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Volumn 583, Issue 17, 2009, Pages 2947-2953

"The preadipocyte factor" DLK1 marks adult mouse adipose tissue residing vascular cells that lack in vitro adipogenic differentiation potential

Author keywords

Adipogenesis; Adipose; Adult stem cells; Cell surface markers; Differentiation; Endothelial cell; Endothelial differentiation

Indexed keywords

ACETYL LOW DENSITY LIPOPROTEIN; DELTA LIKE PROTEIN 1; MEMBRANE PROTEIN; UNCLASSIFIED DRUG;

EID: 69249244277     PISSN: 00145793     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.febslet.2009.08.002     Document Type: Article
Times cited : (11)

References (47)
  • 3
    • 0033885174 scopus 로고    scopus 로고
    • Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation
    • Floridon C., Jensen C.H., Thorsen P., Nielsen O., Sunde L., Westergaard J.G., Thomsen S.G., and Teisner B. Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation. Differentiation 66 (2000) 49-59
    • (2000) Differentiation , vol.66 , pp. 49-59
    • Floridon, C.1    Jensen, C.H.2    Thorsen, P.3    Nielsen, O.4    Sunde, L.5    Westergaard, J.G.6    Thomsen, S.G.7    Teisner, B.8
  • 4
    • 0035930492 scopus 로고    scopus 로고
    • Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk
    • Jensen C.H., Meyer M., Schroder H.D., Kliem A., Zimmer J., and Teisner B. Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk. Neuroreport 12 (2001) 3959-3963
    • (2001) Neuroreport , vol.12 , pp. 3959-3963
    • Jensen, C.H.1    Meyer, M.2    Schroder, H.D.3    Kliem, A.4    Zimmer, J.5    Teisner, B.6
  • 5
    • 33645463110 scopus 로고    scopus 로고
    • Dlk1 expression marks developing endothelium and sites of branching morphogenesis in the mouse embryo and placenta
    • Yevtodiyenko A., and Schmidt J.V. Dlk1 expression marks developing endothelium and sites of branching morphogenesis in the mouse embryo and placenta. Dev. Dyn. 235 (2006) 1115-1123
    • (2006) Dev. Dyn. , vol.235 , pp. 1115-1123
    • Yevtodiyenko, A.1    Schmidt, J.V.2
  • 6
    • 1642398160 scopus 로고    scopus 로고
    • Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1
    • Jensen C.H., Jauho E.I., Santoni-Rugiu E., Holmskov U., Teisner B., Tygstrup N., and Bisgaard H.C. Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1. Am. J. Pathol. 164 (2004) 1347-1359
    • (2004) Am. J. Pathol. , vol.164 , pp. 1347-1359
    • Jensen, C.H.1    Jauho, E.I.2    Santoni-Rugiu, E.3    Holmskov, U.4    Teisner, B.5    Tygstrup, N.6    Bisgaard, H.C.7
  • 7
    • 0028017528 scopus 로고
    • Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2
    • Jensen C.H., Krogh T.N., Hojrup P., Clausen P.P., Skjodt K., Larsson L.I., Enghild J.J., and Teisner B. Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2. Eur. J. Biochem. 225 (1994) 83-92
    • (1994) Eur. J. Biochem. , vol.225 , pp. 83-92
    • Jensen, C.H.1    Krogh, T.N.2    Hojrup, P.3    Clausen, P.P.4    Skjodt, K.5    Larsson, L.I.6    Enghild, J.J.7    Teisner, B.8
  • 8
    • 33745866965 scopus 로고    scopus 로고
    • Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation
    • Wang Y., and Sul H.S. Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol. Cell. Biol. 26 (2006) 5421-5435
    • (2006) Mol. Cell. Biol. , vol.26 , pp. 5421-5435
    • Wang, Y.1    Sul, H.S.2
  • 10
    • 0031730288 scopus 로고    scopus 로고
    • Cloning of a membrane-spanning protein with epidermal growth factor-like repeat motifs from adrenal glomerulosa cells
    • Halder S.K., Takemori H., Hatano O., Nonaka Y., Wada A., and Okamoto M. Cloning of a membrane-spanning protein with epidermal growth factor-like repeat motifs from adrenal glomerulosa cells. Endocrinology 139 (1998) 3316-3328
