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Volumn 15, Issue 2, 2003, Pages 91-97

Microenvironmental regulation of Notch signalling in T cell development

Author keywords

Lymphoid progenitor; Microenvironment; Notch; T cell development

Indexed keywords

LIGAND; NOTCH RECEPTOR; RECEPTOR;

EID: 0037382075     PISSN: 10445323     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1044-5323(03)00005-8     Document Type: Review
Times cited : (32)

References (56)
  • 2
    • 0028122624 scopus 로고
    • Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization
    • Rodewald H.R., Kretzschmar K., Takeda S., Hohl C., Dessing M. Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J. 13:1994;4229-4240.
    • (1994) EMBO J. , vol.13 , pp. 4229-4240
    • Rodewald, H.R.1    Kretzschmar, K.2    Takeda, S.3    Hohl, C.4    Dessing, M.5
  • 3
    • 0036485175 scopus 로고    scopus 로고
    • Redefinition of lymphoid progenitors
    • Katsura Y. Redefinition of lymphoid progenitors. Nat. Rev. Immunol. 2:2002;127-131.
    • (2002) Nat. Rev. Immunol. , vol.2 , pp. 127-131
    • Katsura, Y.1
  • 4
    • 0032135207 scopus 로고    scopus 로고
    • Requirement for the thymus in αβ T lymphocyte lineage commitment
    • Carlyle J.R., Zuniga-Pflucker J.C. Requirement for the thymus in αβ T lymphocyte lineage commitment. Immunity. 9:1998;187-197.
    • (1998) Immunity , vol.9 , pp. 187-197
    • Carlyle, J.R.1    Zuniga-Pflucker, J.C.2
  • 5
    • 0033428172 scopus 로고    scopus 로고
    • Notch and the immune system
    • Osborne B., Miele L. Notch and the immune system. Immunity. 11:1999;653-663.
    • (1999) Immunity , vol.11 , pp. 653-663
    • Osborne, B.1    Miele, L.2
  • 6
    • 0025237332 scopus 로고
    • The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis
    • Xu T., Rebay I., Fleming R.J., Scottgale T.N., Artavanis-Tsakonas S. The Notch locus and the genetic circuitry involved in early Drosophila neurogenesis. Genes Dev. 4:1990;464-475.
    • (1990) Genes Dev. , vol.4 , pp. 464-475
    • Xu, T.1    Rebay, I.2    Fleming, R.J.3    Scottgale, T.N.4    Artavanis-Tsakonas, S.5
  • 7
    • 0030869670 scopus 로고    scopus 로고
    • A dominant-negative form of Serrate acts as a general antagonist of notch activation
    • Hukriede N.A., Gu Y., Fleming R.J. A dominant-negative form of Serrate acts as a general antagonist of notch activation. Development. 124:1997;3427-3437.
    • (1997) Development , vol.124 , pp. 3427-3437
    • Hukriede, N.A.1    Gu, Y.2    Fleming, R.J.3
  • 8
    • 0030882580 scopus 로고    scopus 로고
    • Secreted forms of DELTA and SERRATE define dominant negative forms of the Drosophila Notch ligands
    • Sun X., Artavanis-Tsakonas S. Secreted forms of DELTA and SERRATE define dominant negative forms of the Drosophila Notch ligands. Development. 124:1997;3439-3448.
    • (1997) Development , vol.124 , pp. 3439-3448
    • Sun, X.1    Artavanis-Tsakonas, S.2
  • 9
    • 0036467663 scopus 로고    scopus 로고
    • Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway
    • Reizis B., Leder P. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev. 16:2002;295-300.
    • (2002) Genes Dev. , vol.16 , pp. 295-300
    • Reizis, B.1    Leder, P.2
  • 11
    • 0034644110 scopus 로고    scopus 로고
    • The notch signalling regulator fringe acts in the golgi apparatus and requires the glycosyltransferase signature motif DXD
    • Munro S., Freeman M. The notch signalling regulator fringe acts in the golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr. Biol. 10:2000;813-820.
    • (2000) Curr. Biol. , vol.10 , pp. 813-820
    • Munro, S.1    Freeman, M.2
  • 12
    • 0030953531 scopus 로고    scopus 로고
    • Radical fringe positions the apical ectodermal ridge at the ventrodorsal boundary of the vertebrate limb
    • Rodriguez-Esteban C., Schwabe J.W., De La Pena J., Foys B., Eshelman B., Belmonte J.C. Radical fringe positions the apical ectodermal ridge at the ventrodorsal boundary of the vertebrate limb. Nature. 386:1997;360-366.
