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Volumn 162, Issue 7, 1999, Pages 4045-4052

Similarities and differences between human and murine TNF promoters in their response to lipopolysaccharide

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIPOPOLYSACCHARIDE; TUMOR NECROSIS FACTOR;

EID: 0033120071     PISSN: 00221767     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article
Times cited : (141)

References (46)
  • 2
    • 0027971696 scopus 로고
    • Control of tumor necrosis factor gene expression
    • Pauli, U. 1994. Control of tumor necrosis factor gene expression. Crit. Rev. Eukaryotic Gene Expr. 4:323.
    • (1994) Crit. Rev. Eukaryotic Gene Expr. , vol.4 , pp. 323
    • Pauli, U.1
  • 4
    • 0023916712 scopus 로고
    • Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes
    • Sariban, E., K. Imamura, R. Luebbers, and D. Kufe. 1988. Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes. J. Clin. Invest. 81:1506.
    • (1988) J. Clin. Invest. , vol.81 , pp. 1506
    • Sariban, E.1    Imamura, K.2    Luebbers, R.3    Kufe, D.4
  • 5
    • 0031964902 scopus 로고    scopus 로고
    • Relative contribution of transcription and translation to the induction of tumor necrosis factor-α by lipopolysaccharide
    • Raabe, T., M. Bukrinsky, and R. A. Currie. 1998. Relative contribution of transcription and translation to the induction of tumor necrosis factor-α by lipopolysaccharide. J. Biol. Chem. 273:974.
    • (1998) J. Biol. Chem. , vol.273 , pp. 974
    • Raabe, T.1    Bukrinsky, M.2    Currie, R.A.3
  • 6
    • 0028991950 scopus 로고
    • Transcriptional regulation of the tumor necrosis factor α gene
    • Jongeneel, C. V. 1995. Transcriptional regulation of the tumor necrosis factor α gene. Immunobiology 193:210.
    • (1995) Immunobiology , vol.193 , pp. 210
    • Jongeneel, C.V.1
  • 7
    • 0028983373 scopus 로고
    • Lipopolysaccharide-induced expression of TNF-α gene in the macrophage cell line ANA-1 is regulated at the level of transcription processivity
    • Biragyn, A., and S. A. Nedospasov. 1995. Lipopolysaccharide-induced expression of TNF-α gene in the macrophage cell line ANA-1 is regulated at the level of transcription processivity. J. Immunol. 155:674.
    • (1995) J. Immunol. , vol.155 , pp. 674
    • Biragyn, A.1    Nedospasov, S.A.2
  • 8
    • 0030868611 scopus 로고    scopus 로고
    • The role of 3′ poly(A) tail metabolism in tumor necrosis factor-α regulation
    • Crawford, E. K., J. E. Ensor, I. Kalvakolanu, and J. D. Hasday. 1997. The role of 3′ poly(A) tail metabolism in tumor necrosis factor-α regulation. J. Biol. Chem. 272:21120.
    • (1997) J. Biol. Chem. , vol.272 , pp. 21120
    • Crawford, E.K.1    Ensor, J.E.2    Kalvakolanu, I.3    Hasday, J.D.4
  • 9
    • 0029874138 scopus 로고    scopus 로고
    • The NF-κB and IκB proteins: New discoveries and insights
    • Baldwin, A. S., Jr. 1996. The NF-κB and IκB proteins: new discoveries and insights. Annu. Rev. Immunol. 14:649.
    • (1996) Annu. Rev. Immunol. , vol.14 , pp. 649
    • Baldwin A.S., Jr.1
  • 11
    • 0028308257 scopus 로고
    • Synergistic transcriptional activation of the IL-8 gene by NF-κB p65 (RelA) and NF-IL-6
    • Kunsch, C., R. K. Lang, C. A. Rosen, and M. F. Shannon. 1994. Synergistic transcriptional activation of the IL-8 gene by NF-κB p65 (RelA) and NF-IL-6. J. Immunol. 153:153.