    • (1998) Endocrinology , vol.139 , pp. 3316-3328
    • Halder, S.K.1    Takemori, H.2    Hatano, O.3    Nonaka, Y.4    Wada, A.5    Okamoto, M.6
  • 11
    • 0037093526 scopus 로고    scopus 로고
    • Only the large soluble form of preadipocyte factor-1 (Pref-1), but not the small soluble and membrane forms, inhibits adipocyte differentiation: role of alternative splicing
    • Mei B., Zhao L., Chen L., and Sul H.S. Only the large soluble form of preadipocyte factor-1 (Pref-1), but not the small soluble and membrane forms, inhibits adipocyte differentiation: role of alternative splicing. Biochem. J. 364 (2002) 137-144
    • (2002) Biochem. J. , vol.364 , pp. 137-144
    • Mei, B.1    Zhao, L.2    Chen, L.3    Sul, H.S.4
  • 12
    • 0038080915 scopus 로고    scopus 로고
    • Insulin-like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation
    • Zhang H., et al. Insulin-like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation. J. Biol. Chem. 278 (2003) 20906-20914
    • (2003) J. Biol. Chem. , vol.278 , pp. 20906-20914
    • Zhang, H.1
  • 13
    • 44849132591 scopus 로고    scopus 로고
    • Dynamics of fat cell turnover in humans
    • Spalding K.L., et al. Dynamics of fat cell turnover in humans. Nature 453 (2008) 783-787
    • (2008) Nature , vol.453 , pp. 783-787
    • Spalding, K.L.1
  • 14
    • 0037327403 scopus 로고    scopus 로고
    • Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1)
    • Lee K., Villena J.A., Moon Y.S., Kim K.H., Lee S., Kang C., and Sul H.S. Inhibition of adipogenesis and development of glucose intolerance by soluble preadipocyte factor-1 (Pref-1). J. Clin. Invest. 111 (2003) 453-461
    • (2003) J. Clin. Invest. , vol.111 , pp. 453-461
    • Lee, K.1    Villena, J.A.2    Moon, Y.S.3    Kim, K.H.4    Lee, S.5    Kang, C.6    Sul, H.S.7
  • 15
    • 0032532152 scopus 로고    scopus 로고
    • Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy
    • Shimomura I., Hammer R.E., Richardson J.A., Ikemoto S., Bashmakov Y., Goldstein J.L., and Brown M.S. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12 (1998) 3182-3194
    • (1998) Genes Dev. , vol.12 , pp. 3182-3194
    • Shimomura, I.1    Hammer, R.E.2    Richardson, J.A.3    Ikemoto, S.4    Bashmakov, Y.5    Goldstein, J.L.6    Brown, M.S.7
  • 17
    • 57049140045 scopus 로고    scopus 로고
    • Cloning and expression of delta-like protein 1 messenger ribonucleic acid during development of adipose and muscle tissues in chickens
    • Shin J., Lim S., Latshaw J.D., and Lee K. Cloning and expression of delta-like protein 1 messenger ribonucleic acid during development of adipose and muscle tissues in chickens. Poult. Sci. 87 (2008) 2636-2646
    • (2008) Poult. Sci. , vol.87 , pp. 2636-2646
    • Shin, J.1    Lim, S.2    Latshaw, J.D.3    Lee, K.4
  • 20
    • 58949100296 scopus 로고    scopus 로고
    • Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats
    • Barbu A., Hedlund G.P., Lind J., and Carlsson C. Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats. Mol. Cell. Endocrinol. 299 (2009) 163-171
    • (2009) Mol. Cell. Endocrinol. , vol.299 , pp. 163-171
    • Barbu, A.1    Hedlund, G.P.2    Lind, J.3    Carlsson, C.4
  • 21
    • 43449099439 scopus 로고    scopus 로고
    • Dlk1 specifically interacts with insulin-like growth factor binding protein 1 to modulate adipogenesis of 3T3-L1 cells
    • Nueda M.L., Garcia-Ramirez J.J., Laborda J., and Baladron V. Dlk1 specifically interacts with insulin-like growth factor binding protein 1 to modulate adipogenesis of 3T3-L1 cells. J. Mol. Biol. 379 (2008) 428-442
