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Volumn 128, Issue 6, 2015, Pages 1230-1240

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions

Author keywords

Cytoneme; GPCR; Lgr5; Stem cell

Indexed keywords

ACTIN; BETA ARRESTIN 2; CARRIER PROTEIN; CYTOCHALASIN B; F ACTIN; G PROTEIN COUPLED RECEPTOR; LGR4 PROTEIN; LGR5 PROTEIN; MYOSIN X; UNCLASSIFIED DRUG; ARRB2 PROTEIN, HUMAN; BETA ARRESTIN; LGR4 PROTEIN, HUMAN; LGR5 PROTEIN, HUMAN; RETINA S ANTIGEN;

EID: 84925422793     PISSN: 00219533     EISSN: 14779137     Source Type: Journal    
DOI: 10.1242/jcs.166322     Document Type: Article
Times cited : (40)

References (59)
  • 1
    • 0034698675 scopus 로고    scopus 로고
    • Stimulation of fascin spikes by thrombospondin-1 is mediated by the GTPases Rac and Cdc42
    • Adams, J. C. and Schwartz, M. A. (2000). Stimulation of fascin spikes by thrombospondin-1 is mediated by the GTPases Rac and Cdc42. J. Cell Biol. 150, 807-822.
    • (2000) J. Cell Biol. , vol.150 , pp. 807-822
    • Adams, J.C.1    Schwartz, M.A.2
  • 2
    • 79954621221 scopus 로고    scopus 로고
    • Cell biology. Cytonemes show their colors
    • Affolter, M. and Basler, K. (2011). Cell biology. Cytonemes show their colors. Science 332, 312-313.
    • (2011) Science , vol.332 , pp. 312-313
    • Affolter, M.1    Basler, K.2
  • 3
    • 65549086510 scopus 로고    scopus 로고
    • Temporally precise in vivo control of intracellular signalling
    • Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H. and Deisseroth, K. (2009). Temporally precise in vivo control of intracellular signalling. Nature 458, 1025-1029.
    • (2009) Nature , vol.458 , pp. 1025-1029
    • Airan, R.D.1    Thompson, K.R.2    Fenno, L.E.3    Bernstein, H.4    Deisseroth, K.5
  • 5
    • 0030736417 scopus 로고    scopus 로고
    • A betaarrestin/ green fluorescent protein biosensor for detecting G protein-coupled receptor activation
    • Barak, L. S., Ferguson, S. S., Zhang, J. and Caron, M. G. (1997). A betaarrestin/ green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J. Biol. Chem. 272, 27497-27500.
    • (1997) J. Biol. Chem. , vol.272 , pp. 27497-27500
    • Barak, L.S.1    Ferguson, S.S.2    Zhang, J.3    Caron, M.G.4
  • 10
    • 0036122307 scopus 로고    scopus 로고
    • Myosin-X is an unconventional myosin that undergoes intrafilopodial motility
    • Berg, J. S. and Cheney, R. E. (2002). Myosin-X is an unconventional myosin that undergoes intrafilopodial motility. Nat. Cell Biol. 4, 246-250.
    • (2002) Nat. Cell Biol. , vol.4 , pp. 246-250
    • Berg, J.S.1    Cheney, R.E.2
  • 11
    • 36749017979 scopus 로고    scopus 로고
    • Filopodial actin bundles are not necessary for microtubule advance into the peripheral domain of Aplysia neuronal growth cones
    • Burnette, D. T., Schaefer, A. W., Ji, L., Danuser, G. and Forscher, P. (2007). Filopodial actin bundles are not necessary for microtubule advance into the peripheral domain of Aplysia neuronal growth cones. Nat. Cell Biol. 9, 1360-1369.
    • (2007) Nat. Cell Biol. , vol.9 , pp. 1360-1369
    • Burnette, D.T.1    Schaefer, A.W.2    Ji, L.3    Danuser, G.4    Forscher, P.5
  • 12
    • 84905279377 scopus 로고    scopus 로고
    • Elevated expression of myosin X in tumours contributes to breast cancer aggressiveness and metastasis
    • Cao, R., Chen, J., Zhang, X., Zhai, Y., Qing, X., Xing, W., Zhang, L., Malik, Y. S., Yu, H. and Zhu, X. (2014). Elevated expression of myosin X in tumours contributes to breast cancer aggressiveness and metastasis. Br. J. Cancer 111, 539-550.
