메뉴 건너뛰기




Volumn 61, Issue 3, 2013, Pages 409-419

Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype

Author keywords

Amyotrophic lateral sclerosis; Microglia; Protein aggregation; SOD1

Indexed keywords

COPPER ZINC SUPEROXIDE DISMUTASE;

EID: 84872611309     PISSN: 08941491     EISSN: 10981136     Source Type: Journal    
DOI: 10.1002/glia.22444     Document Type: Article
Times cited : (80)

References (57)
  • 1
    • 0035833937 scopus 로고    scopus 로고
    • Immune reactivity in a mouse model of familial ALS correlates with disease progression
    • Alexianu ME, Kozovska M, Appel SH. 2001. Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57: 1282-1289.
    • (2001) Neurology , vol.57 , pp. 1282-1289
    • Alexianu, M.E.1    Kozovska, M.2    Appel, S.H.3
  • 2
    • 0035449358 scopus 로고    scopus 로고
    • Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity
    • Bal-Price A, Brown GC. 2001. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21: 6480-6491.
    • (2001) J Neurosci , vol.21 , pp. 6480-6491
    • Bal-Price, A.1    Brown, G.C.2
  • 3
    • 0037387147 scopus 로고    scopus 로고
    • A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation
    • Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE. 2003. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23: 2665-2674.
    • (2003) J Neurosci , vol.23 , pp. 2665-2674
    • Bamberger, M.E.1    Harris, M.E.2    McDonald, D.R.3    Husemann, J.4    Landreth, G.E.5
  • 7
    • 35349024347 scopus 로고    scopus 로고
    • Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro
    • Carter SL, Muller M, Manders PM, Campbell IL. 2007. Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro. Glia 55: 1728-1739.
    • (2007) Glia , vol.55 , pp. 1728-1739
    • Carter, S.L.1    Muller, M.2    Manders, P.M.3    Campbell, I.L.4
  • 8
    • 0037154851 scopus 로고    scopus 로고
    • Relationship between beta-AP peptide aggregation and microglial activation
    • Casal C, Serratosa J, Tusell JM. 2002. Relationship between beta-AP peptide aggregation and microglial activation. Brain Res 928: 76-84.
    • (2002) Brain Res , vol.928 , pp. 76-84
    • Casal, C.1    Serratosa, J.2    Tusell, J.M.3
  • 10
    • 0036373780 scopus 로고    scopus 로고
    • CuZn-superoxide dismutase in human thymus: Immunocytochemical localisation and secretion in thymus-derived epithelial and fibroblast cell lines
    • Cimini V, Ruggiero G, Buonomo T, Seru R, Sciorio S, Zanzi C, Santangelo F, Mondola P. 2002. CuZn-superoxide dismutase in human thymus: Immunocytochemical localisation and secretion in thymus-derived epithelial and fibroblast cell lines. Histochem Cell Biol 118: 163-169.
    • (2002) Histochem Cell Biol , vol.118 , pp. 163-169
    • Cimini, V.1    Ruggiero, G.2    Buonomo, T.3    Seru, R.4    Sciorio, S.5    Zanzi, C.6    Santangelo, F.7    Mondola, P.8
  • 12
    • 0036141148 scopus 로고    scopus 로고
    • CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils
    • Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB. 2002. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160: 101-112.
    • (2002) Am J Pathol , vol.160 , pp. 101-112
    • Coraci, I.S.1    Husemann, J.2    Berman, J.W.3    Hulette, C.4    Dufour, J.H.5    Campanella, G.K.6    Luster, A.D.7    Silverstein, S.C.8    El-Khoury, J.B.9
  • 17
    • 79953183632 scopus 로고    scopus 로고
    • Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy
    • Fushimi K, Long C, Jayaram N, Chen X, Li L, Wu JY. 2011. Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein Cell 2: 141-149.
    • (2011) Protein Cell , vol.2 , pp. 141-149
    • Fushimi, K.1    Long, C.2    Jayaram, N.3    Chen, X.4    Li, L.5    Wu, J.Y.6
  • 18
    • 35448956015 scopus 로고    scopus 로고
    • Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis
    • Gomes C, Keller S, Altevogt P, Costa J. 2007. Evidence for secretion of Cu, Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis. Neurosci Lett 428: 43-46.
    • (2007) Neurosci Lett , vol.428 , pp. 43-46
    • Gomes, C.1    Keller, S.2    Altevogt, P.3    Costa, J.4
  • 19
    • 0035067030 scopus 로고    scopus 로고
    • The collagenous domain of class A scavenger receptors is involved in macrophage adhesion to collagens