    • (1997) Nature , vol.386 , pp. 360-366
    • Rodriguez-Esteban, C.1    Schwabe, J.W.2    De La Pena, J.3    Foys, B.4    Eshelman, B.5    Belmonte, J.C.6
  • 13
    • 0030907433 scopus 로고    scopus 로고
    • Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation
    • Laufer E., Dahn R., Orozco O.E., Yeo C.Y., Pisenti J., Henrique D.et al. Expression of Radical fringe in limb-bud ectoderm regulates apical ectodermal ridge formation. Nature. 386:1997;366-373.
    • (1997) Nature , vol.386 , pp. 366-373
    • Laufer, E.1    Dahn, R.2    Orozco, O.E.3    Yeo, C.Y.4    Pisenti, J.5    Henrique, D.6
  • 14
    • 0034869258 scopus 로고    scopus 로고
    • Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch1
    • Koch U., Lacombe T.A., Holland D., Bowman J.L., Cohen B.L., Egan S.E.et al. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch1. Immunity. 15:2001;225-236.
    • (2001) Immunity , vol.15 , pp. 225-236
    • Koch, U.1    Lacombe, T.A.2    Holland, D.3    Bowman, J.L.4    Cohen, B.L.5    Egan, S.E.6
  • 15
    • 0034613734 scopus 로고    scopus 로고
    • The Notch ligand Jagged-1 represents a novel growth factor of human hematopoietic stem cells
    • Karanu F.N., Murdoch B., Gallacher L., Wu D.M., Koremoto M., Sakano S.et al. The Notch ligand Jagged-1 represents a novel growth factor of human hematopoietic stem cells. J. Exp. Med. 192:2000;1365-1372.
    • (2000) J. Exp. Med. , vol.192 , pp. 1365-1372
    • Karanu, F.N.1    Murdoch, B.2    Gallacher, L.3    Wu, D.M.4    Koremoto, M.5    Sakano, S.6
  • 16
    • 0032170451 scopus 로고    scopus 로고
    • Stromal expression of Jagged 1 promotes colony formation by fetal liver hematopoietic progenitor cells
    • Jones P., May G., Brown J., Hoyne G., Delassus S., Enver T. Stromal expression of Jagged 1 promotes colony formation by fetal liver hematopoietic progenitor cells. Blood. 92:1998;1505-1511.
    • (1998) Blood , vol.92 , pp. 1505-1511
    • Jones, P.1    May, G.2    Brown, J.3    Hoyne, G.4    Delassus, S.5    Enver, T.6
  • 17
    • 0036529989 scopus 로고    scopus 로고
    • Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome
    • Stier S., Cheng T., Dombkowski D., Carlesso N., Scadden D.T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood. 99:2002;2369-2378.
    • (2002) Blood , vol.99 , pp. 2369-2378
    • Stier, S.1    Cheng, T.2    Dombkowski, D.3    Carlesso, N.4    Scadden, D.T.5
  • 18
    • 0035176397 scopus 로고    scopus 로고
    • The notch receptor and its ligands are selectively expressed during hematopoietic development in the mouse
    • Walker L., Carlson A., Tan-Pertel H.T., Weinmaster G., Gasson J. The notch receptor and its ligands are selectively expressed during hematopoietic development in the mouse. Stem Cells. 19:2001;543-552.
    • (2001) Stem Cells , vol.19 , pp. 543-552
    • Walker, L.1    Carlson, A.2    Tan-Pertel, H.T.3    Weinmaster, G.4    Gasson, J.5
  • 19
    • 0032904239 scopus 로고    scopus 로고
    • Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics
    • Carlesso N., Aster J.C., Sklar J., Scadden D.T. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood. 93:1999;838-848.
    • (1999) Blood , vol.93 , pp. 838-848
    • Carlesso, N.1    Aster, J.C.2    Sklar, J.3    Scadden, D.T.4
  • 20
    • 0035313174 scopus 로고    scopus 로고
    • Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells
    • Karanu F.N., Murdoch B., Miyabayashi T., Ohno M., Koremoto M., Gallacher L.et al. Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood. 97:2001;1960-1967.