    • (1994) J. Immunol. , vol.153 , pp. 153
    • Kunsch, C.1    Lang, R.K.2    Rosen, C.A.3    Shannon, M.F.4
  • 12
    • 0026774239 scopus 로고
    • Selection of optimal κB/Rel DNA-binding motifs: Interaction of both subunits of NF-κB with DNA is required for transcriptional activation
    • Kunsch, C., S. M. Ruben, and C. A. Rosen. 1992. Selection of optimal κB/Rel DNA-binding motifs: interaction of both subunits of NF-κB with DNA is required for transcriptional activation. Mol. Cell. Biol. 12:4412.
    • (1992) Mol. Cell. Biol. , vol.12 , pp. 4412
    • Kunsch, C.1    Ruben, S.M.2    Rosen, C.A.3
  • 13
    • 0026592340 scopus 로고
    • A novel complex between the p65 subunit of NF-κB and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene
    • Hansen, S. K., C. Nerlov, U. Zabel, P. Verde, M. Johnsen, P. A. Baeuerle, and F. Blasi. 1992. A novel complex between the p65 subunit of NF-κB and c-Rel binds to a DNA element involved in the phorbol ester induction of the human urokinase gene. EMBO J. 11:205.
    • (1992) EMBO J. , vol.11 , pp. 205
    • Hansen, S.K.1    Nerlov, C.2    Zabel, U.3    Verde, P.4    Johnsen, M.5    Baeuerle, P.A.6    Blasi, F.7
  • 14
    • 0025943986 scopus 로고
    • The p65 subunit is responsible for the strong transcription activating potential of NF-κB
    • Schmitz, M. L., and P. A. Baeuerle. 1991. The p65 subunit is responsible for the strong transcription activating potential of NF-κB. EMBO J. 10:3805.
    • (1991) EMBO J. , vol.10 , pp. 3805
    • Schmitz, M.L.1    Baeuerle, P.A.2
  • 15
    • 0027190466 scopus 로고
    • KBF1 (p50 NF-κB homodimer) acts as a represser of H-2Kb gene expression in metastatic tumor cells
    • Plaksin, D., P. A. Baeuerle, and L. Eisenbach. 1993. KBF1 (p50 NF-κB homodimer) acts as a represser of H-2Kb gene expression in metastatic tumor cells. J. Exp. Med. 177:1651.
    • (1993) J. Exp. Med. , vol.177 , pp. 1651
    • Plaksin, D.1    Baeuerle, P.A.2    Eisenbach, L.3
  • 16
    • 0028889159 scopus 로고
    • Regulation of cell-type-specific interleukin-2 receptor α-chain gene expression: Potential role of physical interactions between Elf-1. HMG-I(Y), and NF-κB family proteins
    • John, S., R. B. Reeves, J. X. Lin, R. Child, J. M. Leiden, C. B. Thompson, and W. J. Leonard. 1995. Regulation of cell-type-specific interleukin-2 receptor α-chain gene expression: potential role of physical interactions between Elf-1. HMG-I(Y), and NF-κB family proteins. Mol. Cell. Biol. 15:1786.
    • (1995) Mol. Cell. Biol. , vol.15 , pp. 1786
    • John, S.1    Reeves, R.B.2    Lin, J.X.3    Child, R.4    Leiden, J.M.5    Thompson, C.B.6    Leonard, W.J.7
  • 17
    • 0027209915 scopus 로고
    • A cooperative interaction between NF-κB and Sp1 is required for HIV-1 enhancer activation
    • Perkins, N. D., N. L. Edwards, C. S. Duckett, A. B. Agranoff, R. M. Schmid, and G. J. Nabel. 1993. A cooperative interaction between NF-κB and Sp1 is required for HIV-1 enhancer activation. EMBO J. 12:3551.
