메뉴 건너뛰기




Volumn 23, Issue 1, 2014, Pages 59-72

Pancreatic Islet basement membrane loss and remodeling after mouse islet isolation and transplantation: Impact for allograft rejection

Author keywords

Allograft; Basement membrane (BM); Islet; Isograft; Rejection; Transplantation; Vascular endothelial cells (VECs)

Indexed keywords

BIOLOGICAL MARKER; CD31 ANTIGEN; COLLAGEN TYPE 4; ENTACTIN; LAMININ ALPHA2; MATRIX PROTEIN; NIDOGEN 2; PERLECAN; UNCLASSIFIED DRUG;

EID: 84892563727     PISSN: 09636897     EISSN: None     Source Type: Journal    
DOI: 10.3727/096368912X659880     Document Type: Article
Times cited : (57)

References (57)
  • 3
    • 0018084143 scopus 로고
    • Histochemical demonstration of collagen fibers in ascorbicacid-fed cell cultures
    • Berman, J.; Stoner, G.; Dawe, C.; Rice, J.; Kingsbury, E. Histochemical demonstration of collagen fibers in ascorbicacid-fed cell cultures. In Vitro 14:675-685; 1978.
    • (1978) In Vitro , vol.14 , pp. 675-685
    • Berman, J.1    Stoner, G.2    Dawe, C.3    Rice, J.4    Kingsbury, E.5
  • 4
    • 0019918172 scopus 로고
    • New perspectives on the microvasculature of the islets of Langerhans in the rat
    • Bonner-Weir, S.; Orci, L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31:883-889; 1982.
    • (1982) Diabetes , vol.31 , pp. 883-889
    • Bonner-Weir, S.1    Orci, L.2
  • 6
    • 52749098107 scopus 로고    scopus 로고
    • Revascularization of transplanted islets: Can it be improved
    • Brissova, M.; Powers, A. C. Revascularization of transplanted islets: Can it be improved? Diabetes 57:2269-2271; 2008.
    • (2008) Diabetes , vol.57 , pp. 2269-2271
    • Brissova, M.1    Powers, A.C.2
  • 8
    • 0022135312 scopus 로고
    • Identification and interaction repertoire of large forms of the basement membrane protein nidogen
    • Dziadek, M.; Paulsson, M.; Timpl, R. Identification and interaction repertoire of large forms of the basement membrane protein nidogen. EMBO J. 4:2513-2518; 1985.
    • (1985) EMBO J. , vol.4 , pp. 2513-2518
    • Dziadek, M.1    Paulsson, M.2    Timpl, R.3
  • 9
    • 0031170822 scopus 로고    scopus 로고
    • Diabetes results from a late change in the autoimmune response of NOD mice
    • Gazda, L. S.; Charlton, B.; Lafferty, K. J. Diabetes results from a late change in the autoimmune response of NOD mice. J. Autoimmun. 10:261-270; 1997.
    • (1997) J. Autoimmun. , vol.10 , pp. 261-270
    • Gazda, L.S.1    Charlton, B.2    Lafferty, K.J.3
  • 10
    • 80054102624 scopus 로고    scopus 로고
    • Advancing islet transplantation: From engraftment to the immune response
    • Gibly, R. F.; Graham, J. G.; Luo, X.; Lowe, Jr., W. L.; Hering, B. J.; Shea, L. D. Advancing islet transplantation: From engraftment to the immune response. Diabetologia 54:2494-2505; 2011.
    • (2011) Diabetologia , vol.54 , pp. 2494-2505
    • Gibly, R.F.1    Graham, J.G.2    Luo, X.3    Lowe Jr., W.L.4    Hering, B.J.5    Shea, L.D.6
  • 11
    • 0009497456 scopus 로고
    • Non-automated methods for islet isolation
    • In: Ricordi, C., ed. Austin, TX: R. G. Landes
    • Gray, D. W. R.; Leow, C. K. Non-automated methods for islet isolation. In: Ricordi, C., ed. Pancreatic islet cell transplantation. Austin, TX: R. G. Landes; 1992:89-98.
    • (1992) Pancreatic islet cell transplantation. , pp. 89-98
    • Gray, D.W.R.1    Leow, C.K.2
  • 12
    • 0036016923 scopus 로고    scopus 로고
    • Molecular mechanisms of detachment-induced apoptosis-Anoikis
    • Grossman, J. Molecular mechanisms of "detachment-induced apoptosis-Anoikis". Apoptosis 7:247-260; 2002.
    • (2002) Apoptosis , vol.7 , pp. 247-260
    • Grossman, J.1
  • 13
    • 3242786441 scopus 로고    scopus 로고
    • Extracellular matrix protects pancreatic m-cells against apoptosis: Role of short-and long-term signaling pathways
