunol. , vol.178 , pp. 39-48
    • Ponomarev, E.D.1    Shriver, L.P.2    Maresz, K.3    Pedras-Vasconcelos, J.4    Verthelyi, D.5    Dittel, B.N.6
  • 10
    • 35148835215 scopus 로고    scopus 로고
    • CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells
    • Ponomarev, E. D., K. Maresz, Y. Tan, and B. N. Dittel. 2007. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J. Neurosci. 27: 10714-10721.
    • (2007) J. Neurosci. , vol.27 , pp. 10714-10721
    • Ponomarev, E.D.1    Maresz, K.2    Tan, Y.3    Dittel, B.N.4
  • 11
    • 0036544764 scopus 로고    scopus 로고
    • Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions
    • DOI 10.1002/glia.10050
    • Hulshof, S., L. Montagne, C. J. De Groot, and P. Van Der Valk. 2002. Cellular localization and expression patterns of interleukin-10, interleukin-4, and their receptors in multiple sclerosis lesions. Glia 38: 24-35. (Pubitemid 34890653)
    • (2002) GLIA , vol.38 , Issue.1 , pp. 24-35
    • Hulshof, S.1    Montagne, L.2    De Groot, C.J.A.3    Van Valk, P.D.4
  • 14
    • 0034651767 scopus 로고    scopus 로고
    • Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells
    • Aloisi, F., R. De Simone, S. Columba-Cabezas, G. Penna, and L. Adorini. 2000. Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells. J. Immunol. 164: 1705-1712. (Pubitemid 30108719)
    • (2000) Journal of Immunology , vol.164 , Issue.4 , pp. 1705-1712
    • Aloisi, F.1    De Simone, R.2    Columba-Cabezas, S.3    Penna, G.4    Adorini, L.5
  • 17
    • 34047116376 scopus 로고    scopus 로고
    • Effects of low dose GM-CSF on microglial inflammatory profiles to diverse pathogen-associated molecular patterns (PAMPs)
    • Esen, N., and T. Kielian. 2007. Effects of low dose GM-CSF on microglial inflammatory profiles to diverse pathogen-associated molecular patterns (PAMPs). J. Neuroinflamm. 4: 1-18.
    • (2007) J. Neuroinflamm. , vol.4 , pp. 1-18
    • Esen, N.1    Kielian, T.2
  • 19
    • 0028122330 scopus 로고
    • HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro
    • Ulvestad, E., K. Williams, L. Bo, B. Trapp, J. Antel, and S. Mork. 1994. HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro. Immunology 82: 535-541.
    • (1994) Immunology , vol.82 , pp. 535-541
    • Ulvestad, E.1    Williams, K.2    Bo, L.3    Trapp, B.4    Antel, J.5    Mork, S.6
  • 21
    • 20444397764 scopus 로고    scopus 로고
    • Development of a culture system that supports adult microglial cell proliferation and maintenance in the resting state
    • Ponomarev, E. D., M. Novikova, K. Maresz, L. P. Shriver, and B. N. Dittel. 2005. Development of a culture system that supports adult microglial cell proliferation and maintenance in the resting state. J. Immunol. Methods 300: 32-46.
    • (2005) J. Immunol. Methods , vol.300 , pp. 32-46
    • Ponomarev, E.D.1    Novikova, M.2    Maresz, K.3    Shriver, L.P.4    Dittel, B.N.5
  • 22
    • 2442698974 scopus 로고    scopus 로고
    • Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis
    • Kim, H. J., I. Ifergan, J. P. Antel, R. Seguin, M. Duddy, Y. Lapierre, F. Jalili, and A. Bar-Or. 2004. Type 2 monocyte and microglia differentiation mediated by glatiramer acetate therapy in patients with multiple sclerosis. J. Immunol. 172: 7144-7153.
    • (2004) J. Immunol. , vol.172 , pp. 7144-7153
    • Kim, H.J.1    Ifergan, I.2    Antel, J.P.3    Seguin, R.4    Duddy, M.5    Lapierre, Y.6    Jalili, F.7    Bar-Or, A.8
  • 23
    • 0028838289 scopus 로고
    • Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury
    • D'Souza, S., K. Alinauskas, E. McCrea, C. Goodyer, and J. P. Antel. 1995. Differential susceptibility of human CNS-derived cell populations to TNF-dependent and independent immune-mediated injury. J. Neurosci. 15: 7293-7300.