    • Gowen BB, Borg TK, Ghaffar A, Mayer EP. 2001. The collagenous domain of class A scavenger receptors is involved in macrophage adhesion to collagens. J Leukocyte Biol 69: 575-582.
    • (2001) J Leukocyte Biol , vol.69 , pp. 575-582
    • Gowen, B.B.1    Borg, T.K.2    Ghaffar, A.3    Mayer, E.P.4
  • 21
    • 0032125587 scopus 로고    scopus 로고
    • Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS
    • Hall ED, Oostveen JA, Gurney ME. 1998. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23: 249-256.
    • (1998) Glia , vol.23 , pp. 249-256
    • Hall, E.D.1    Oostveen, J.A.2    Gurney, M.E.3
  • 22
    • 33644821966 scopus 로고    scopus 로고
    • The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS
    • Henkel JS, Beers DR, Siklos L, Appel SH. 2006. The chemokine MCP-1 and the dendritic and myeloid cells it attracts are increased in the mSOD1 mouse model of ALS. Mol Cell Neurosci 31: 427-437.
    • (2006) Mol Cell Neurosci , vol.31 , pp. 427-437
    • Henkel, J.S.1    Beers, D.R.2    Siklos, L.3    Appel, S.H.4
  • 24
    • 0346100518 scopus 로고    scopus 로고
    • Scavenger receptors for oxidized and glycated proteins
    • Horiuchi S, Sakamoto Y, Sakai M. 2003. Scavenger receptors for oxidized and glycated proteins. Amino acids 25: 283-292.
    • (2003) Amino acids , vol.25 , pp. 283-292
    • Horiuchi, S.1    Sakamoto, Y.2    Sakai, M.3
  • 25
    • 79961022340 scopus 로고    scopus 로고
    • Spinal inhibitory interneuron pathology follows motor neuron degeneration independent of glial mutant superoxide dismutase 1 expression in SOD1-ALS mice
    • Hossaini M, Cano SC, van Dis V, Haasdijk ED, Hoogenraad CC, Holstege JC, Jaarsma D. 2011. Spinal inhibitory interneuron pathology follows motor neuron degeneration independent of glial mutant superoxide dismutase 1 expression in SOD1-ALS mice. J Neuropathol Exper Neurol 70: 662-677.
    • (2011) J Neuropathol Exper Neurol , vol.70 , pp. 662-677
    • Hossaini, M.1    Cano, S.C.2    van Dis, V.3    Haasdijk, E.D.4    Hoogenraad, C.C.5    Holstege, J.C.6    Jaarsma, D.7
  • 26
    • 0034956740 scopus 로고    scopus 로고
    • Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations
    • Jacobsson J, Jonsson PA, Andersen PM, Forsgren L, Marklund SL. 2001. Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations. Brain: J Neurol 124(Pt 7): 1461-1466.
    • (2001) Brain: J Neurol 124(Pt , vol.7 , pp. 1461-1466
    • Jacobsson, J.1    Jonsson, P.A.2    Andersen, P.M.3    Forsgren, L.4    Marklund, S.L.5
  • 27
    • 67749133873 scopus 로고    scopus 로고
    • TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity
    • Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. 2009. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284: 20329-20339.
    • (2009) J Biol Chem , vol.284 , pp. 20329-20339
    • Johnson, B.S.1    Snead, D.2    Lee, J.J.3    McCaffery, J.M.4    Shorter, J.5    Gitler, A.D.6
  • 28
    • 54949126674 scopus 로고    scopus 로고
    • Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease
    • Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. 2008. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 11: 1294-1301.
    • (2008) Nat Neurosci , vol.11 , pp. 1294-1301
    • Lepore, A.C.1    Rauck, B.2    Dejea, C.3    Pardo, A.C.4    Rao, M.S.5    Rothstein, J.D.6    Maragakis, N.J.7
  • 29
    • 0037168643 scopus 로고    scopus 로고
    • Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state
    • Lindberg MJ, Tibell L, Oliveberg M. 2002. Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state. Proc Natl Acad Sci USA 99: 16607-16612.
    • (2002) Proc Natl Acad Sci USA , vol.99 , pp. 16607-16612
    • Lindberg, M.J.1    Tibell, L.2    Oliveberg, M.3
  • 30
    • 79952810857 scopus 로고    scopus 로고
    • Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity
    • Maezawa I, Zimin PI, Wulff H, Jin LW. 2011. Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 286: 3693-3706.
    • (2011) J Biol Chem , vol.286 , pp. 3693-3706
    • Maezawa, I.1    Zimin, P.I.2    Wulff, H.3    Jin, L.W.4
  • 32
    • 26444471905 scopus 로고    scopus 로고
    • Structural properties and neuronal toxicity of amyotrophic lateral sclerosis-associated Cu/Zn superoxide dismutase 1 aggregates
