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Volumn 114, Issue 8, 2013, Pages 1760-1771

Rapamycin inhibits BMP-7-induced osteogenic and lipogenic marker expressions in fetal rat calvarial cells

Author keywords

ADIPOGENIC DIFFERENTIATION; BMP 7; FRC; mTOR; OSTEOBLAST DIFFERENTIATION; RAPAMYCIN

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; OSTEOGENIC PROTEIN 1; PALMITIC ACID; RAPAMYCIN;

EID: 84879172415     PISSN: 07302312     EISSN: 10974644     Source Type: Journal    
DOI: 10.1002/jcb.24519     Document Type: Article
Times cited : (23)

References (50)
  • 1
    • 0025312172 scopus 로고
    • Factors that promote progressive development of osteoblast phenotype in cultured fetal rat calvaria cells
    • Aronow MA, Gerstenfeld LC, Owen TA, Tassinari MS, Stein GS, Lian JB,. 1990. Factors that promote progressive development of osteoblast phenotype in cultured fetal rat calvaria cells. J Cell Physiol 143: 213-221.
    • (1990) J Cell Physiol , vol.143 , pp. 213-221
    • Aronow, M.A.1    Gerstenfeld, L.C.2    Owen, T.A.3    Tassinari, M.S.4    Stein, G.S.5    Lian, J.B.6
  • 2
    • 0030056920 scopus 로고    scopus 로고
    • Human osteogenic protein-1 induces chondroblastic, osteoblastic, and/or adipocytic differentiation of clonal murine target cells
    • Asahina I, Sampath TK, Hauschka PV,. 1996. Human osteogenic protein-1 induces chondroblastic, osteoblastic, and/or adipocytic differentiation of clonal murine target cells. Exp Cell Res 222: 38-47.
    • (1996) Exp Cell Res , vol.222 , pp. 38-47
    • Asahina, I.1    Sampath, T.K.2    Hauschka, P.V.3
  • 3
    • 0032323828 scopus 로고    scopus 로고
    • Advances in the osteoblast lineage
    • Aubin JE,. 1998. Advances in the osteoblast lineage. Biochem Cell Biol 76: 899-910.
    • (1998) Biochem Cell Biol , vol.76 , pp. 899-910
    • Aubin, J.E.1
  • 4
    • 33750044299 scopus 로고    scopus 로고
    • When translation meets transformation: The mTOR story
    • Averous J, Proud CG,. 2006. When translation meets transformation: The mTOR story. Oncogene 25: 6423-6435.
    • (2006) Oncogene , vol.25 , pp. 6423-6435
    • Averous, J.1    Proud, C.G.2
  • 5
    • 0034782842 scopus 로고    scopus 로고
    • The frequency of common progenitors for adipocytes and osteoblasts and of committed and restricted adipocyte and osteoblast progenitors in fetal rat calvaria cell populations
    • Bellows CG, Heersche JN,. 2001. The frequency of common progenitors for adipocytes and osteoblasts and of committed and restricted adipocyte and osteoblast progenitors in fetal rat calvaria cell populations. J Bone Miner Res 16: 1983-1993.
    • (2001) J Bone Miner Res , vol.16 , pp. 1983-1993
    • Bellows, C.G.1    Heersche, J.N.2
  • 6
    • 0017184389 scopus 로고
    • A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
    • Bradford MM,. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254.
    • (1976) Anal Biochem , vol.72 , pp. 248-254
    • Bradford, M.M.1
  • 7
    • 77951166692 scopus 로고    scopus 로고
    • Mammalian target of rapamycin complex 1 suppresses lipolyisis, stimulates lipogenesis, and promotes fat storage
    • Chakrabarti P, English T, Shi J, Smas CM, Kandror KV,. 2010. Mammalian target of rapamycin complex 1 suppresses lipolyisis, stimulates lipogenesis, and promotes fat storage. Diabetes 59: 775-781.