    • (1993) EMBO J. , vol.12 , pp. 3551
    • Perkins, N.D.1    Edwards, N.L.2    Duckett, C.S.3    Agranoff, A.B.4    Schmid, R.M.5    Nabel, G.J.6
  • 18
    • 0027426212 scopus 로고
    • Cyclic AMP-independent ATF family members interact with NF-κB and function in the activation of the E-selectin promoter in response to cytokines
    • Kaszubska, W., R. H. van Huijsduijnen, P. Ghersa, A. M. DeRaemy-Schenk, B. P. Chen, T. Hai, J. F. DeLamarter, and J. Whelan. 1993. Cyclic AMP-independent ATF family members interact with NF-κB and function in the activation of the E-selectin promoter in response to cytokines. Mol. Cell. Biol. 13:7180.
    • (1993) Mol. Cell. Biol. , vol.13 , pp. 7180
    • Kaszubska, W.1    Van Huijsduijnen, R.H.2    Ghersa, P.3    DeRaemy-Schenk, A.M.4    Chen, B.P.5    Hai, T.6    Delamarter, J.F.7    Whelan, J.8
  • 19
    • 0027316201 scopus 로고
    • Functional and physical associations between NF-κB and C/EBP family members: A Rel domain-bZIP interaction
    • Stein, B., P. C. Cogswell, and A. S. Baldwin, Jr. 1993. Functional and physical associations between NF-κB and C/EBP family members: a Rel domain-bZIP interaction. Mol. Cell. Biol. 13:3964.
    • (1993) Mol. Cell. Biol. , vol.13 , pp. 3964
    • Stein, B.1    Cogswell, P.C.2    Baldwin A.S., Jr.3
  • 20
    • 0029617947 scopus 로고
    • Virus induction of human IFN β gene expression requires the assembly of an enhanceosome
    • Thanos, D., and T. Maniatis. 1995. Virus induction of human IFN β gene expression requires the assembly of an enhanceosome. Cell 83:1091.
    • (1995) Cell , vol.83 , pp. 1091
    • Thanos, D.1    Maniatis, T.2
  • 21
    • 0025186678 scopus 로고
    • κB-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor α gene in primary macrophages
    • Shakhov, A. N., M. A. Collart, P. Vassalli, S. A. Nedospasov, and C. V. Jongeneel. 1990. κB-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor α gene in primary macrophages. J. Exp. Med. 171:35.
    • (1990) J. Exp. Med. , vol.171 , pp. 35
    • Shakhov, A.N.1    Collart, M.A.2    Vassalli, P.3    Nedospasov, S.A.4    Jongeneel, C.V.5
  • 22
    • 0025223225 scopus 로고
    • Structural analysis of the rabbit TNF locus, containing the genes encoding TNF-β (lymphotoxin) and TNF-α (tumor necrosis factor)
    • Shakhov, A. N., D. V. Kuprash, M. M. Azizov, C. V. Jongeneel, and S. A. Nedospasov. 1990. Structural analysis of the rabbit TNF locus, containing the genes encoding TNF-β (lymphotoxin) and TNF-α (tumor necrosis factor). Gene 95:215.
    • (1990) Gene , vol.95 , pp. 215
    • Shakhov, A.N.1    Kuprash, D.V.2    Azizov, M.M.3    Jongeneel, C.V.4    Nedospasov, S.A.5
  • 23
    • 0028980260 scopus 로고
    • Conserved κB element located downstream of the tumor necrosis factor α gene: Distinct NF-κB binding pattern and enhancer activity in LPS activated murine macrophages
    • Kuprash, D. V., I. A. Udalova, R. L. Turetskaya, N. R. Rice, and S. A. Nedospasov. 1995. Conserved κB element located downstream of the tumor necrosis factor α gene: distinct NF-κB binding pattern and enhancer activity in LPS activated murine macrophages. Oncogene 11:97.
    • (1995) Oncogene , vol.11 , pp. 97
    • Kuprash, D.V.1    Udalova, I.A.2    Turetskaya, R.L.3    Rice, N.R.4    Nedospasov, S.A.5
  • 24
    • 0024447719 scopus 로고
    • Heterogeneity of hematopoietic cells immortalized by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver
    • Cox, G. W., B. J. Mathieson, L. Gandino, E. Blasi, D. Radzioch, and L. Varesio. 1989. Heterogeneity of hematopoietic cells immortalized by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver. J. Natl. Cancer Inst. 81:1492.