    • (2008) J. Mol. Biol. , vol.379 , pp. 428-442
    • Nueda, M.L.1    Garcia-Ramirez, J.J.2    Laborda, J.3    Baladron, V.4
  • 22
    • 33845322632 scopus 로고    scopus 로고
    • Pref-1, a preadipocyte secreted factor that inhibits adipogenesis
    • Wang Y., Kim K.A., Kim J.H., and Sul H.S. Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. J. Nutr. 136 (2006) 2953-2956
    • (2006) J. Nutr. , vol.136 , pp. 2953-2956
    • Wang, Y.1    Kim, K.A.2    Kim, J.H.3    Sul, H.S.4
  • 23
    • 0036318227 scopus 로고    scopus 로고
    • Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity
    • Moon Y.S., Smas C.M., Lee K., Villena J.A., Kim K.H., Yun E.J., and Sul H.S. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol. Cell. Biol. 22 (2002) 5585-5592
    • (2002) Mol. Cell. Biol. , vol.22 , pp. 5585-5592
    • Moon, Y.S.1    Smas, C.M.2    Lee, K.3    Villena, J.A.4    Kim, K.H.5    Yun, E.J.6    Sul, H.S.7
  • 24
    • 51649095823 scopus 로고    scopus 로고
    • Non-cultured adipose-derived CD45-side population cells are enriched for progenitors that give rise to myofibres in vivo
    • Andersen D.C., Schroder H.D., and Jensen C.H. Non-cultured adipose-derived CD45-side population cells are enriched for progenitors that give rise to myofibres in vivo. Exp. Cell. Res. 314 (2008) 2951-2964
    • (2008) Exp. Cell. Res. , vol.314 , pp. 2951-2964
    • Andersen, D.C.1    Schroder, H.D.2    Jensen, C.H.3
  • 25
    • 44949109953 scopus 로고    scopus 로고
    • Demonstration of the presence of independent pre-osteoblastic and pre-adipocytic cell populations in bone marrow-derived mesenchymal stem cells
    • Post S., Abdallah B.M., Bentzon J.F., and Kassem M. Demonstration of the presence of independent pre-osteoblastic and pre-adipocytic cell populations in bone marrow-derived mesenchymal stem cells. Bone 43 (2008) 32-39
    • (2008) Bone , vol.43 , pp. 32-39
    • Post, S.1    Abdallah, B.M.2    Bentzon, J.F.3    Kassem, M.4
  • 26
    • 68049123595 scopus 로고    scopus 로고
    • Murine "cardiospheres" are not a source of stem cells with cardiomyogenic potential
    • Andersen D.C., Andersen P., Schneider M., Jensen H.B., and Sheikh S.P. Murine "cardiospheres" are not a source of stem cells with cardiomyogenic potential. Stem Cells 27 (2009) 1571-1581
    • (2009) Stem Cells , vol.27 , pp. 1571-1581
    • Andersen, D.C.1    Andersen, P.2    Schneider, M.3    Jensen, H.B.4    Sheikh, S.P.5
  • 27
    • 65649117643 scopus 로고    scopus 로고
    • Characterization of dlk1+ cells emerging during skeletal muscle remodeling in response to myositis, myopathies and acute injury
    • Andersen D.C., et al. Characterization of dlk1+ cells emerging during skeletal muscle remodeling in response to myositis, myopathies and acute injury. Stem Cells 27 April (2009) 898-908
    • (2009) Stem Cells , vol.27 , Issue.April , pp. 898-908
    • Andersen, D.C.1
  • 28
    • 0029763970 scopus 로고    scopus 로고
    • Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology
    • Bachmann E., Krogh T.N., Hojrup P., Skjodt K., and Teisner B. Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology. J. Reprod. Fertil. 107 (1996) 279-285
    • (1996) J. Reprod. Fertil. , vol.107 , pp. 279-285
    • Bachmann, E.1    Krogh, T.N.2    Hojrup, P.3    Skjodt, K.4    Teisner, B.5
  • 29
    • 0037129827 scopus 로고    scopus 로고
    • Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes
    • RESEARCH0034
    • Vandesompele, J., De Preter, K., Pattyn, F., Poppe, B., Van Roy, N., De Paepe, A. and Speleman, F. (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3, RESEARCH0034.
