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Volumn 16, Issue 1, 2015, Pages

Six host-range restricted poxviruses from three genera induce distinct gene expression profiles in an in vivo mouse model

Author keywords

Avipoxviruses; LSDV; Micro array; MVA; Poxvirus; Vaccine

Indexed keywords

IMMUNOGLOBULIN G3; IMMUNOGLOBULIN G3 ANTIBODY; IMMUNOGLOBULIN M; INTERFERON; VIRUS VECTOR; IMMUNOGLOBULIN G; TRANSCRIPTOME; VACCINE;

EID: 84936091620     PISSN: None     EISSN: 14712164     Source Type: Journal    
DOI: 10.1186/s12864-015-1659-1     Document Type: Article
Times cited : (12)

References (73)
  • 1
    • 84908374121 scopus 로고    scopus 로고
    • Enhancing poxvirus vectors vaccine immunogenicity
    • Garcia-Arriaza J, Esteban M. Enhancing poxvirus vectors vaccine immunogenicity. Hum Vaccin Immunother. 2014;10(8):2235-44.
    • (2014) Hum Vaccin Immunother , vol.10 , Issue.8 , pp. 2235-2244
    • Garcia-Arriaza, J.1    Esteban, M.2
  • 4
    • 84882916976 scopus 로고    scopus 로고
    • Utilizing poxviral vectored vaccines for antibody induction-progress and prospects
    • Draper SJ, Cottingham MG, Gilbert SC. Utilizing poxviral vectored vaccines for antibody induction-progress and prospects. Vaccine. 2013;31(39):4223-30.
    • (2013) Vaccine , vol.31 , Issue.39 , pp. 4223-4230
    • Draper, S.J.1    Cottingham, M.G.2    Gilbert, S.C.3
  • 5
    • 84863387673 scopus 로고    scopus 로고
    • Poxviral vectors for cancer immunotherapy
    • Kim JW, Gulley JL. Poxviral vectors for cancer immunotherapy. Expert Opin Biol Ther. 2012;12(4):463-78.
    • (2012) Expert Opin Biol Ther , vol.12 , Issue.4 , pp. 463-478
    • Kim, J.W.1    Gulley, J.L.2
  • 6
    • 0041666575 scopus 로고    scopus 로고
    • Evaluation of lumpy skin disease virus, a capripoxvirus, as a replication-deficient vaccine vector
    • Aspden K, Passmore JA, Tiedt F, Williamson AL. Evaluation of lumpy skin disease virus, a capripoxvirus, as a replication-deficient vaccine vector. J Gen Virol. 2003;84(Pt 8):1985-96.
    • (2003) J Gen Virol , vol.84 , pp. 1985-1996
    • Aspden, K.1    Passmore, J.A.2    Tiedt, F.3    Williamson, A.L.4
  • 8
    • 0026604536 scopus 로고
    • Potential use of non-replicating vectors as recombinant vaccines
    • Baxby D, Paoletti E. Potential use of non-replicating vectors as recombinant vaccines. Vaccine. 1992;10(1):8-9.
    • (1992) Vaccine , vol.10 , Issue.1 , pp. 8-9
    • Baxby, D.1    Paoletti, E.2
  • 9
    • 0026939125 scopus 로고
    • Vaccinia and other poxvirus expression vectors
    • Moss B. Vaccinia and other poxvirus expression vectors. Curr Opin Biotechnol. 1992;3(5):518-22.
    • (1992) Curr Opin Biotechnol , vol.3 , Issue.5 , pp. 518-522
    • Moss, B.1
  • 11
    • 2442638941 scopus 로고    scopus 로고
    • Microarray analysis reveals characteristic changes of host cell gene expression in response to attenuated modified vaccinia virus Ankara infection of human HeLa cells
    • Guerra S, Lopez-Fernandez LA, Conde R, Pascual-Montano A, Harshman K, Esteban M. Microarray analysis reveals characteristic changes of host cell gene expression in response to attenuated modified vaccinia virus Ankara infection of human HeLa cells. J Virol. 2004;78(11):5820-34.