    • (1989) J. Natl. Cancer Inst. , vol.81 , pp. 1492
    • Cox, G.W.1    Mathieson, B.J.2    Gandino, L.3    Blasi, E.4    Radzioch, D.5    Varesio, L.6
  • 25
    • 0029122799 scopus 로고
    • N-and C-terminal sequences control degradation of MAD3/1 κBα in response to inducers of NF-κB activity
    • Whiteside, S. T., M. K. Ernst, O. LeBail, C. Laurent-Winter, N. Rice, and A. Israel. 1995. N-and C-terminal sequences control degradation of MAD3/1 κBα in response to inducers of NF-κB activity. Mol. Cell. Biol. 15:5339.
    • (1995) Mol. Cell. Biol. , vol.15 , pp. 5339
    • Whiteside, S.T.1    Ernst, M.K.2    LeBail, O.3    Laurent-Winter, C.4    Rice, N.5    Israel, A.6
  • 26
    • 0029301029 scopus 로고
    • Two steps in activation of human TNF gene in macrophages: The role of NF-κB/ Rel family proteins in the effect of LPS
    • Udalova, I. A., R. L. Turetskaia, D. V. Kuprash, and S. A. Nedospasov. 1995. Two steps in activation of human TNF gene in macrophages: the role of NF-κB/ Rel family proteins in the effect of LPS. Proc. Russ. Acadi. Sci. (Dokl. Akad. Nauk) 342:413.
    • (1995) Proc. Russ. Acadi. Sci. (Dokl. Akad. Nauk) , vol.342 , pp. 413
    • Udalova, I.A.1    Turetskaia, R.L.2    Kuprash, D.V.3    Nedospasov, S.A.4
  • 28
    • 0026601458 scopus 로고
    • Site-directed mutagenesis of virtually any plasmid by eliminating a unique site
    • Deng, W. P., and J. A. Nickoloff. 1992. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site. Anal. Biochem. 200:81.
    • (1992) Anal. Biochem. , vol.200 , pp. 81
    • Deng, W.P.1    Nickoloff, J.A.2
  • 29
    • 0032516519 scopus 로고    scopus 로고
    • Complex NF-κB interactions at the distal tumor necrosis factor promoter region in human monocytes
    • Udalova, I. A., J. C. Knight, V. Vidal, S. A. Nedospasov, and D. Kwiatkowski. 1998. Complex NF-κB interactions at the distal tumor necrosis factor promoter region in human monocytes. J. Biol. Chem. 273:21178.
    • (1998) J. Biol. Chem. , vol.273 , pp. 21178
    • Udalova, I.A.1    Knight, J.C.2    Vidal, V.3    Nedospasov, S.A.4    Kwiatkowski, D.5
  • 30
    • 0024380087 scopus 로고
    • Rapid detection of octamer binding proteins with mini-extracts, prepared from a small number of cells
    • Schreiber, E., P. Matthias, M. M. Muller, and W. Schaffner. 1989. Rapid detection of octamer binding proteins with mini-extracts, prepared from a small number of cells. Nucleic Acids Res. 17:6419.
    • (1989) Nucleic Acids Res. , vol.17 , pp. 6419
    • Schreiber, E.1    Matthias, P.2    Muller, M.M.3    Schaffner, W.4
  • 31
    • 0027451924 scopus 로고
    • In vivo control of NF-κB activation by I κBα
    • Rice, N. R., and M. K. Ernst. 1993. In vivo control of NF-κB activation by I κBα. EMBO J. 12:4685.
    • (1993) EMBO J. , vol.12 , pp. 4685
    • Rice, N.R.1    Ernst, M.K.2
  • 32
    • 0026742527 scopus 로고
    • The precursor of NF-κB p50 has IκB-like functions
    • Rice, N. R., M. L. MacKichan, and A. Israel. 1992. The precursor of NF-κB p50 has IκB-like functions. Cell 71:243.