    • (1995) J. Neurosci. , vol.15 , pp. 7293-7300
    • D'Souza, S.1    Alinauskas, K.2    McCrea, E.3    Goodyer, C.4    Antel, J.P.5
  • 24
    • 0002370344 scopus 로고
    • Culture of glial cells from human biopsies
    • S. Fedoroff and A. Richardson, eds. Humana, New York
    • Yong, V. W., and J. P. Antel. 1992. Culture of glial cells from human biopsies. In Protocols for Neural Cell Culture. S. Fedoroff and A. Richardson, eds. Humana, New York, pp. 81-96.
    • (1992) Protocols for Neural Cell Culture , pp. 81-96
    • Yong, V.W.1    Antel, J.P.2
  • 26
    • 0022922108 scopus 로고
    • Characterization of ameboid microglia isolated from developing mammalian brain
    • Giulian, D., and T. J. Baker. 1986. Characterization of ameboid microglia isolated from developing mammalian brain. J. Neurosci. 6: 2163-2178. (Pubitemid 16043659)
    • (1986) Journal of Neuroscience , vol.6 , Issue.8 , pp. 2163-2178
    • Giulian, D.1    Baker, T.J.2
  • 28
    • 0028289244 scopus 로고
    • Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α
    • Sallusto, F., and A. Lanzavecchia. 1994. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony- stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J. Exp. Med. 179: 1109-1118. (Pubitemid 24091769)
    • (1994) Journal of Experimental Medicine , vol.179 , Issue.4 , pp. 1109-1118
    • Sallusto, F.1    Lanzavecchia, A.2
  • 29
    • 0034598934 scopus 로고    scopus 로고
    • Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses
    • Geijtenbeek, T. B., R. Torensma, S. J. van Vliet, G. C. van Duijnhoven, G. J. Adema, Y. van Kooyk, and C. G. Figdor. 2000. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100: 575-585.
    • (2000) Cell , vol.100 , pp. 575-585
    • Geijtenbeek, T.B.1    Torensma, R.2    Van Vliet, S.J.3    Van Duijnhoven, G.C.4    Adema, G.J.5    Van Kooyk, Y.6    Figdor, C.G.7
  • 30
    • 36448952375 scopus 로고    scopus 로고
    • CD1 antigen presentation: How it works
    • Barral, D. C., and M. B. Brenner. 2007. CD1 antigen presentation: how it works. Nat. Rev. Immunol. 7: 929-941.
    • (2007) Nat. Rev. Immunol. , vol.7 , pp. 929-941
    • Barral, D.C.1    Brenner, M.B.2
  • 31
    • 0033054350 scopus 로고    scopus 로고
    • Lipopolysaccharide can block the potential of monocytes to differentiate into dendritic cells
    • Palucka, K. A., N. Taquet, F. Sanchez-Chapuis, and J. C. Gluckman. 1999. Lipopolysaccharide can block the potential of monocytes to differentiate into dendritic cells. J. Leukocyte Biol. 65: 232-240.
    • (1999) J. Leukocyte Biol. , vol.65 , pp. 232-240
    • Palucka, K.A.1    Taquet, N.2    Sanchez-Chapuis, F.3    Gluckman, J.C.4
  • 32
    • 0029148878 scopus 로고
    • Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Downregulation by cytokines and bacterial products
    • Sallusto, F., M. Cella, C. Danieli, and A. Lanzavecchia. 1995. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182: 389-400.
    • (1995) J. Exp. Med. , vol.182 , pp. 389-400
    • Sallusto, F.1    Cella, M.2    Danieli, C.3    Lanzavecchia, A.4
  • 33
    • 41549134361 scopus 로고    scopus 로고
    • Th17 cell differentiation: The long and winding road
    • McGeachy, M. J., and D. J. Cua. 2008. Th17 cell differentiation: the long and winding road. Immunity 28: 445-453.