    • (2014) Br. J. Cancer , vol.111 , pp. 539-550
    • Cao, R.1    Chen, J.2    Zhang, X.3    Zhai, Y.4    Qing, X.5    Xing, W.6    Zhang, L.7    Malik, Y.S.8    Yu, H.9    Zhu, X.10
  • 13
    • 79960990066 scopus 로고    scopus 로고
    • R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/ beta-catenin signaling
    • Carmon, K. S., Gong, X., Lin, Q., Thomas, A. and Liu, Q. (2011). R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/ beta-catenin signaling. Proc. Natl. Acad. Sci. USA 108, 11452-11457.
    • (2011) Proc. Natl. Acad. Sci. USA , vol.108 , pp. 11452-11457
    • Carmon, K.S.1    Gong, X.2    Lin, Q.3    Thomas, A.4    Liu, Q.5
  • 14
    • 84864021917 scopus 로고    scopus 로고
    • LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/b-catenin signaling
    • Carmon, K. S., Lin, Q., Gong, X., Thomas, A. and Liu, Q. (2012). LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/b-catenin signaling. Mol. Cell. Biol. 32, 2054-2064.
    • (2012) Mol. Cell. Biol. , vol.32 , pp. 2054-2064
    • Carmon, K.S.1    Lin, Q.2    Gong, X.3    Thomas, A.4    Liu, Q.5
  • 15
    • 84897565798 scopus 로고    scopus 로고
    • RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling
    • Carmon, K. S., Gong, X., Yi, J., Thomas, A. and Liu, Q. (2014). RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling. Proc. Natl. Acad. Sci. USA 111, E1221-E1229.
    • (2014) Proc. Natl. Acad. Sci. USA , vol.111 , pp. E1221-E1229
    • Carmon, K.S.1    Gong, X.2    Yi, J.3    Thomas, A.4    Liu, Q.5
  • 16
    • 0024414571 scopus 로고
    • Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells
    • Chen, W. T. (1989). Proteolytic activity of specialized surface protrusions formed at rosette contact sites of transformed cells. J. Exp. Zool. 251, 167-185.
    • (1989) J. Exp. Zool. , vol.251 , pp. 167-185
    • Chen, W.T.1
  • 17
    • 84881480493 scopus 로고    scopus 로고
    • Adenosine-A3 receptors in neutrophil microdomains promote the formation of bacteria-tethering cytonemes
    • Corriden, R., Self, T., Akong-Moore, K., Nizet, V., Kellam, B., Briddon, S. J. and Hill, S. J. (2013). Adenosine-A3 receptors in neutrophil microdomains promote the formation of bacteria-tethering cytonemes. EMBO Rep. 14, 726- 732.
    • (2013) EMBO Rep. , vol.14 , pp. 726-732
    • Corriden, R.1    Self, T.2    Akong-Moore, K.3    Nizet, V.4    Kellam, B.5    Briddon, S.J.6    Hill, S.J.7
  • 18
    • 0032581498 scopus 로고    scopus 로고
    • The gene encoding the granulocyte colony-stimulating factor receptor is a target for deregulation in pre-B ALL by the t(1;19)-specific oncoprotein E2A-Pbx1
    • de Lau, W. B., Hurenkamp, J., Berendes, P., Touw, I. P., Clevers, H. C. and van Dijk, M. A. (1998). The gene encoding the granulocyte colony-stimulating factor receptor is a target for deregulation in pre-B ALL by the t(1;19)-specific oncoprotein E2A-Pbx1. Oncogene 17, 503-510.
    • (1998) Oncogene , vol.17 , pp. 503-510
    • de Lau, W.B.1    Hurenkamp, J.2    Berendes, P.3    Touw, I.P.4    Clevers, H.C.5    van Dijk, M.A.6
  • 20
    • 33645785590 scopus 로고    scopus 로고
    • Spemann's organizer and self-regulation in amphibian embryos
    • De Robertis, E. M. (2006). Spemann's organizer and self-regulation in amphibian embryos. Nat. Rev. Mol. Cell Biol. 7, 296-302.
    • (2006) Nat. Rev. Mol. Cell Biol. , vol.7 , pp. 296-302
    • De Robertis, E.M.1
  • 21
  • 22
    • 84878657424 scopus 로고    scopus 로고
    • Multi-functional norrin is a ligand for the LGR4 receptor
    • Deng, C., Reddy, P., Cheng, Y., Luo, C. W., Hsiao, C. L. and Hsueh, A. J. (2013). Multi-functional norrin is a ligand for the LGR4 receptor. J. Cell Sci. 126, 2060-2068.