    • (1992) Cell , vol.71 , pp. 243
    • Rice, N.R.1    MacKichan, M.L.2    Israel, A.3
  • 33
    • 0027973632 scopus 로고
    • Characterization of an Krox-24/Egr-1-responsive element in the human tumor necrosis factor promoter
    • Kramer, B., A. Meichle, G. Hensel, P. Charnay, and M. Kronke. 1994. Characterization of an Krox-24/Egr-1-responsive element in the human tumor necrosis factor promoter. Biochim. Biophys. Acta 1219:413.
    • (1994) Biochim. Biophys. Acta , vol.1219 , pp. 413
    • Kramer, B.1    Meichle, A.2    Hensel, G.3    Charnay, P.4    Kronke, M.5
  • 34
    • 0028931318 scopus 로고
    • Regulation of the human TNF promoter by the transcription factor Ets
    • Kramer, B., K. Wiegmann, and M. Kronke. 1995. Regulation of the human TNF promoter by the transcription factor Ets. J. Biol. Chem. 270:6577.
    • (1995) J. Biol. Chem. , vol.270 , pp. 6577
    • Kramer, B.1    Wiegmann, K.2    Kronke, M.3
  • 35
    • 0030050784 scopus 로고    scopus 로고
    • Tumor necrosis factor α gene regulation in activated T cells involves ATF-2/Jun and NFATp
    • Tsai, E. Y., J. Jain, P. A. Pesavento, A. Rao, and A. E. Goldfeld. 1996. Tumor necrosis factor α gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol. Cell. Biol. 16:459.
    • (1996) Mol. Cell. Biol. , vol.16 , pp. 459
    • Tsai, E.Y.1    Jain, J.2    Pesavento, P.A.3    Rao, A.4    Goldfeld, A.E.5
  • 36
    • 0029068239 scopus 로고
    • Transcriptional activation of the human TNF-α promoter by superantigen in human monocytic cells: Role of NF-κB
    • Trede, N. S., A. V. Tsytsykova, T. Chatila, A. E. Goldfeld, and R. S. Geha. 1995. Transcriptional activation of the human TNF-α promoter by superantigen in human monocytic cells: role of NF-κB. J. Immunol. 155:902.
    • (1995) J. Immunol. , vol.155 , pp. 902
    • Trede, N.S.1    Tsytsykova, A.V.2    Chatila, T.3    Goldfeld, A.E.4    Geha, R.S.5
  • 37
    • 0028073754 scopus 로고
    • The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-α gene transcription
    • McCaffrey, P. G., A. E. Goldfeld, and A. Rao. 1994. The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-α gene transcription. J. Biol. Chem. 269:30445.
    • (1994) J. Biol. Chem. , vol.269 , pp. 30445
    • McCaffrey, P.G.1    Goldfeld, A.E.2    Rao, A.3
  • 38
    • 0025607864 scopus 로고
    • Human tumor necrosis factor α gene regulation by virus and lipopolysaccharide
    • Goldfeld, A. E., C. Doyle, and T. Maniatis. 1990. Human tumor necrosis factor α gene regulation by virus and lipopolysaccharide. Proc. Natl. Acad. Sci. USA 87:9769.
    • (1990) Proc. Natl. Acad. Sci. USA , vol.87 , pp. 9769
    • Goldfeld, A.E.1    Doyle, C.2    Maniatis, T.3
  • 39
    • 1842809115 scopus 로고
    • Interferon-induced transcription of a major histocompatibility class I gene accompanies binding of inducible nuclear factors to the interferon consensus sequence
    • Shirayoshi, Y., P. A. Burke, E. Appella, and K. Ozato. 1988. Interferon-induced transcription of a major histocompatibility class I gene accompanies binding of inducible nuclear factors to the interferon consensus sequence. Proc. Natl. Acad. Sci. USA 85:5884.
    • (1988) Proc. Natl. Acad. Sci. USA , vol.85 , pp. 5884
    • Shirayoshi, Y.1    Burke, P.A.2    Appella, E.3    Ozato, K.4
  • 40
    • 0025789094 scopus 로고
    • Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-α promoter in primary macrophages
    • Drouet, C., A. N. Shakhov, and C. V. Jongeneel. 1991. Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-α promoter in primary macrophages. J. Immunol. 147:1694.