    • (2001) Blood , vol.97 , pp. 1960-1967
    • Karanu, F.N.1    Murdoch, B.2    Miyabayashi, T.3    Ohno, M.4    Koremoto, M.5    Gallacher, L.6
  • 22
    • 0032101002 scopus 로고    scopus 로고
    • The Notch ligand Jagged-1 influences the development of primitive hematopoietic precursor cells
    • Varnum-Finney B., Purton L.E., Yu M., Brashem-Stein C., Flowers D., Staats S.et al. The Notch ligand Jagged-1 influences the development of primitive hematopoietic precursor cells. Blood. 91:1998;4084-4091.
    • (1998) Blood , vol.91 , pp. 4084-4091
    • Varnum-Finney, B.1    Purton, L.E.2    Yu, M.3    Brashem-Stein, C.4    Flowers, D.5    Staats, S.6
  • 23
    • 0035179818 scopus 로고    scopus 로고
    • Distinct and regulated expression of Notch receptors in haematopoietic lineages and during myeloid differentiation
    • Jonsson J.-I., Xiang Z., Pettersson M., Lardelli M., Nilsson G. Distinct and regulated expression of Notch receptors in haematopoietic lineages and during myeloid differentiation. Eur. J. Immunol. 31:2001;3240-3247.
    • (2001) Eur. J. Immunol. , vol.31 , pp. 3240-3247
    • Jonsson, J.-I.1    Xiang, Z.2    Pettersson, M.3    Lardelli, M.4    Nilsson, G.5
  • 24
    • 0031930238 scopus 로고    scopus 로고
    • The human homologue of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1
    • Li L., Milner L.A., Deng Y., Iwata M., Banta A., Graf L.et al. The human homologue of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 8:1998;43-55.
    • (1998) Immunity , vol.8 , pp. 43-55
    • Li, L.1    Milner, L.A.2    Deng, Y.3    Iwata, M.4    Banta, A.5    Graf, L.6
  • 25
    • 0034021393 scopus 로고    scopus 로고
    • Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis
    • Singh N., Phillips R.A., Iscove N.N., Egan S.E. Expression of notch receptors, notch ligands, and fringe genes in hematopoiesis. Exp. Hematol. 28:2000;527-534.
    • (2000) Exp. Hematol. , vol.28 , pp. 527-534
    • Singh, N.1    Phillips, R.A.2    Iscove, N.N.3    Egan, S.E.4
  • 26
    • 0034520811 scopus 로고    scopus 로고
    • Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells
    • Bertrand F.E., Eckfeldt C.E., Lysholm A.S., LeBien T.W. Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells. Leukemia. 14:2000;2095-2102.
    • (2000) Leukemia , vol.14 , pp. 2095-2102
    • Bertrand, F.E.1    Eckfeldt, C.E.2    Lysholm, A.S.3    LeBien, T.W.4
  • 27
    • 0033561454 scopus 로고    scopus 로고
    • Notch as a mediator of cell fate determination in haematopoiesis: Evidence and speculation
    • Milner L.A., Bigas A. Notch as a mediator of cell fate determination in haematopoiesis: evidence and speculation. Blood. 93:1999;2431-2448.
    • (1999) Blood , vol.93 , pp. 2431-2448
    • Milner, L.A.1    Bigas, A.2
  • 28
    • 0037105544 scopus 로고    scopus 로고
    • Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease
    • Dorsch M., Zheng G., Yowe D., Rao P.K., Wang Y., Shen Q.et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood. 100:2002;2046-2055.
    • (2002) Blood , vol.100 , pp. 2046-2055
    • Dorsch, M.1    Zheng, G.2    Yowe, D.3    Rao, P.K.4    Wang, Y.5    Shen, Q.6
  • 29
    • 20244389684 scopus 로고    scopus 로고
    • Notch1 expression in early lymphopoiesis influences B versus T lineage determination
    • Pui J.C., Allman D., Xu L., DeRocco S., Karnell F.G., Bakkour S.et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity. 11:1999;299-308.
    • (1999) Immunity , vol.11 , pp. 299-308
    • Pui, J.C.1    Allman, D.2    Xu, L.3    DeRocco, S.4    Karnell, F.G.5    Bakkour, S.6
  • 30
    • 0033681860 scopus 로고    scopus 로고
    • T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver
    • Kawamoto H., Ikawa T., Ohmura K., Fujimoto S., Katsura Y. T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver. Immunity. 12:2000;1-20.