    • (2004) J Virol , vol.78 , Issue.11 , pp. 5820-5834
    • Guerra, S.1    Lopez-Fernandez, L.A.2    Conde, R.3    Pascual-Montano, A.4    Harshman, K.5    Esteban, M.6
  • 13
    • 30344453950 scopus 로고    scopus 로고
    • Host response to the attenuated poxvirus vector NYVAC: upregulation of apoptotic genes and NF-kappaB-responsive genes in infected HeLa cells
    • Guerra S, Lopez-Fernandez LA, Pascual-Montano A, Najera JL, Zaballos A, Esteban M. Host response to the attenuated poxvirus vector NYVAC: upregulation of apoptotic genes and NF-kappaB-responsive genes in infected HeLa cells. J Virol. 2006;80(2):985-98.
    • (2006) J Virol , vol.80 , Issue.2 , pp. 985-998
    • Guerra, S.1    Lopez-Fernandez, L.A.2    Pascual-Montano, A.3    Najera, J.L.4    Zaballos, A.5    Esteban, M.6
  • 14
    • 34547747839 scopus 로고    scopus 로고
    • Distinct gene expression profiling after infection of immature human monocyte-derived dendritic cells by the attenuated poxvirus vectors MVA and NYVAC
    • Guerra S, Najera JL, Gonzalez JM, Lopez-Fernandez LA, Climent N, Gatell JM, et al. Distinct gene expression profiling after infection of immature human monocyte-derived dendritic cells by the attenuated poxvirus vectors MVA and NYVAC. J Virol. 2007;81(16):8707-21.
    • (2007) J Virol , vol.81 , Issue.16 , pp. 8707-8721
    • Guerra, S.1    Najera, J.L.2    Gonzalez, J.M.3    Lopez-Fernandez, L.A.4    Climent, N.5    Gatell, J.M.6    Gallart, T.7    Esteban, M.8
  • 15
    • 50549101923 scopus 로고    scopus 로고
    • Gene profiling analysis of ALVAC infected human monocyte derived dendritic cells
    • Harenberg A, Guillaume F, Ryan EJ, Burdin N, Spada F. Gene profiling analysis of ALVAC infected human monocyte derived dendritic cells. Vaccine. 2008;26(39):5004-13.
    • (2008) Vaccine , vol.26 , Issue.39 , pp. 5004-5013
    • Harenberg, A.1    Guillaume, F.2    Ryan, E.J.3    Burdin, N.4    Spada, F.5
  • 16
    • 84892450553 scopus 로고    scopus 로고
    • The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys
    • Teigler JE, Phogat S, Franchini G, Hirsch VM, Michael NL, Barouch DH. The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. J Virol. 2014;88(3):1809-14.
    • (2014) J Virol , vol.88 , Issue.3 , pp. 1809-1814
    • Teigler, J.E.1    Phogat, S.2    Franchini, G.3    Hirsch, V.M.4    Michael, N.L.5    Barouch, D.H.6
  • 17
    • 77953324889 scopus 로고    scopus 로고
    • Canarypox and fowlpox viruses as recombinant vaccine vectors: an ultrastructural comparative analysis
    • Pacchioni S, Volonte L, Zanotto C, Pozzi E, De Giuli MC, Radaelli A. Canarypox and fowlpox viruses as recombinant vaccine vectors: an ultrastructural comparative analysis. Arch Virol. 2010;155(6):915-24.
    • (2010) Arch Virol , vol.155 , Issue.6 , pp. 915-924
    • Pacchioni, S.1    Volonte, L.2    Zanotto, C.3    Pozzi, E.4    Giuli, M.C.5    Radaelli, A.6
  • 18
    • 77956930202 scopus 로고    scopus 로고
    • Canarypox and fowlpox viruses as recombinant vaccine vectors: a biological and immunological comparison
    • Zanotto C, Pozzi E, Pacchioni S, Volonte L, De Giuli MC, Radaelli A. Canarypox and fowlpox viruses as recombinant vaccine vectors: a biological and immunological comparison. Antivir Res. 2010;88(1):53-63.