    • (2010) Diabetes , vol.59 , pp. 775-781
    • Chakrabarti, P.1    English, T.2    Shi, J.3    Smas, C.M.4    Kandror, K.V.5
  • 8
    • 0034957648 scopus 로고    scopus 로고
    • Human BMP-7/OP-1 induces the growth and differentiation of adipocytes and osteoblasts in bone marrow stromal cell cultures
    • Chen TL, Shen WJ, Kraemer FB,. 2001. Human BMP-7/OP-1 induces the growth and differentiation of adipocytes and osteoblasts in bone marrow stromal cell cultures. J Cell Biochem 82: 187-199.
    • (2001) J Cell Biochem , vol.82 , pp. 187-199
    • Chen, T.L.1    Shen, W.J.2    Kraemer, F.B.3
  • 11
    • 0142104985 scopus 로고    scopus 로고
    • Smad-dependent and Smad-independent pathways in TGF-b family signaling
    • Derynck R, Zhang YE,. 2003. Smad-dependent and Smad-independent pathways in TGF-b family signaling. Nature 425: 577-584.
    • (2003) Nature , vol.425 , pp. 577-584
    • Derynck, R.1    Zhang, Y.E.2
  • 12
    • 80052545899 scopus 로고    scopus 로고
    • The role of osteocalcin in the endocrine cross-talk between bone remodeling and energy metabolism
    • Ducy P,. 2011. The role of osteocalcin in the endocrine cross-talk between bone remodeling and energy metabolism. Diabetologia 54: 1291-1297.
    • (2011) Diabetologia , vol.54 , pp. 1291-1297
    • Ducy, P.1
  • 13
    • 77953948509 scopus 로고    scopus 로고
    • Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro
    • Elbaz A, Wu X, Rivas D, Gimble JM, Duque G,. 2010. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro. J Cell Mol Med 14: 982-991.
    • (2010) J Cell Mol Med , vol.14 , pp. 982-991
    • Elbaz, A.1    Wu, X.2    Rivas, D.3    Gimble, J.M.4    Duque, G.5
  • 15
    • 0032879350 scopus 로고    scopus 로고
    • Differentiation of human marrow stromal precursor cells: Bone morphogenetic protein-2 increases OSF2/CBFA1, enhances osteoblast commitment, and inhibits late adipocyte maturation
    • Gori F, Thomas T, Hicok KC, Spelsberg TC, Riggs BL,. 1999. Differentiation of human marrow stromal precursor cells: Bone morphogenetic protein-2 increases OSF2/CBFA1, enhances osteoblast commitment, and inhibits late adipocyte maturation. J Bone Miner Res 14: 1522-1535.
    • (1999) J Bone Miner Res , vol.14 , pp. 1522-1535
    • Gori, F.1    Thomas, T.2    Hicok, K.C.3    Spelsberg, T.C.4    Riggs, B.L.5
  • 16
    • 48349130853 scopus 로고    scopus 로고
    • The PPARgamma-selective ligand BRL-49653 differentially regulates the fate choices of rat calvaria versus rat bone marrow stromal cell populations
    • Hasegawa T, Oizumi K, Yoshiko Y, Tanne K, Maeda N, Aubin JE,. 2008. The PPARgamma-selective ligand BRL-49653 differentially regulates the fate choices of rat calvaria versus rat bone marrow stromal cell populations. BMC Devel Biol 8: 71.
    • (2008) BMC Devel Biol , vol.8 , pp. 71
    • Hasegawa, T.1    Oizumi, K.2    Yoshiko, Y.3    Tanne, K.4    Maeda, N.5    Aubin, J.E.6
  • 18
    • 33846513349 scopus 로고    scopus 로고
    • Rapamycin as an inhibitor of osteogenic differentiation in bone marrow-derived mesenchymal stem cells
    • Isomoto S, Hattori K, Ohgushi H, Nakajima H, Tanaka Y, Takakura Y,. 2007. Rapamycin as an inhibitor of osteogenic differentiation in bone marrow-derived mesenchymal stem cells. J Orthop Sci 12: 83-88.