    • (2000) Immunity , vol.12 , pp. 1-20
    • Kawamoto, H.1    Ikawa, T.2    Ohmura, K.3    Fujimoto, S.4    Katsura, Y.5
  • 31
    • 0030831130 scopus 로고    scopus 로고
    • Identification of clonogenic common lymphoid progenitors in mouse bone marrow
    • Kondo M., Weissman I.L. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 91:1997;661-672.
    • (1997) Cell , vol.91 , pp. 661-672
    • Kondo, M.1    Weissman, I.L.2
  • 33
    • 0036749748 scopus 로고    scopus 로고
    • The role of Notch signaling during hematopoietic lineage commitment
    • Radtke F., Wilson A., Ernst B., MacDonald H.R. The role of Notch signaling during hematopoietic lineage commitment. Immunol. Rev. 187:2002;65-74.
    • (2002) Immunol. Rev. , vol.187 , pp. 65-74
    • Radtke, F.1    Wilson, A.2    Ernst, B.3    MacDonald, H.R.4
  • 34
    • 0036749786 scopus 로고    scopus 로고
    • Notch signaling in hematopoiesis and early lymphocyte development
    • Allman D., Aster J.C., Pear W.S. Notch signaling in hematopoiesis and early lymphocyte development. Immunol. Rev. 187:2002;75-86.
    • (2002) Immunol. Rev. , vol.187 , pp. 75-86
    • Allman, D.1    Aster, J.C.2    Pear, W.S.3
  • 35
    • 0033136717 scopus 로고    scopus 로고
    • Deficient T cell fate specification in mice with an induced inactivation of Notch1
    • Radtke F., Wilson A., Stark G., Bauer M., van Meervijk J., MacDonald H.R.et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity. 10:1999;547-558.
    • (1999) Immunity , vol.10 , pp. 547-558
    • Radtke, F.1    Wilson, A.2    Stark, G.3    Bauer, M.4    Van Meervijk, J.5    MacDonald, H.R.6
  • 36
    • 0035477668 scopus 로고    scopus 로고
    • Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus
    • Wilson A., MacDonald H.R., Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. J. Exp. Med. 194:2001;1003-1012.
    • (2001) J. Exp. Med. , vol.194 , pp. 1003-1012
    • Wilson, A.1    MacDonald, H.R.2    Radtke, F.3
  • 37
    • 5844299536 scopus 로고    scopus 로고
    • Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8 T-cell development
    • Wolfer A., Bakker T., Wilson A., Nicolaas M., Ionnidis V., Littman D.R.et al. Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8 T-cell development. Nat. Immunol. 2:2001;235-241.
    • (2001) Nat. Immunol. , vol.2 , pp. 235-241
    • Wolfer, A.1    Bakker, T.2    Wilson, A.3    Nicolaas, M.4    Ionnidis, V.5    Littman, D.R.6
  • 38
    • 0036070308 scopus 로고    scopus 로고
    • Inactivation of Notch 1 impairs VDJ β rearrangement and allows pre-TCR independent survival of early αβ lineage cells
    • Wolfer A., Wilson A., Nemir M., MacDonald H.R., Radtke F. Inactivation of Notch 1 impairs VDJ β rearrangement and allows pre-TCR independent survival of early αβ lineage cells. Immunity. 16:2002;869-879.
    • (2002) Immunity , vol.16 , pp. 869-879
    • Wolfer, A.1    Wilson, A.2    Nemir, M.3    MacDonald, H.R.4    Radtke, F.5
  • 39
    • 0032798711 scopus 로고    scopus 로고
    • Expression of Notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: Distinct ligand-receptor interactions in intrathymic T cell development
    • Felli M.P., Maroder M., Mitsiadis T.A., Campese A.F., Bellavia D., Vacca A.et al. Expression of Notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int. Immunol. 11:1999;1017-1025.
    • (1999) Int. Immunol. , vol.11 , pp. 1017-1025
    • Felli, M.P.1    Maroder, M.2    Mitsiadis, T.A.3    Campese, A.F.4    Bellavia, D.5    Vacca, A.6
  • 40
    • 0035179878 scopus 로고    scopus 로고
    • Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signalling in thymocytes independently of T cell signaling
    • Anderson G., Pongracz J., Parnell S., Jenkinson E.J. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signalling in thymocytes independently of T cell signaling. Eur. J. Immunol. 31:2001;3349-3354.