    • (2013) J. Cell Sci. , vol.126 , pp. 2060-2068
    • Deng, C.1    Reddy, P.2    Cheng, Y.3    Luo, C.W.4    Hsiao, C.L.5    Hsueh, A.J.6
  • 23
    • 84907222540 scopus 로고    scopus 로고
    • Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses
    • Guan, X., Duan, Y., Zeng, Q., Pan, H., Qian, Y., Li, D., Cao, X. and Liu, M. (2014). Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses. J. Biol. Chem. 289, 26492-26504.
    • (2014) J. Biol. Chem. , vol.289 , pp. 26492-26504
    • Guan, X.1    Duan, Y.2    Zeng, Q.3    Pan, H.4    Qian, Y.5    Li, D.6    Cao, X.7    Liu, M.8
  • 24
    • 0345314118 scopus 로고
    • Cellular mechanisms in the morphogenesis of the sea urchin embryo Cell contacts within the ectoderm and between mesenchyme and ectoderm cells.
    • Gustafson, T. (1963). Cellular mechanisms in the morphogenesis of the sea urchin embryo. Cell contacts within the ectoderm and between mesenchyme and ectoderm cells. Exp. Cell Res. 32, 570-589.
    • (1963) Exp. Cell Res. , vol.32 , pp. 570-589
    • Gustafson, T.1
  • 25
    • 25644439969 scopus 로고    scopus 로고
    • Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic
    • Hsiung, F., Ramirez-Weber, F.-A., Iwaki, D. D. and Kornberg, T. B. (2005). Dependence of Drosophila wing imaginal disc cytonemes on Decapentaplegic. Nature 437, 560-563.
    • (2005) Nature , vol.437 , pp. 560-563
    • Hsiung, F.1    Ramirez-Weber, F.-A.2    Iwaki, D.D.3    Kornberg, T.B.4
  • 26
    • 0000437998 scopus 로고    scopus 로고
    • Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region
    • Hsu, S. Y., Liang, S.-G. and Hsueh, A. J. W. (1998). Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol. 12, 1830-1845.
    • (1998) Mol. Endocrinol. , vol.12 , pp. 1830-1845
    • Hsu, S.Y.1    Liang, S.-G.2    Hsueh, A.J.W.3
  • 27
    • 0034464024 scopus 로고    scopus 로고
    • The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7
    • Hsu, S. Y., Kudo, M., Chen, T., Nakabayashi, K., Bhalla, A., van der Spek, P. J., van Duin, M. and Hsueh, A. J. (2000). The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol. Endocrinol. 14, 1257-1271.
    • (2000) Mol. Endocrinol. , vol.14 , pp. 1257-1271
    • Hsu, S.Y.1    Kudo, M.2    Chen, T.3    Nakabayashi, K.4    Bhalla, A.5    van der Spek, P.J.6    van Duin, M.7    Hsueh, A.J.8
  • 31
    • 53449087760 scopus 로고    scopus 로고
    • GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development
    • Jin, C., Yin, F., Lin, M., Li, H., Wang, Z., Weng, J., Liu, M., Da Dong, X., Qu, J. and Tu, L. (2008). GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest. Ophthalmol. Vis. Sci. 49, 4245-4253.
    • (2008) Invest. Ophthalmol. Vis. Sci. , vol.49 , pp. 4245-4253
    • Jin, C.1    Yin, F.2    Lin, M.3    Li, H.4    Wang, Z.5    Weng, J.6    Liu, M.7    Da Dong, X.8    Qu, J.9    Tu, L.10
  • 35
    • 84893267054 scopus 로고    scopus 로고
    • Cytonemes as specialized signaling filopodia
    • Kornberg, T. B. and Roy, S. (2014). Cytonemes as specialized signaling filopodia. Development 141, 729-736.
    • (2014) Development , vol.141 , pp. 729-736
    • Kornberg, T.B.1    Roy, S.2
  • 36
    • 44349118518 scopus 로고    scopus 로고
    • Arp2/3 complex is important for filopodia formation, growth cone motility, and neuritogenesis in neuronal cells
    • Korobova, F. and Svitkina, T. (2008). Arp2/3 complex is important for filopodia formation, growth cone motility, and neuritogenesis in neuronal cells. Mol. Biol. Cell 19, 1561-1574.