    • (1991) J. Immunol. , vol.147 , pp. 1694
    • Drouet, C.1    Shakhov, A.N.2    Jongeneel, C.V.3
  • 41
    • 0025809325 scopus 로고
    • Human tumor necrosis factor α gene regulation in phorbol ester stimulated T and B cell lines
    • Goldfeld, A. E., J. L. Strominger, and C. Doyle. 1991. Human tumor necrosis factor α gene regulation in phorbol ester stimulated T and B cell lines. J. Exp. Med. 174:73.
    • (1991) J. Exp. Med. , vol.174 , pp. 73
    • Goldfeld, A.E.1    Strominger, J.L.2    Doyle, C.3
  • 42
    • 0026489365 scopus 로고
    • The high mobility group protein HMG I(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene
    • Thanos, D., and T. Maniatis. 1992. The high mobility group protein HMG I(Y) is required for NF-κB-dependent virus induction of the human IFN-β gene. Cell 71:777.
    • (1992) Cell , vol.71 , pp. 777
    • Thanos, D.1    Maniatis, T.2
  • 43
    • 0028197265 scopus 로고
    • The bZIP transactivator of Epstein-Barr virus. BZLF1, functionally and physically interacts with the p65 subunit of NF-κB
    • Gutsch, D. E., E. A. Holley-Guthrie, Q. Zhang, B. Stein, M. A. Blanar, A. S. Baldwin, and S. C. Kenney. 1994. The bZIP transactivator of Epstein-Barr virus. BZLF1, functionally and physically interacts with the p65 subunit of NF-κB. Mol. Cell. Biol. 14:1939.
    • (1994) Mol. Cell. Biol. , vol.14 , pp. 1939
    • Gutsch, D.E.1    Holley-Guthrie, E.A.2    Zhang, Q.3    Stein, B.4    Blanar, M.A.5    Baldwin, A.S.6    Kenney, S.C.7
  • 44
    • 0031437833 scopus 로고    scopus 로고
    • p50 (NF-κB1) is upregulated in LPS tolerant P388D1 murine macrophages
    • Ziegler-Heitbrock, H. W., I. Petersmann, and M. Frankenberger. 1997. p50 (NF-κB1) is upregulated in LPS tolerant P388D1 murine macrophages. Immunobiology 198:73.
    • (1997) Immunobiology , vol.198 , pp. 73
    • Ziegler-Heitbrock, H.W.1    Petersmann, I.2    Frankenberger, M.3
  • 45
    • 0031684844 scopus 로고    scopus 로고
    • TNF α transcription in macrophages is attenuated by an autocrine factor thai preferentially induces NF-κB p50
    • Baer, M., A. Dillner, R. C. Schwartz, C. Sedon, S. A. Nedospasov, and P. F. Johnston. 1998. TNF α transcription in macrophages is attenuated by an autocrine factor thai preferentially induces NF-κB p50. Mol. Cell. Biol. 18: 5678.
    • (1998) Mol. Cell. Biol. , vol.18 , pp. 5678
    • Baer, M.1    Dillner, A.2    Schwartz, R.C.3    Sedon, C.4    Nedospasov, S.A.5    Johnston, P.F.6
  • 46
    • 0032493278 scopus 로고    scopus 로고
    • Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent
    • Foxwell, B., K. Browne, J. Bondeson, C. Clarke, R. de Martin, F. Brennan, and M. Feldmann. 1998. Efficient adenoviral infection with IκBα reveals that macrophage tumor necrosis factor α production in rheumatoid arthritis is NF-κB dependent. Proc. Natl. Acad. Sci. USA 95:8211.
    • (1998) Proc. Natl. Acad. Sci. USA , vol.95 , pp. 8211
    • Foxwell, B.1    Browne, K.2    Bondeson, J.3    Clarke, C.4    De Martin, R.5    Brennan, F.6    Feldmann, M.7


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