    • (2010) Antivir Res , vol.88 , Issue.1 , pp. 53-63
    • Zanotto, C.1    Pozzi, E.2    Pacchioni, S.3    Volonte, L.4    Giuli, M.C.5    Radaelli, A.6
  • 19
    • 58049202272 scopus 로고    scopus 로고
    • Innate immunity to virus infection
    • Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009;227(1):75-86.
    • (2009) Immunol Rev , vol.227 , Issue.1 , pp. 75-86
    • Takeuchi, O.1    Akira, S.2
  • 25
    • 33744901943 scopus 로고    scopus 로고
    • Cellular and biochemical differences between two attenuated poxvirus vaccine candidates (MVA and NYVAC) and role of the C7L gene
    • Najera JL, Gomez CE, Domingo-Gil E, Gherardi MM, Esteban M. Cellular and biochemical differences between two attenuated poxvirus vaccine candidates (MVA and NYVAC) and role of the C7L gene. J Virol. 2006;80(12):6033-47.
    • (2006) J Virol , vol.80 , Issue.12 , pp. 6033-6047
    • Najera, J.L.1    Gomez, C.E.2    Domingo-Gil, E.3    Gherardi, M.M.4    Esteban, M.5
  • 26
    • 84884198105 scopus 로고    scopus 로고
    • Phylogenetic and histological variation in avipoxviruses isolated in South Africa
    • Offerman K, Carulei O, Gous TA, Douglass N, Williamson AL. Phylogenetic and histological variation in avipoxviruses isolated in South Africa. J Gen Virol. 2013;94(Pt 10):2338-51.
    • (2013) J Gen Virol , vol.94 , pp. 2338-2351
    • Offerman, K.1    Carulei, O.2    Gous, T.A.3    Douglass, N.4    Williamson, A.L.5
  • 27
    • 84908345608 scopus 로고    scopus 로고
    • The complete genome sequences of poxviruses isolated from a penguin and a pigeon in South Africa and comparison to other sequenced avipoxviruses
    • Offerman K, Carulei O, van der Walt AP, Douglass N, Williamson AL. The complete genome sequences of poxviruses isolated from a penguin and a pigeon in South Africa and comparison to other sequenced avipoxviruses. BMC Genomics. 2014;15:463.
    • (2014) BMC Genomics , vol.15 , pp. 463
    • Offerman, K.1    Carulei, O.2    Walt, A.P.3    Douglass, N.4    Williamson, A.L.5
  • 28
    • 0031824053 scopus 로고    scopus 로고
    • Evidence for incomplete replication of a penguin poxvirus in cells of mammalian origin
    • Stannard LM, Marais D, Kow D, Dumbell KR. Evidence for incomplete replication of a penguin poxvirus in cells of mammalian origin. J Gen Virol. 1998;79(Pt 7):1637-46.
    • (1998) J Gen Virol , vol.79 , pp. 1637-1646
    • Stannard, L.M.1    Marais, D.2    Kow, D.3    Dumbell, K.R.4
  • 29
    • 67649970580 scopus 로고    scopus 로고
    • Phylogenetic analysis of three genes of Penguinpox virus corresponding to Vaccinia virus G8R (VLTF-1), A3L (P4b) and H3L reveals that it is most closely related to Turkeypox virus, Ostrichpox virus and Pigeonpox virus
    • Carulei O, Douglass N, Williamson AL. Phylogenetic analysis of three genes of Penguinpox virus corresponding to Vaccinia virus G8R (VLTF-1), A3L (P4b) and H3L reveals that it is most closely related to Turkeypox virus, Ostrichpox virus and Pigeonpox virus. Virol J. 2009;6:52.