    • (2007) J Orthop Sci , vol.12 , pp. 83-88
    • Isomoto, S.1    Hattori, K.2    Ohgushi, H.3    Nakajima, H.4    Tanaka, Y.5    Takakura, Y.6
  • 20
    • 84857279874 scopus 로고    scopus 로고
    • Biology without walls: The novel endocrinology of bone
    • Karsenty G, Oury F,. 2012. Biology without walls: The novel endocrinology of bone. Annu Rev Physiol 74: 87-105.
    • (2012) Annu Rev Physiol , vol.74 , pp. 87-105
    • Karsenty, G.1    Oury, F.2
  • 21
    • 84863229795 scopus 로고    scopus 로고
    • BMPs and their clinical potentials
    • Kim M, Choe S,. 2011. BMPs and their clinical potentials. BMB Reports 44: 619-634.
    • (2011) BMB Reports , vol.44 , pp. 619-634
    • Kim, M.1    Choe, S.2
  • 22
    • 77955504728 scopus 로고    scopus 로고
    • Fad104, a positive regulator of adipogenesis, negatively regulates osteoblast differentiation
    • Kishimoto K, Kato A, Osada S, Nishizuka M, Imagawa M,. 2010. Fad104, a positive regulator of adipogenesis, negatively regulates osteoblast differentiation. Biochem Biophys Res Commun 397: 187-191.
    • (2010) Biochem Biophys Res Commun , vol.397 , pp. 187-191
    • Kishimoto, K.1    Kato, A.2    Osada, S.3    Nishizuka, M.4    Imagawa, M.5
  • 23
    • 29944440746 scopus 로고    scopus 로고
    • Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin
    • Langenfeld EM, Kong Y, Langenfeld J,. 2005. Bone morphogenetic protein-2-induced transformation involves the activation of mammalian target of rapamycin. Mol Cancer Res 3: 679-684.
    • (2005) Mol Cancer Res , vol.3 , pp. 679-684
    • Langenfeld, E.M.1    Kong, Y.2    Langenfeld, J.3
  • 24
    • 77649251207 scopus 로고    scopus 로고
    • MTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis
    • Laplante M, Sabatini DM,. 2010. mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. Proc Natl Acad Sci USA 107: 3281-3282.
    • (2010) Proc Natl Acad Sci USA , vol.107 , pp. 3281-3282
    • Laplante, M.1    Sabatini, D.M.2
  • 25
    • 77950603770 scopus 로고    scopus 로고
    • Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway
    • Lee KW, Yook JY, Son MY, Kim MJ, Koo DB, Han YM, Cho YS,. 2010. Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cell Develop 19: 557-568.
    • (2010) Stem Cell Develop , vol.19 , pp. 557-568
    • Lee, K.W.1    Yook, J.Y.2    Son, M.Y.3    Kim, M.J.4    Koo, D.B.5    Han, Y.M.6    Cho, Y.S.7
  • 26
    • 77649264504 scopus 로고    scopus 로고
    • Bifurcation of insulin signaling pathway in rat liver: MTORC1 required for stimulation of lipogenesis but not inhibition of gluconeogenesis
    • Li S, Brown MS, Goldstein JL,. 2010. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 107: 3441-3446.
    • (2010) Proc Natl Acad Sci USA , vol.107 , pp. 3441-3446
    • Li, S.1    Brown, M.S.2    Goldstein, J.L.3
  • 27
    • 77957686102 scopus 로고    scopus 로고
    • NVP-BEZ235, a dual pan class i PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells
    • Martin SK, Fitter S, Bong LF, Drew JJ, Gronthos S, Shepherd PR, Zannettino AC,. 2010. NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells. J Bone Miner Res 25: 2126-2137.