    • (2008) Immunity , vol.28 , pp. 445-453
    • McGeachy, M.J.1    Cua, D.J.2
  • 34
    • 33846146647 scopus 로고    scopus 로고
    • Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation
    • Krasowska-Zoladek, A., M. Banaszewska, M. Kraszpulski, and G. W. Konat. 2007. Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation. J. Neurosci. Res. 85: 205-212.
    • (2007) J. Neurosci. Res. , vol.85 , pp. 205-212
    • Krasowska-Zoladek, A.1    Banaszewska, M.2    Kraszpulski, M.3    Konat, G.W.4
  • 35
    • 0034092962 scopus 로고    scopus 로고
    • Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue
    • De Groot, C. J., L. Montagne, I. Janssen, R. Ravid, P. Van Der Valk, and R. Veerhuis. 2000. Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue. Brain Res. Brain Res. Protoc. 5: 85-94.
    • (2000) Brain Res. Brain Res. Protoc. , vol.5 , pp. 85-94
    • De Groot, C.J.1    Montagne, L.2    Janssen, I.3    Ravid, R.4    Van Der Valk, P.5    Veerhuis, R.6
  • 37
    • 0029781523 scopus 로고    scopus 로고
    • Regulation of CD14 expression on human adult central nervous system- Derived microglia
    • DOI 10.1002/(SICI)1097-4547(19960815)45:4<375::AID-JNR6>3.0.CO;2-6
    • Becher, B., V. Fedorowicz, and J. P. Antel. 1996. Regulation of CD14 expression on human adult central nervous system-derived microglia. J. Neurosci. Res. 45: 375-381. (Pubitemid 26299592)
    • (1996) Journal of Neuroscience Research , vol.45 , Issue.4 , pp. 375-381
    • Becher, B.1    Fedorowicz, V.2    Antel, J.P.3
  • 38
    • 0019743246 scopus 로고
    • Microglia in the prenatal mouse neostriatum and spinal cord
    • Sturrock, R. R. 1981. Microglia in the prenatal mouse neostriatum and spinal cord. J. Anat. 133: 499-512.
    • (1981) J. Anat. , vol.133 , pp. 499-512
    • Sturrock, R.R.1
  • 39
    • 0036346058 scopus 로고    scopus 로고
    • Motility and ramification of human fetal microglia in culture: An investigation using time-lapse video microscopy and image analysis
    • DOI 10.1006/excr.2001.5431
    • Rezaie, P., G. Trillo-Pazos, J. Greenwood, I. P. Everall, and D. K. Male. 2002. Motility and ramification of human fetal microglia in culture: an investigation using time-lapse video microscopy and image analysis. Exp. Cell Res. 274: 68-82. (Pubitemid 34936830)
    • (2002) Experimental Cell Research , vol.274 , Issue.1 , pp. 68-82
    • Rezaie, P.1    Trillo-Pazos, G.2    Greenwood, J.3    Everall, I.P.4    Male, D.K.5
  • 40
    • 0025696092 scopus 로고
    • Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes
    • Ferrer, I., E. Bernet, E. Soriano, T. del Rio, and M. Fonseca. 1990. Naturally occurring cell death in the cerebral cortex of the rat and removal of dead cells by transitory phagocytes. Neuroscience 39: 451-458.
    • (1990) Neuroscience , vol.39 , pp. 451-458
    • Ferrer, I.1    Bernet, E.2    Soriano, E.3    Del Rio, T.4    Fonseca, M.5
  • 41
    • 0028026864 scopus 로고
    • Interleukin-4 induces proliferation and activation of microglia but suppresses their induction of class II major histocompatibility complex antigen expression
    • DOI 10.1016/0165-5728(94)90031-0
    • Suzumura, A., M. Sawada, Y. Itoh, and T. Marunouchi. 1994. Interleukin-4 induces proliferation and activation of microglia but suppresses their induction of class II major histocompatibility complex antigen expression. J. Neuroimmunol. 53: 209-218. (Pubitemid 24272012)
    • (1994) Journal of Neuroimmunology , vol.53 , Issue.2 , pp. 209-218
    • Suzumura, A.1    Sawada, M.2    Itoh, Y.3    Marunouchi, T.4
  • 42
    • 0027238093 scopus 로고
    • Macrophage colony-stimulating factor in human fetal astrocytes and microglia: Differential regulation by cytokines and lipopolysaccharide, and modulation of class II MHC on microglia
    • Lee, S. C., W. Liu, P. Roth, D. W. Dickson, J. W. Berman, and C. F. Brosnan. 1993. Macrophage colony-stimulating factor in human fetal astrocytes and microglia: differential regulation by cytokines and lipopolysaccharide, and modulation of class II MHC on microglia. J. Immunol. 150: 594-604.