    • (2009) Virol J , vol.6 , pp. 52
    • Carulei, O.1    Douglass, N.2    Williamson, A.L.3
  • 30
    • 79251578390 scopus 로고    scopus 로고
    • Stunned silence: gene expression programs in human cells infected with monkeypox or vaccinia virus
    • Rubins KH, Hensley LE, Relman DA, Brown PO. Stunned silence: gene expression programs in human cells infected with monkeypox or vaccinia virus. PLoS One. 2011;6(1):e15615.
    • (2011) PLoS One , vol.6 , Issue.1 , pp. e15615
    • Rubins, K.H.1    Hensley, L.E.2    Relman, D.A.3    Brown, P.O.4
  • 31
    • 0142185283 scopus 로고    scopus 로고
    • Microarray analysis of A549 cells infected with rabbitpox virus (RPV): a comparison of wild-type RPV and RPV deleted for the host range gene, SPI-1
    • Brum LM, Lopez MC, Varela JC, Baker HV, Moyer RW. Microarray analysis of A549 cells infected with rabbitpox virus (RPV): a comparison of wild-type RPV and RPV deleted for the host range gene, SPI-1. Virology. 2003;315(2):322-34.
    • (2003) Virology , vol.315 , Issue.2 , pp. 322-334
    • Brum, L.M.1    Lopez, M.C.2    Varela, J.C.3    Baker, H.V.4    Moyer, R.W.5
  • 32
    • 78650048628 scopus 로고    scopus 로고
    • Function and regulation of retinoic acid-inducible gene-I
    • Matsumiya T, Stafforini DM. Function and regulation of retinoic acid-inducible gene-I. Crit Rev Immunol. 2010;30(6):489-513.
    • (2010) Crit Rev Immunol , vol.30 , Issue.6 , pp. 489-513
    • Matsumiya, T.1    Stafforini, D.M.2
  • 34
    • 0032491401 scopus 로고    scopus 로고
    • The role of C/EBP isoforms in the control of inflammatory and native immunity functions
    • Poli V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem. 1998;273(45):29279-82.
    • (1998) J Biol Chem , vol.273 , Issue.45 , pp. 29279-29282
    • Poli, V.1
  • 35
    • 0032721515 scopus 로고    scopus 로고
    • Function of the transport complex TAP in cellular immune recognition
    • Abele R, Tampe R. Function of the transport complex TAP in cellular immune recognition. Biochim Biophys Acta. 1999;1461(2):405-19.
    • (1999) Biochim Biophys Acta , vol.1461 , Issue.2 , pp. 405-419
    • Abele, R.1    Tampe, R.2
  • 37
    • 80555156691 scopus 로고    scopus 로고
    • MARCO regulates early inflammatory responses against influenza: a useful macrophage function with adverse outcome
    • Ghosh S, Gregory D, Smith A, Kobzik L. MARCO regulates early inflammatory responses against influenza: a useful macrophage function with adverse outcome. Am J Respir Cell Mol Biol. 2011;45(5):1036-44.
    • (2011) Am J Respir Cell Mol Biol , vol.45 , Issue.5 , pp. 1036-1044
    • Ghosh, S.1    Gregory, D.2    Smith, A.3    Kobzik, L.4
  • 40
    • 0036467429 scopus 로고    scopus 로고
    • Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice
    • Chen SC, Vassileva G, Kinsley D, Holzmann S, Manfra D, Wiekowski MT, et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J Immunol. 2002;168(3):1001-8.
    • (2002) J Immunol , vol.168 , Issue.3 , pp. 1001-1008
    • Chen, S.C.1    Vassileva, G.2    Kinsley, D.3    Holzmann, S.4    Manfra, D.5    Wiekowski, M.T.6    Romani, N.7    Lira, S.A.8
  • 45
    • 0032417696 scopus 로고    scopus 로고
    • Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays
    • Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A. 1998;95(26):15623-8.
    • (1998) Proc Natl Acad Sci U S A , vol.95 , Issue.26 , pp. 15623-15628
    • Der, S.D.1    Zhou, A.2    Williams, B.R.3    Silverman, R.H.4
  • 47
    • 32944455665 scopus 로고    scopus 로고
    • Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity
    • Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006;203(2):413-24.