    • (2010) J Bone Miner Res , vol.25 , pp. 2126-2137
    • Martin, S.K.1    Fitter, S.2    Bong, L.F.3    Drew, J.J.4    Gronthos, S.5    Shepherd, P.R.6    Zannettino, A.C.7
  • 28
    • 0034574298 scopus 로고    scopus 로고
    • How cells read TGF-beta signals
    • Massague J,. 2000. How cells read TGF-beta signals. Nature Rev Mol Cell Biol 1: 169-178.
    • (2000) Nature Rev Mol Cell Biol , vol.1 , pp. 169-178
    • Massague, J.1
  • 29
    • 0023718497 scopus 로고
    • Further biochemical and molecular characterization of primary rat parietal bone cell cultures
    • McCarthy TL, Centrella M, Canalis E,. 1988. Further biochemical and molecular characterization of primary rat parietal bone cell cultures. J Bone Miner Res 3: 401-408.
    • (1988) J Bone Miner Res , vol.3 , pp. 401-408
    • McCarthy, T.L.1    Centrella, M.2    Canalis, E.3
  • 30
    • 78650634664 scopus 로고    scopus 로고
    • Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells
    • Mikami Y, Lee M, Irie S, Honda MJ,. 2011. Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells. J Cell Physiol 226: 739-748.
    • (2011) J Cell Physiol , vol.226 , pp. 739-748
    • Mikami, Y.1    Lee, M.2    Irie, S.3    Honda, M.J.4
  • 31
    • 66149119052 scopus 로고    scopus 로고
    • Akt promotes BMP-2 mediated osteoblast differentiation and bone development
    • Mukherjee A, Rotwein P,. 2009. Akt promotes BMP-2 mediated osteoblast differentiation and bone development. J Cell Sci 122: 716-726.
    • (2009) J Cell Sci , vol.122 , pp. 716-726
    • Mukherjee, A.1    Rotwein, P.2
  • 32
    • 70449698050 scopus 로고    scopus 로고
    • Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent Parathyroid Hormone treatment
    • Niziolek PJ, Murthy S, Ellis SN, Sukhija KB, Hornberger TA, Turner CH, Robling AG,. 2009. Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent Parathyroid Hormone treatment. J Cell Physiol 221: 579-585.
    • (2009) J Cell Physiol , vol.221 , pp. 579-585
    • Niziolek, P.J.1    Murthy, S.2    Ellis, S.N.3    Sukhija, K.B.4    Hornberger, T.A.5    Turner, C.H.6    Robling, A.G.7
  • 33
    • 55649086838 scopus 로고    scopus 로고
    • Reassessing triglyceride synthesis in adipose tissues
    • Nye C, Kim J, Kalhan SC, Hanson RW,. 2008. Reassessing triglyceride synthesis in adipose tissues. Trends Endo Metab 19: 356-361.
    • (2008) Trends Endo Metab , vol.19 , pp. 356-361
    • Nye, C.1    Kim, J.2    Kalhan, S.C.3    Hanson, R.W.4
  • 35
    • 84862744882 scopus 로고    scopus 로고
    • The endocrine role of the skeleton: Background and clinical evidence
    • Schwetz V, Pieber T, Obermayer-Pietsch B,. 2012. The endocrine role of the skeleton: Background and clinical evidence. Eur J Endo 166: 959-967.
    • (2012) Eur J Endo , vol.166 , pp. 959-967
    • Schwetz, V.1    Pieber, T.2    Obermayer-Pietsch, B.3
  • 36
    • 0037445980 scopus 로고    scopus 로고
    • Inhibition of phosphatidylinositol 3-kinase and p70S6 kinase blocks Osteogenic Protein-1 induction of alkaline phosphatase activity in fetal rat calvaria cells
    • Shoba LNN, Lee JC,. 2003. Inhibition of phosphatidylinositol 3-kinase and p70S6 kinase blocks Osteogenic Protein-1 induction of alkaline phosphatase activity in fetal rat calvaria cells. J Cell Biochem 88: 1247-1255.