    • Matsumoto G, Stojanovic A, Holmberg CI, Kim S, Morimoto RI. 2005. Structural properties and neuronal toxicity of amyotrophic lateral sclerosis-associated Cu/Zn superoxide dismutase 1 aggregates. J Cell Biol 171: 75-85.
    • (2005) J Cell Biol , vol.171 , pp. 75-85
    • Matsumoto, G.1    Stojanovic, A.2    Holmberg, C.I.3    Kim, S.4    Morimoto, R.I.5
  • 33
    • 27744484059 scopus 로고    scopus 로고
    • Glial cell inclusions and the pathogenesis of neurodegenerative diseases
    • Miller DW, Cookson MR, Dickson DW. 2004. Glial cell inclusions and the pathogenesis of neurodegenerative diseases. Neuron Glia Biol 1: 13-21.
    • (2004) Neuron Glia Biol , vol.1 , pp. 13-21
    • Miller, D.W.1    Cookson, M.R.2    Dickson, D.W.3
  • 34
    • 0029884093 scopus 로고    scopus 로고
    • Evidence for secretion of cytosolic CuZn superoxide dismutase by Hep G2 cells and human fibroblasts
    • Mondola P, Annella T, Santillo M, Santangelo F. 1996. Evidence for secretion of cytosolic CuZn superoxide dismutase by Hep G2 cells and human fibroblasts. Int J Biochem Cell Biol 28: 677-681.
    • (1996) Int J Biochem Cell Biol , vol.28 , pp. 677-681
    • Mondola, P.1    Annella, T.2    Santillo, M.3    Santangelo, F.4
  • 35
    • 0032521619 scopus 로고    scopus 로고
    • Secretion and increase of intracellular CuZn superoxide dismutase content in human neuroblastoma SK-N-BE cells subjected to oxidative stress
    • Mondola P, Annella T, Seru R, Santangelo F, Iossa S, Gioielli A, Santillo M. 1998. Secretion and increase of intracellular CuZn superoxide dismutase content in human neuroblastoma SK-N-BE cells subjected to oxidative stress. Brain Research Bull 45: 517-520.
    • (1998) Brain Research Bull , vol.45 , pp. 517-520
    • Mondola, P.1    Annella, T.2    Seru, R.3    Santangelo, F.4    Iossa, S.5    Gioielli, A.6    Santillo, M.7
  • 37
    • 79952743365 scopus 로고    scopus 로고
    • Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells
    • Munch C, O'Brien J, Bertolotti A. 2011. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci USA 108: 3548-3553.
    • (2011) Proc Natl Acad Sci USA , vol.108 , pp. 3548-3553
    • Munch, C.1    O'Brien, J.2    Bertolotti, A.3
  • 39
    • 33747605320 scopus 로고    scopus 로고
    • Molecular biology of amyotrophic lateral sclerosis: Insights from genetics
    • Pasinelli P, Brown RH. 2006. Molecular biology of amyotrophic lateral sclerosis: Insights from genetics. Nat Rev Neurosci 7: 710-723.
    • (2006) Nat Rev Neurosci , vol.7 , pp. 710-723
    • Pasinelli, P.1    Brown, R.H.2
  • 40
    • 0035873076 scopus 로고    scopus 로고
    • Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment
    • Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA. 2001. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21: 3369-3374.
    • (2001) J Neurosci , vol.21 , pp. 3369-3374
    • Pramatarova, A.1    Laganiere, J.2    Roussel, J.3    Brisebois, K.4    Rouleau, G.A.5
  • 41
    • 70349323417 scopus 로고    scopus 로고
    • CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation
    • Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. 2009. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 29: 11982-11992.
    • (2009) J Neurosci , vol.29 , pp. 11982-11992
    • Reed-Geaghan, E.G.1    Savage, J.C.2    Hise, A.G.3    Landreth, G.E.4
  • 43
    • 34447307381 scopus 로고    scopus 로고
    • Evidence of calcium- and SNARE-dependent release of CuZn superoxide dismutase from rat pituitary GH3 cells and synaptosomes in response to depolarization
    • Santillo M, Secondo A, Seru R, Damiano S, Garbi C, Taverna E, Rosa P, Giovedi S, Benfenati F, Mondola P. 2007. Evidence of calcium- and SNARE-dependent release of CuZn superoxide dismutase from rat pituitary GH3 cells and synaptosomes in response to depolarization. J Neurochem 102: 679-685.
    • (2007) J Neurochem , vol.102 , pp. 679-685
    • Santillo, M.1    Secondo, A.2    Seru, R.3    Damiano, S.4    Garbi, C.5    Taverna, E.6    Rosa, P.7    Giovedi, S.8    Benfenati, F.9    Mondola, P.10
  • 44
    • 58149345588 scopus 로고    scopus 로고
    • Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosis-associated SOD1 mutations