    • (2006) J Exp Med , vol.203 , Issue.2 , pp. 413-424
    • Querec, T.1    Bennouna, S.2    Alkan, S.3    Laouar, Y.4    Gorden, K.5    Flavell, R.6    Akira, S.7    Ahmed, R.8    Pulendran, B.9
  • 48
    • 14044257261 scopus 로고    scopus 로고
    • Variegation of the immune response with dendritic cells and pathogen recognition receptors
    • Pulendran B. Variegation of the immune response with dendritic cells and pathogen recognition receptors. J Immunol. 2005;174(5):2457-65.
    • (2005) J Immunol , vol.174 , Issue.5 , pp. 2457-2465
    • Pulendran, B.1
  • 49
    • 0027443053 scopus 로고
    • Fowlpox virus host range restriction: gene expression, DNA replication, and morphogenesis in nonpermissive mammalian cells
    • Somogyi P, Frazier J, Skinner MA. Fowlpox virus host range restriction: gene expression, DNA replication, and morphogenesis in nonpermissive mammalian cells. Virology. 1993;197(1):439-44.
    • (1993) Virology , vol.197 , Issue.1 , pp. 439-444
    • Somogyi, P.1    Frazier, J.2    Skinner, M.A.3
  • 50
    • 84936107177 scopus 로고    scopus 로고
    • Investigation of local South African avipoxviruses as potential vaccine vectors
    • Cape Town: University of Cape Town;
    • Offerman K. Investigation of local South African avipoxviruses as potential vaccine vectors. Cape Town: University of Cape Town; 2014.
    • (2014)
    • Offerman, K.1
  • 53
    • 84873976597 scopus 로고    scopus 로고
    • Comparison of host cell gene expression in cowpox, monkeypox or vaccinia virus-infected cells reveals virus-specific regulation of immune response genes
    • Bourquain D, Dabrowski PW, Nitsche A. Comparison of host cell gene expression in cowpox, monkeypox or vaccinia virus-infected cells reveals virus-specific regulation of immune response genes. Virol J. 2013;10:61.
    • (2013) Virol J , vol.10 , pp. 61
    • Bourquain, D.1    Dabrowski, P.W.2    Nitsche, A.3
  • 55
    • 30344463834 scopus 로고    scopus 로고
    • Deletion of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy
    • Clark RH, Kenyon JC, Bartlett NW, Tscharke DC, Smith GL. Deletion of gene A41L enhances vaccinia virus immunogenicity and vaccine efficacy. J Gen Virol. 2006;87(Pt 1):29-38.
    • (2006) J Gen Virol , vol.87 , pp. 29-38
    • Clark, R.H.1    Kenyon, J.C.2    Bartlett, N.W.3    Tscharke, D.C.4    Smith, G.L.5
  • 56
    • 79957551445 scopus 로고    scopus 로고
    • A novel candidate HIV vaccine vector based on the replication deficient Capripoxvirus, Lumpy skin disease virus (LSDV)
    • Shen YJ, Shephard E, Douglass N, Johnston N, Adams C, Williamson C, et al. A novel candidate HIV vaccine vector based on the replication deficient Capripoxvirus, Lumpy skin disease virus (LSDV). Virol J. 2011;8:265.
    • (2011) Virol J , vol.8 , pp. 265
    • Shen, Y.J.1    Shephard, E.2    Douglass, N.3    Johnston, N.4    Adams, C.5    Williamson, C.6    Williamson, A.L.7
  • 58
    • 39149107423 scopus 로고    scopus 로고
    • MDA5/RIG-I and virus recognition
    • Takeuchi O, Akira S. MDA5/RIG-I and virus recognition. Curr Opin Immunol. 2008;20(1):17-22.