    • (2008) Mol. Biol. Cell , vol.19 , pp. 1561-1574
    • Korobova, F.1    Svitkina, T.2
  • 37
    • 34249867935 scopus 로고    scopus 로고
    • Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway
    • Lin, Y.-L., Lei, Y.-T., Hong, C.-J. and Hsueh, Y.-P. (2007). Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J. Cell Biol. 177, 829-841.
    • (2007) J. Cell Biol. , vol.177 , pp. 829-841
    • Lin, Y.-L.1    Lei, Y.-T.2    Hong, C.-J.3    Hsueh, Y.-P.4
  • 38
    • 33847343034 scopus 로고    scopus 로고
    • The matrix corroded: podosomes and invadopodia in extracellular matrix degradation
    • Linder, S. (2007). The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 17, 107-117.
    • (2007) Trends Cell Biol. , vol.17 , pp. 107-117
    • Linder, S.1
  • 39
    • 84906536746 scopus 로고    scopus 로고
    • Leucine-rich repeat-containing G-protein-coupled Receptor 5 marks short-term hematopoietic stem and progenitor cells during mouse embryonic development
    • Liu, D., He, X. C., Qian, P., Barker, N., Trainor, P. A., Clevers, H., Liu, H. and Li, L. (2014). Leucine-rich repeat-containing G-protein-coupled Receptor 5 marks short-term hematopoietic stem and progenitor cells during mouse embryonic development. J. Biol. Chem. 289, 23809-23816.
    • (2014) J. Biol. Chem. , vol.289 , pp. 23809-23816
    • Liu, D.1    He, X.C.2    Qian, P.3    Barker, N.4    Trainor, P.A.5    Clevers, H.6    Liu, H.7    Li, L.8
  • 40
    • 34547136471 scopus 로고    scopus 로고
    • Nterminal tyrosine modulation of the endocytic adaptor function of the betaarrestins
    • Marion, S., Fralish, G. B., Laporte, S., Caron, M. G. and Barak, L. S. (2007). Nterminal tyrosine modulation of the endocytic adaptor function of the betaarrestins. J. Biol. Chem. 282, 18937-18944.
    • (2007) J. Biol. Chem. , vol.282 , pp. 18937-18944
    • Marion, S.1    Fralish, G.B.2    Laporte, S.3    Caron, M.G.4    Barak, L.S.5
  • 41
    • 4043115604 scopus 로고    scopus 로고
    • Lamellipodial versus filopodial mode of the actin nanomachinery: pivotal role of the filament barbed end
    • Mejillano, M. R., Kojima, S., Applewhite, D. A., Gertler, F. B., Svitkina, T. M. and Borisy, G. G. (2004). Lamellipodial versus filopodial mode of the actin nanomachinery: pivotal role of the filament barbed end. Cell 118, 363-373.
    • (2004) Cell , vol.118 , pp. 363-373
    • Mejillano, M.R.1    Kojima, S.2    Applewhite, D.A.3    Gertler, F.B.4    Svitkina, T.M.5    Borisy, G.G.6
  • 42
    • 0029073651 scopus 로고
    • Dynamics of thin filopodia during sea urchin gastrulation
    • Miller, J., Fraser, S. E. and McClay, D. (1995). Dynamics of thin filopodia during sea urchin gastrulation. Development 121, 2501-2511.
    • (1995) Development , vol.121 , pp. 2501-2511
    • Miller, J.1    Fraser, S.E.2    McClay, D.3
  • 43
    • 23244441861 scopus 로고    scopus 로고
    • The physics of filopodial protrusion
    • Mogilner, A. and Rubinstein, B. (2005). The physics of filopodial protrusion. Biophys. J. 89, 782-795.
    • (2005) Biophys. J. , vol.89 , pp. 782-795
    • Mogilner, A.1    Rubinstein, B.2
  • 45
    • 77956495200 scopus 로고    scopus 로고
    • Wnt trafficking: new insights into Wnt maturation, secretion and spreading
    • Port, F. and Basler, K. (2010). Wnt trafficking: new insights into Wnt maturation, secretion and spreading. Traffic 11, 1265-1271.
    • (2010) Traffic , vol.11 , pp. 1265-1271
    • Port, F.1    Basler, K.2
  • 46
    • 77951844975 scopus 로고    scopus 로고
    • Teaching old receptors new tricks: biasing seven-transmembrane receptors
    • Rajagopal, S., Rajagopal, K. and Lefkowitz, R. J. (2010). Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 9, 373-386.