    • (2001) Eur. J. Immunol. , vol.31 , pp. 3349-3354
    • Anderson, G.1    Pongracz, J.2    Parnell, S.3    Jenkinson, E.J.4
  • 42
  • 44
    • 0033681301 scopus 로고    scopus 로고
    • Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes
    • Deftos M.L., Huang E., Ojala E.W., Forbush K.A., Bevan M.J. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity. 13:2000;73-84.
    • (2000) Immunity , vol.13 , pp. 73-84
    • Deftos, M.L.1    Huang, E.2    Ojala, E.W.3    Forbush, K.A.4    Bevan, M.J.5
  • 45
    • 0030297895 scopus 로고    scopus 로고
    • An activated form of Notch influences the choice between CD4 and CD8 T cell lineages
    • Robey E., Chang D., Itano A., Cado D., Alexander H., Lans D.et al. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell. 87:1996;483-492.
    • (1996) Cell , vol.87 , pp. 483-492
    • Robey, E.1    Chang, D.2    Itano, A.3    Cado, D.4    Alexander, H.5    Lans, D.6
  • 46
    • 0035979234 scopus 로고    scopus 로고
    • Presenilin-dependent gamma-secretase activity modulates thymocyte development
    • Doerfler P., Shearman M.S., Perlmutter R.M. Presenilin-dependent gamma-secretase activity modulates thymocyte development. Proc. Natl. Acad. Sci. U.S.A. 98:2001;9312-9317.
    • (2001) Proc. Natl. Acad. Sci. U.S.A. , vol.98 , pp. 9312-9317
    • Doerfler, P.1    Shearman, M.S.2    Perlmutter, R.M.3
  • 48
    • 0032442040 scopus 로고    scopus 로고
    • Correlating Notch signalling with thymocyte maturation
    • Deftos M.L., He Y.-W., Ojala E.W., Bevan M.J. Correlating Notch signalling with thymocyte maturation. Immunity. 9:1998;777-786.
    • (1998) Immunity , vol.9 , pp. 777-786
    • Deftos, M.L.1    He, Y.-W.2    Ojala, E.W.3    Bevan, M.J.4
  • 51
    • 0035313978 scopus 로고    scopus 로고
    • Signal strength in thymic selection and lineage commitment
    • Hogquist K.A. Signal strength in thymic selection and lineage commitment. Curr. Opin. Immunol. 13:2001;225-231.
    • (2001) Curr. Opin. Immunol. , vol.13 , pp. 225-231
    • Hogquist, K.A.1
  • 53
    • 0036533339 scopus 로고    scopus 로고
    • Deciphering the role of Notch signaling in lymphopoiesis
    • Izon D.J., Punt J.A., Pear W.S. Deciphering the role of Notch signaling in lymphopoiesis. Curr. Opin. Immunol. 14:2002;192-199.
    • (2002) Curr. Opin. Immunol. , vol.14 , pp. 192-199
    • Izon, D.J.1    Punt, J.A.2    Pear, W.S.3
  • 54
    • 0036169960 scopus 로고    scopus 로고
    • Induction of thymocyte positive selection does not convey immediate resistance to negative selection
    • Hare K.J., Pongracz J., Jenkinson E.J., Anderson G. Induction of thymocyte positive selection does not convey immediate resistance to negative selection. Immunology. 105:2002;163-170.
    • (2002) Immunology , vol.105 , pp. 163-170
    • Hare, K.J.1    Pongracz, J.2    Jenkinson, E.J.3    Anderson, G.4
  • 55
    • 0035476891 scopus 로고    scopus 로고
    • Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation
    • Jaleco A.C., Neves H., Hooijberg E., Gameiro P., Clode N., Haury M.et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194:2001;991-1001.
    • (2001) J. Exp. Med. , vol.194 , pp. 991-1001
    • Jaleco, A.C.1    Neves, H.2    Hooijberg, E.3    Gameiro, P.4    Clode, N.5    Haury, M.6
  • 56
    • 0037310525 scopus 로고    scopus 로고
    • Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell precursors
    • Harman B.C., Jenkinson E.J., Anderson G. Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell precursors. J. Immunol. 170:2003;1299-1303.
    • (2003) J. Immunol. , vol.170 , pp. 1299-1303
    • Harman, B.C.1    Jenkinson, E.J.2    Anderson, G.3


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.