    • (2003) J Cell Biochem , vol.88 , pp. 1247-1255
    • Shoba, L.N.N.1    Lee, J.C.2
  • 37
    • 38649110155 scopus 로고    scopus 로고
    • Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells
    • Singha UK, Jiang Y, Yu S, Luo M, Lu Y, Zhang J, Xiao G,. 2008. Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells. J Cell Biochem 103: 434-446.
    • (2008) J Cell Biochem , vol.103 , pp. 434-446
    • Singha, U.K.1    Jiang, Y.2    Yu, S.3    Luo, M.4    Lu, Y.5    Zhang, J.6    Xiao, G.7
  • 38
    • 0028919516 scopus 로고
    • Rapidly forming apatitic mineral in an osteoblastic cell line (UMR 106-01 BSP)
    • Stanford CM, Jacobson PA, Eanes ED, Lembke LA, Midura RJ,. 1995. Rapidly forming apatitic mineral in an osteoblastic cell line (UMR 106-01 BSP). J Biol Chem 270: 9420-9428.
    • (1995) J Biol Chem , vol.270 , pp. 9420-9428
    • Stanford, C.M.1    Jacobson, P.A.2    Eanes, E.D.3    Lembke, L.A.4    Midura, R.J.5
  • 39
    • 68649097537 scopus 로고    scopus 로고
    • Osteogenic and adipogenic cell fractions isolated from postnatal mouse calvaria
    • Steenhuis P, Carr KM, Pettway GJ, Ignelzi MA,. 2009. Osteogenic and adipogenic cell fractions isolated from postnatal mouse calvaria. Cells Tissues Organs 190: 150-157.
    • (2009) Cells Tissues Organs , vol.190 , pp. 150-157
    • Steenhuis, P.1    Carr, K.M.2    Pettway, G.J.3    Ignelzi, M.A.4
  • 40
    • 0042134658 scopus 로고    scopus 로고
    • Signal transduction of bone morphogenetic proteins in osteoblast differentiation
    • ten Dijke P, Fu J, Schaap P, Roelen BA,. 2003. Signal transduction of bone morphogenetic proteins in osteoblast differentiation. J Bone Joint Surg Am 85A (Suppl 3): 34-38.
    • (2003) J Bone Joint Surg Am , vol.85 A , Issue.SUPPL. 3 , pp. 34-38
    • Ten Dijke, P.1    Fu, J.2    Schaap, P.3    Roelen, B.A.4
  • 41
    • 0037005903 scopus 로고    scopus 로고
    • Inhibition of PI3K/p70 S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2
    • Vinals F, Lopez-Rovira T, Rosa JL, Ventura F,. 2002. Inhibition of PI3K/p70 S6K and p38 MAPK cascades increases osteoblastic differentiation induced by BMP-2. FEBS Lett 510: 99-104.
    • (2002) FEBS Lett , vol.510 , pp. 99-104
    • Vinals, F.1    Lopez-Rovira, T.2    Rosa, J.L.3    Ventura, F.4
  • 43
    • 0029989193 scopus 로고    scopus 로고
    • Osteogenic protein-1-mediated insulin-like growth factor gene expression in primary cultures of rat osteoblastic cells
    • Yeh LCC, Adamo ML, Kitten AM, Olson MS, Lee JC,. 1996. Osteogenic protein-1-mediated insulin-like growth factor gene expression in primary cultures of rat osteoblastic cells. Endocrinology 137: 1921-1931.
    • (1996) Endocrinology , vol.137 , pp. 1921-1931
    • Yeh, L.C.C.1    Adamo, M.L.2    Kitten, A.M.3    Olson, M.S.4    Lee, J.C.5
  • 44
    • 0030885311 scopus 로고    scopus 로고
    • Osteogenic protein-1 and insulin-like growth factor synergistically stimulate rat osteoblastic cell differentiation and proliferation
    • Yeh LCC, Adamo ML, Olson MS, Lee JC,. 1997. Osteogenic protein-1 and insulin-like growth factor synergistically stimulate rat osteoblastic cell differentiation and proliferation. Endocrinology 138: 4181-4190.