    • (2010) Nat. Rev. Drug Discov. , vol.9 , pp. 373-386
    • Rajagopal, S.1    Rajagopal, K.2    Lefkowitz, R.J.3
  • 47
    • 0033612317 scopus 로고    scopus 로고
    • Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs
    • Ramírez-Weber, F.-A. and Kornberg, T. B. (1999). Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell 97, 599-607.
    • (1999) Cell , vol.97 , pp. 599-607
    • Ramírez-Weber, F.-A.1    Kornberg, T.B.2
  • 48
    • 84859958093 scopus 로고    scopus 로고
    • Cytonememediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila
    • Rojas-Riós, P., Guerrero, I. and González-Reyes, A. (2012). Cytonememediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol. 10, e1001298.
    • (2012) PLoS Biol. , vol.10 , pp. e1001298
    • Rojas-Riós, P.1    Guerrero, I.2    González-Reyes, A.3
  • 49
    • 79954580548 scopus 로고    scopus 로고
    • Specificity of Drosophila cytonemes for distinct signaling pathways
    • Roy, S., Hsiung, F. and Kornberg, T. B. (2011). Specificity of Drosophila cytonemes for distinct signaling pathways. Science 332, 354-358.
    • (2011) Science , vol.332 , pp. 354-358
    • Roy, S.1    Hsiung, F.2    Kornberg, T.B.3
  • 50
    • 84891652285 scopus 로고    scopus 로고
    • Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein
    • Roy, S., Huang, H., Liu, S. and Kornberg, T. B. (2014). Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein. Science 343, 1244624.
    • (2014) Science , vol.343 , pp. 1244624
    • Roy, S.1    Huang, H.2    Liu, S.3    Kornberg, T.B.4
  • 52
    • 77951771838 scopus 로고    scopus 로고
    • Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia
    • Schoumacher, M., Goldman, R. D., Louvard, D. and Vignjevic, D. M. (2010). Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia. J. Cell Biol. 189, 541-556.
    • (2010) J. Cell Biol. , vol.189 , pp. 541-556
    • Schoumacher, M.1    Goldman, R.D.2    Louvard, D.3    Vignjevic, D.M.4
  • 53
    • 84902185292 scopus 로고    scopus 로고
    • Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut
    • Scopelliti, A., Cordero, J. B., Diao, F., Strathdee, K., White, B. H., Sansom, O. J. and Vidal, M. (2014). Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut. Curr. Biol. 24, 1199- 1211.
    • (2014) Curr. Biol. , vol.24 , pp. 1199-1211
    • Scopelliti, A.1    Cordero, J.B.2    Diao, F.3    Strathdee, K.4    White, B.H.5    Sansom, O.J.6    Vidal, M.7
  • 54
    • 0026645452 scopus 로고
    • Extension of filopodia by motor-dependent actin assembly
    • Sheetz, M. P., Wayne, D. B. and Pearlman, A. L. (1992). Extension of filopodia by motor-dependent actin assembly. Cell Motil. Cytoskeleton 22, 160-169.
    • (1992) Cell Motil. Cytoskeleton , vol.22 , pp. 160-169
    • Sheetz, M.P.1    Wayne, D.B.2    Pearlman, A.L.3
  • 56
    • 84893605383 scopus 로고    scopus 로고
    • The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to b-arrestin-2 recruitment
    • Snyder, J. C., Rochelle, L. K., Barak, L. S. and Caron, M. G. (2013a). The stem cell-expressed receptor Lgr5 possesses canonical and functionally active molecular determinants critical to b-arrestin-2 recruitment. PLoS ONE 8, e84476.
    • (2013) PLoS ONE , vol.8 , pp. e84476
    • Snyder, J.C.1    Rochelle, L.K.2    Barak, L.S.3    Caron, M.G.4
  • 57
    • 84876209624 scopus 로고    scopus 로고
    • Constitutive internalization of the Leucine-rich G protein-coupled Receptor-5 (LGR5) to the trans-Golgi network
    • Snyder, J. C., Rochelle, L. K., Lyerly, H. K., Caron, M. G. and Barak, L. S. (2013b). Constitutive internalization of the Leucine-rich G protein-coupled Receptor-5 (LGR5) to the trans-Golgi network. J. Biol. Chem. 288, 10286-10297.
    • (2013) J. Biol. Chem. , vol.288 , pp. 10286-10297
    • Snyder, J.C.1    Rochelle, L.K.2    Lyerly, H.K.3    Caron, M.G.4    Barak, L.S.5


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