    • (1993) J. Immunol. , vol.150 , pp. 594-604
    • Lee, S.C.1    Liu, W.2    Roth, P.3    Dickson, D.W.4    Berman, J.W.5    Brosnan, C.F.6
  • 43
    • 0030250932 scopus 로고    scopus 로고
    • Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia
    • DOI 10.1002/(SICI)1098-1136(199609)18:1<1::AID-GLIA1>3.0.CO;2-6
    • Becher, B., and J. P. Antel. 1996. Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 18: 1-10. (Pubitemid 26369596)
    • (1996) GLIA , vol.18 , Issue.1 , pp. 1-10
    • Becher, B.1    Antel, J.P.2
  • 44
    • 0032519925 scopus 로고    scopus 로고
    • Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and PAF
    • Fadok, V. A., D. L. Bratton, A. Konowal, P. W. Freed, J. Y. Westcott, and P. M. Henson. 1998. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and PAF. J. Clin. Invest. 101: 890-898.
    • (1998) J. Clin. Invest. , vol.101 , pp. 890-898
    • Fadok, V.A.1    Bratton, D.L.2    Konowal, A.3    Freed, P.W.4    Westcott, J.Y.5    Henson, P.M.6
  • 45
    • 0027434423 scopus 로고
    • Differentiation driven by granulocyte-macrophage colonystimulating factor endows microglia with interferon-gamma-independent antigen presentation function
    • Fischer, H. G., B. Nitzgen, T. Germann, K. Degitz, W. Daubener, and U. Hadding. 1993. Differentiation driven by granulocyte-macrophage colonystimulating factor endows microglia with interferon-gamma-independent antigen presentation function. J. Neuroimmunol. 42: 87-95.
    • (1993) J. Neuroimmunol. , vol.42 , pp. 87-95
    • Fischer, H.G.1    Nitzgen, B.2    Germann, T.3    Degitz, K.4    Daubener, W.5    Hadding, U.6
  • 46
    • 0033992220 scopus 로고    scopus 로고
    • CD40 engagement stimulates IL-12 p70 production by human microglial cells: Basis for Th1 polarization in the CNS
    • Becher, B., M. Blain, and J. P. Antel. 2000. CD40 engagement stimulates IL-12 p70 production by human microglial cells: basis for Th1 polarization in the CNS. J. Neuroimmunol. 102: 44-50.
    • (2000) J. Neuroimmunol. , vol.102 , pp. 44-50
    • Becher, B.1    Blain, M.2    Antel, J.P.3
  • 47
    • 10344256789 scopus 로고    scopus 로고
    • Resistance of human adult oligodendrocytes to AMPA/kainate receptormediated glutamate injury
    • Wosik, K., F. Ruffini, G. Almazan, A. Olivier, J. Nalbantoglu, and J. P. Antel. 2004. Resistance of human adult oligodendrocytes to AMPA/kainate receptormediated glutamate injury. Brain 127: 2636-2648.
    • (2004) Brain , vol.127 , pp. 2636-2648
    • Wosik, K.1    Ruffini, F.2    Almazan, G.3    Olivier, A.4    Nalbantoglu, J.5    Antel, J.P.6
  • 50
    • 33846593869 scopus 로고    scopus 로고
    • Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia
    • DOI 10.1093/brain/awl273
    • Li, Y., N. Chu, A. Hu, B. Gran, A. Rostami, and G. X. Zhang. 2007. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 130: 490-501. (Pubitemid 46181102)
    • (2007) Brain , vol.130 , Issue.2 , pp. 490-501
    • Li, Y.1    Chu, N.2    Hu, A.3    Gran, B.4    Rostami, A.5    Zhang, G.-X.6


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