    • (2008) Curr Opin Immunol , vol.20 , Issue.1 , pp. 17-22
    • Takeuchi, O.1    Akira, S.2
  • 59
    • 0035904463 scopus 로고    scopus 로고
    • Function and regulation of the transcription factors of the Myc/Max/Mad network
    • Luscher B. Function and regulation of the transcription factors of the Myc/Max/Mad network. Gene. 2001;277(1-2):1-14.
    • (2001) Gene , vol.277 , Issue.1-2 , pp. 1-14
    • Luscher, B.1
  • 60
    • 77951984369 scopus 로고    scopus 로고
    • Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication
    • Wang X, Han Y, Dang Y, Fu W, Zhou T, Ptak RG, et al. Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication. J Biol Chem. 2010;285(19):14346-55.
    • (2010) J Biol Chem , vol.285 , Issue.19 , pp. 14346-14355
    • Wang, X.1    Han, Y.2    Dang, Y.3    Fu, W.4    Zhou, T.5    Ptak, R.G.6    Zheng, Y.H.7
  • 62
    • 79951671973 scopus 로고    scopus 로고
    • New developments in the induction and antiviral effectors of type I interferon
    • Liu SY, Sanchez DJ, Cheng G. New developments in the induction and antiviral effectors of type I interferon. Curr Opin Immunol. 2011;23(1):57-64.
    • (2011) Curr Opin Immunol , vol.23 , Issue.1 , pp. 57-64
    • Liu, S.Y.1    Sanchez, D.J.2    Cheng, G.3
  • 63
    • 0035489511 scopus 로고    scopus 로고
    • IFNs activate toll-like receptor gene expression in viral infections
    • Miettinen M, Sareneva T, Julkunen I, Matikainen S. IFNs activate toll-like receptor gene expression in viral infections. Genes Immun. 2001;2(6):349-55.
    • (2001) Genes Immun , vol.2 , Issue.6 , pp. 349-355
    • Miettinen, M.1    Sareneva, T.2    Julkunen, I.3    Matikainen, S.4
  • 66
    • 84871206169 scopus 로고    scopus 로고
    • Fold change and p-value cutoffs significantly alter microarray interpretations
    • Dalman MR, Deeter A, Nimishakavi G, Duan ZH. Fold change and p-value cutoffs significantly alter microarray interpretations. BMC Bioinformatics. 2012;13 Suppl 2:S11.
    • (2012) BMC Bioinformatics , vol.13 , pp. S11
    • Dalman, M.R.1    Deeter, A.2    Nimishakavi, G.3    Duan, Z.H.4
  • 67
    • 84914179053 scopus 로고    scopus 로고
    • R: a language and environment for statistical computing
    • Vienna: R Foundation for Statistical Computing; 2012. 2013.
    • Team RC. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2012. 2013. Available from: http://www.R-project.org ISBN 3-900051-07-0.
    • (2013)
  • 69
    • 1342288026 scopus 로고    scopus 로고
    • affy--analysis of Affymetrix GeneChip data at the probe level
    • Gautier L, Cope L, Bolstad BM, Irizarry RA. affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20(3):307-15.
    • (2004) Bioinformatics , vol.20 , Issue.3 , pp. 307-315
    • Gautier, L.1    Cope, L.2    Bolstad, B.M.3    Irizarry, R.A.4
  • 70
    • 72449150227 scopus 로고    scopus 로고
    • Genefilter: Methods for filtering genes from microarray experiments
    • R package version
    • Gentleman R, Carey V, Huber W, Hahne F. Genefilter: Methods for filtering genes from microarray experiments. R package version 2011, 1(0). http://www.bioconductor.org/packages/release/bioc/html/genefilter.html .
    • (2011) , vol.1
    • Gentleman, R.1    Carey, V.2    Huber, W.3    Hahne, F.4
  • 73
    • 57649133991 scopus 로고    scopus 로고
    • VENNY. An interactive tool for comparing lists with Venn Diagrams.
    • Oliveros JC. VENNY. An interactive tool for comparing lists with Venn Diagrams. 2007.
    • (2007)
    • Oliveros, J.C.1


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