    • (2002) Genome Biol , vol.3
    • Vandesompele, J.1    De Preter, K.2    Pattyn, F.3    Poppe, B.4    Van Roy, N.5    De Paepe, A.6    Speleman, F.7
  • 30
    • 45449087921 scopus 로고    scopus 로고
    • QBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data
    • Hellemans J., Mortier G., De Paepe A., Speleman F., and Vandesompele J. QBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 8 (2007) R19
    • (2007) Genome Biol. , vol.8
    • Hellemans, J.1    Mortier, G.2    De Paepe, A.3    Speleman, F.4    Vandesompele, J.5
  • 31
    • 0027051199 scopus 로고
    • Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization
    • Cousin B., Cinti S., Morroni M., Raimbault S., Ricquier D., Penicaud L., and Casteilla L. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J. Cell Sci. 103 Pt 4 (1992) 931-942
    • (1992) J. Cell Sci. , vol.103 , Issue.PART 4 , pp. 931-942
    • Cousin, B.1    Cinti, S.2    Morroni, M.3    Raimbault, S.4    Ricquier, D.5    Penicaud, L.6    Casteilla, L.7
  • 32
    • 27544475061 scopus 로고    scopus 로고
    • Pericytes and endothelial precursor cells: cellular interactions and contributions to malignancy
    • Bagley R.G., Weber W., Rouleau C., and Teicher B.A. Pericytes and endothelial precursor cells: cellular interactions and contributions to malignancy. Cancer Res. 65 (2005) 9741-9750
    • (2005) Cancer Res. , vol.65 , pp. 9741-9750
    • Bagley, R.G.1    Weber, W.2    Rouleau, C.3    Teicher, B.A.4
  • 33
    • 33750286135 scopus 로고    scopus 로고
    • The multifaceted circulating endothelial cell in cancer: towards marker and target identification
    • Bertolini F., Shaked Y., Mancuso P., and Kerbel R.S. The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat. Rev. Cancer 6 (2006) 835-845
    • (2006) Nat. Rev. Cancer , vol.6 , pp. 835-845
    • Bertolini, F.1    Shaked, Y.2    Mancuso, P.3    Kerbel, R.S.4
  • 34
    • 0033694589 scopus 로고    scopus 로고
    • Function of pref-1 as an inhibitor of adipocyte differentiation
    • Sul H.S., Smas C., Mei B., and Zhou L. Function of pref-1 as an inhibitor of adipocyte differentiation. Int. J. Obes. Relat. Metab. Disord. 24 Suppl. 4 (2000) S15-S19
    • (2000) Int. J. Obes. Relat. Metab. Disord. , vol.24 , Issue.SUPPL. 4
    • Sul, H.S.1    Smas, C.2    Mei, B.3    Zhou, L.4
  • 35
    • 0031821520 scopus 로고    scopus 로고
    • Understanding adipocyte differentiation
    • Gregoire F.M., Smas C.M., and Sul H.S. Understanding adipocyte differentiation. Physiol. Rev. 78 (1998) 783-809
    • (1998) Physiol. Rev. , vol.78 , pp. 783-809
    • Gregoire, F.M.1    Smas, C.M.2    Sul, H.S.3
  • 36
    • 36849029335 scopus 로고    scopus 로고
    • Bone marrow-derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice
    • Koh Y.J., Kang S., Lee H.J., Choi T.S., Lee H.S., Cho C.H., and Koh G.Y. Bone marrow-derived circulating progenitor cells fail to transdifferentiate into adipocytes in adult adipose tissues in mice. J. Clin. Invest. 117 (2007) 3684-3695
    • (2007) J. Clin. Invest. , vol.117 , pp. 3684-3695
    • Koh, Y.J.1    Kang, S.2    Lee, H.J.3    Choi, T.S.4    Lee, H.S.5    Cho, C.H.6    Koh, G.Y.7
  • 37
    • 53549134683 scopus 로고    scopus 로고
    • Identification of white adipocyte progenitor cells in vivo
    • Rodeheffer M.S., Birsoy K., and Friedman J.M. Identification of white adipocyte progenitor cells in vivo. Cell 135 (2008) 240-249
    • (2008) Cell , vol.135 , pp. 240-249
    • Rodeheffer, M.S.1    Birsoy, K.2    Friedman, J.M.3
  • 38
    • 4544353140 scopus 로고    scopus 로고