    • Soo KY, Atkin JD, Horne MK, Nagley P. 2009. Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosis-associated SOD1 mutations. J Neurochem 108: 578-590.
    • (2009) J Neurochem , vol.108 , pp. 578-590
    • Soo, K.Y.1    Atkin, J.D.2    Horne, M.K.3    Nagley, P.4
  • 46
    • 12144249923 scopus 로고    scopus 로고
    • Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis
    • Turner BJ, Atkin JD, Farg MA, Zang DW, Rembach A, Lopes EC, Patch JD, Hill AF, Cheema SS. 2005. Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. J Neurosci 25: 108-117.
    • (2005) J Neurosci , vol.25 , pp. 108-117
    • Turner, B.J.1    Atkin, J.D.2    Farg, M.A.3    Zang, D.W.4    Rembach, A.5    Lopes, E.C.6    Patch, J.D.7    Hill, A.F.8    Cheema, S.S.9
  • 47
    • 1842471942 scopus 로고    scopus 로고
    • Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11C](R)-PK11195 positron emission tomography study
    • Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, Leigh PN, Banati RB. 2004. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 15: 601-609.
    • (2004) Neurobiol Dis , vol.15 , pp. 601-609
    • Turner, M.R.1    Cagnin, A.2    Turkheimer, F.E.3    Miller, C.C.4    Shaw, C.E.5    Brooks, D.J.6    Leigh, P.N.7    Banati, R.B.8
  • 48
    • 29444443348 scopus 로고    scopus 로고
    • Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis
    • Urushitani M, Sik A, Sakurai T, Nukina N, Takahashi R, Julien JP. 2006. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9: 108-118.
    • (2006) Nat Neurosci , vol.9 , pp. 108-118
    • Urushitani, M.1    Sik, A.2    Sakurai, T.3    Nukina, N.4    Takahashi, R.5    Julien, J.P.6
  • 49
    • 0029563373 scopus 로고
    • Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4+ and CD8+ T cells
    • Walker WS, Gatewood J, Olivas E, Askew D, Havenith CE. 1995. Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4+ and CD8+ T cells. J Neuroimmunol 63: 163-174.
    • (1995) J Neuroimmunol , vol.63 , pp. 163-174
    • Walker, W.S.1    Gatewood, J.2    Olivas, E.3    Askew, D.4    Havenith, C.E.5
  • 50
    • 48349090111 scopus 로고    scopus 로고
    • Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival
    • Wang Q, Johnson JL, Agar NY, Agar JN. 2008. Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival. PLoS Biol 6: e170.
    • (2008) PLoS Biol , vol.6
    • Wang, Q.1    Johnson, J.L.2    Agar, N.Y.3    Agar, J.N.4
  • 51
    • 0036199623 scopus 로고    scopus 로고
    • High molecular weight complexes of mutant superoxide dismutase 1: Age-dependent and tissue-specific accumulation
    • Wang J, Xu G, Borchelt DR. 2002. High molecular weight complexes of mutant superoxide dismutase 1: Age-dependent and tissue-specific accumulation. Neurobiol Dis 9: 139-148.
    • (2002) Neurobiol Dis , vol.9 , pp. 139-148
    • Wang, J.1    Xu, G.2    Borchelt, D.R.3
  • 52
    • 0035664213 scopus 로고    scopus 로고
    • Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues
    • Watanabe M, Dykes-Hoberg M, Culotta VC, Price DL, Wong PC, Rothstein JD. 2001. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiology Dis 8: 933-941.
    • (2001) Neurobiology Dis , vol.8 , pp. 933-941
    • Watanabe, M.1    Dykes-Hoberg, M.2    Culotta, V.C.3    Price, D.L.4    Wong, P.C.5    Rothstein, J.D.6
  • 55
    • 0242496176 scopus 로고    scopus 로고
    • Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1
    • Zeng Y, Tao N, Chung KN, Heuser JE, Lublin DM. 2003. Endocytosis of oxidized low density lipoprotein through scavenger receptor CD36 utilizes a lipid raft pathway that does not require caveolin-1. J Biol Chem 278: 45931-45936.
    • (2003) J Biol Chem , vol.278 , pp. 45931-45936
    • Zeng, Y.1    Tao, N.2    Chung, K.N.3    Heuser, J.E.4    Lublin, D.M.5
  • 56
    • 20144389524 scopus 로고    scopus 로고
    • Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson's disease
    • Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhou Y, Hong JS, Zhang J. 2005. Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson's disease. FASEB J 19: 533-542.
    • (2005) FASEB J , vol.19 , pp. 533-542
    • Zhang, W.1    Wang, T.2    Pei, Z.3    Miller, D.S.4    Wu, X.5    Block, M.L.6    Wilson, B.7    Zhou, Y.8    Hong, J.S.9    Zhang, J.10


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.