    • (1997) Endocrinology , vol.138 , pp. 4181-4190
    • Yeh, L.C.C.1    Adamo, M.L.2    Olson, M.S.3    Lee, J.C.4
  • 45
    • 0033847399 scopus 로고    scopus 로고
    • Osteogenic Protein-1 differentially regulates the mRNA expression of bone morphogenetic proteins and their receptors in primary cultures of osteoblasts
    • Yeh LCC, Unda R, Lee JC,. 2000. Osteogenic Protein-1 differentially regulates the mRNA expression of bone morphogenetic proteins and their receptors in primary cultures of osteoblasts. J Cell Physiol 185: 87-97.
    • (2000) J Cell Physiol , vol.185 , pp. 87-97
    • Yeh, L.C.C.1    Unda, R.2    Lee, J.C.3
  • 46
    • 33144468578 scopus 로고    scopus 로고
    • C-type natriuretic peptide enhances osteogenic protein-1-induced osteoblastic cell differentiation via Smad5 phosphorylation
    • Yeh LCC, Zavala MC, Lee JC,. 2006. C-type natriuretic peptide enhances osteogenic protein-1-induced osteoblastic cell differentiation via Smad5 phosphorylation. J Cell Biochem 97: 494-500.
    • (2006) J Cell Biochem , vol.97 , pp. 494-500
    • Yeh, L.C.C.1    Zavala, M.C.2    Lee, J.C.3
  • 47
    • 77957797865 scopus 로고    scopus 로고
    • Protein kinase D mediates the synergistic effects of BMP-7 and IGF-I on osteoblastic cell differentiation
    • Yeh LCC, Ma X, Matheny RW, Jr., Adamo ML, Lee JC,. 2010. Protein kinase D mediates the synergistic effects of BMP-7 and IGF-I on osteoblastic cell differentiation. Growth Factors 28: 318-328.
    • (2010) Growth Factors , vol.28 , pp. 318-328
    • Yeh, L.C.C.1    Ma, X.2    Matheny, Jr.R.W.3    Adamo, M.L.4    Lee, J.C.5
  • 48
    • 77955606279 scopus 로고    scopus 로고
    • A subset of osteoblasts expressing high endogenous levels of PPARgamma switches fate to adipocytes in the rat calvaria cell culture model
    • Yoshiko Y, Oizumi K, Hasegawa T, Minamizaki T, Tanne K, Maeda N, Aubin JE,. 2010. A subset of osteoblasts expressing high endogenous levels of PPARgamma switches fate to adipocytes in the rat calvaria cell culture model. PLoS ONE 5: e11782.
    • (2010) PLoS ONE , vol.5
    • Yoshiko, Y.1    Oizumi, K.2    Hasegawa, T.3    Minamizaki, T.4    Tanne, K.5    Maeda, N.6    Aubin, J.E.7
  • 49
    • 58149213801 scopus 로고    scopus 로고
    • Non-Smad pathways in TGF-β signaling
    • Zhang YE,. 2009. Non-Smad pathways in TGF-β signaling. Cell Res 19: 128-139.
    • (2009) Cell Res , vol.19 , pp. 128-139
    • Zhang, Y.E.1
  • 50
    • 78650510609 scopus 로고    scopus 로고
    • MTOR: From growth signal integration to cancer, diabetes and ageing
    • Zoncu R, Efeyan A, Sabatini DM,. 2011. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12: 21-35.
    • (2011) Nat Rev Mol Cell Biol , vol.12 , pp. 21-35
    • Zoncu, R.1    Efeyan, A.2    Sabatini, D.M.3


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