    • Three-dimensional, quantitative analysis of desmin and smooth muscle alpha actin expression during angiogenesis
    • Brey E.M., McIntire L.V., Johnston C.M., Reece G.P., and Patrick Jr. C.W. Three-dimensional, quantitative analysis of desmin and smooth muscle alpha actin expression during angiogenesis. Ann. Biomed. Eng. 32 (2004) 1100-1107
    • (2004) Ann. Biomed. Eng. , vol.32 , pp. 1100-1107
    • Brey, E.M.1    McIntire, L.V.2    Johnston, C.M.3    Reece, G.P.4    Patrick Jr., C.W.5
  • 39
    • 0036651815 scopus 로고    scopus 로고
    • Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures
    • Justesen J., Stenderup K., Eriksen E.F., and Kassem M. Maintenance of osteoblastic and adipocytic differentiation potential with age and osteoporosis in human marrow stromal cell cultures. Calcif. Tissue Int. 71 (2002) 36-44
    • (2002) Calcif. Tissue Int. , vol.71 , pp. 36-44
    • Justesen, J.1    Stenderup, K.2    Eriksen, E.F.3    Kassem, M.4
  • 40
    • 45549094690 scopus 로고    scopus 로고
    • The influence of thiazolidinediones on adipogenesis in vitro and in vivo: potential modifiers of intramuscular adipose tissue deposition in meat animals
    • Hausman G.J., Poulos S.P., Pringle T.D., and Azain M.J. The influence of thiazolidinediones on adipogenesis in vitro and in vivo: potential modifiers of intramuscular adipose tissue deposition in meat animals. J. Anim. Sci. 86 (2008) E236-E243
    • (2008) J. Anim. Sci. , vol.86
    • Hausman, G.J.1    Poulos, S.P.2    Pringle, T.D.3    Azain, M.J.4
  • 41
    • 33845676640 scopus 로고    scopus 로고
    • Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes
    • Bondjers C., He L., Takemoto M., Norlin J., Asker N., Hellstrom M., Lindahl P., and Betsholtz C. Microarray analysis of blood microvessels from PDGF-B and PDGF-Rbeta mutant mice identifies novel markers for brain pericytes. FASEB J. 20 (2006) 1703-1705
    • (2006) FASEB J. , vol.20 , pp. 1703-1705
    • Bondjers, C.1    He, L.2    Takemoto, M.3    Norlin, J.4    Asker, N.5    Hellstrom, M.6    Lindahl, P.7    Betsholtz, C.8
  • 42
  • 43
    • 0021683002 scopus 로고
    • Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein
    • Voyta J.C., Via D.P., Butterfield C.E., and Zetter B.R. Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J. Cell Biol. 99 (1984) 2034-2040
    • (1984) J. Cell Biol. , vol.99 , pp. 2034-2040
    • Voyta, J.C.1    Via, D.P.2    Butterfield, C.E.3    Zetter, B.R.4
  • 45
    • 67650996754 scopus 로고    scopus 로고
    • Biomarkers for epithelial-mesenchymal transitions
    • Zeisberg M., and Neilson E.G. Biomarkers for epithelial-mesenchymal transitions. J. Clin. Invest. 119 (2009) 1429-1437
    • (2009) J. Clin. Invest. , vol.119 , pp. 1429-1437
    • Zeisberg, M.1    Neilson, E.G.2
  • 46
    • 59649123850 scopus 로고    scopus 로고
    • ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis
    • Gooz P., Gooz M., Baldys A., and Hoffman S. ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis. Biochem. Biophys. Res. Commun. 380 (2009) 33-38
    • (2009) Biochem. Biophys. Res. Commun. , vol.380 , pp. 33-38
    • Gooz, P.1    Gooz, M.2    Baldys, A.3    Hoffman, S.4
  • 47
    • 0019796014 scopus 로고
    • Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy
    • Pitas R.E., Innerarity T.L., Weinstein J.N., and Mahley R.W. Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy. Arteriosclerosis 1 (1981) 177-185
    • (1981) Arteriosclerosis , vol.1 , pp. 177-185
    • Pitas, R.E.1    Innerarity, T.L.2    Weinstein, J.N.3    Mahley, R.W.4


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