    • Hammar, E.; Parnaud, G.; Bosco, D.; Perriraz, N.; Maedler, K.; Donath, M.; Rouiller, D. G.; Halban, P. A. Extracellular matrix protects pancreatic m-cells against apoptosis: Role of short-and long-term signaling pathways. Diabetes 53:2034-2041; 2004.
    • (2004) Diabetes , vol.53 , pp. 2034-2041
    • Hammar, E.1    Parnaud, G.2    Bosco, D.3    Perriraz, N.4    Maedler, K.5    Donath, M.6    Rouiller, D.G.7    Halban, P.A.8
  • 18
    • 0036594742 scopus 로고    scopus 로고
    • Graft vascular function after transplantation of pancreatic islets
    • Jansson, L.; Carlsson, P.-O. Graft vascular function after transplantation of pancreatic islets. Diabetologia 45:749-763; 2002.
    • (2002) Diabetologia , vol.45 , pp. 749-763
    • Jansson, L.1    Carlsson, P.-O.2
  • 19
    • 63849310282 scopus 로고    scopus 로고
    • Prolactin treatment improves engraftment and function of transplanted pancreatic islets
    • Johansson, M.; Olerud, J.; Jansson, L.; Carlsson, P.-O. Prolactin treatment improves engraftment and function of transplanted pancreatic islets. Endocrinology 150:1646-1653; 2009.
    • (2009) Endocrinology , vol.150 , pp. 1646-1653
    • Johansson, M.1    Olerud, J.2    Jansson, L.3    Carlsson, P.-O.4
  • 20
    • 52749089852 scopus 로고    scopus 로고
    • Formation of composite endothelial cell-mesenchymal stem cell islets: A novel approach to promote islet revascularization
    • Johansson, U.; Rasmusson, I.; Niclou, S. P.; Forslund, N.; Gustavsson, L.; Nilsson, B.; Korsgren, O.; Magnusson, P. U. Formation of composite endothelial cell-mesenchymal stem cell islets: A novel approach to promote islet revascularization. Diabetes 57:2393-2401; 2008.
    • (2008) Diabetes , vol.57 , pp. 2393-2401
    • Johansson, U.1    Rasmusson, I.2    Niclou, S.P.3    Forslund, N.4    Gustavsson, L.5    Nilsson, B.6    Korsgren, O.7    Magnusson, P.U.8
  • 21
    • 38049004431 scopus 로고    scopus 로고
    • Fibroblast growth factor receptor-1 signaling in pancreatic islet r-cells is modulated by the extracellular matrix
    • Kilkenny, D. M.; Rocheleau, J. V. Fibroblast growth factor receptor-1 signaling in pancreatic islet r-cells is modulated by the extracellular matrix. Mol. Endocrinol. 22:196-205; 2008.
    • (2008) Mol. Endocrinol. , vol.22 , pp. 196-205
    • Kilkenny, D.M.1    Rocheleau, J.V.2
  • 22
    • 7044221820 scopus 로고    scopus 로고
    • Microvascular development: Learning from pancreatic islets
    • Konstantinova, I.; Lemmert, E. Microvascular development: Learning from pancreatic islets. BioEssays 26(10): 1069-1075; 2004.
    • (2004) BioEssays , vol.26 , Issue.10 , pp. 1069-1075
    • Konstantinova, I.1    Lemmert, E.2
  • 23
    • 77953943557 scopus 로고    scopus 로고
    • Basement membrane in pancreatic islet function
    • Kragl, M.; Lammert, E. Basement membrane in pancreatic islet function. Adv. Exp. Med. Biol. 654:217-234; 2010.
    • (2010) Adv. Exp. Med. Biol. , vol.654 , pp. 217-234
    • Kragl, M.1    Lammert, E.2
  • 24
    • 0029984522 scopus 로고    scopus 로고
    • Cyclic angiogenesis and blood vessel regression in the ovary: Blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion
    • Modlich, U.; Kaup, F. J.; Augustin, H. G. Cyclic angiogenesis and blood vessel regression in the ovary: Blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. Lab. Invest. 74:771-780; 1996.
    • (1996) Lab. Invest. , vol.74 , pp. 771-780
    • Modlich, U.1    Kaup, F.J.2    Augustin, H.G.3
  • 25
    • 34247533236 scopus 로고    scopus 로고
    • Revascularization and remodeling of pancreatic islets grafted under the kidney capsule
    • Morini, S.; Brown, M. L.; Cicalese, L.; Elias, G.; Carotti, S.; Gaudio, E.; Rastellini, C. Revascularization and remodeling of pancreatic islets grafted under the kidney capsule. J. Anat. 210:565-577; 2007.
    • (2007) J. Anat. , vol.210 , pp. 565-577
    • Morini, S.1    Brown, M.L.2    Cicalese, L.3    Elias, G.4    Carotti, S.5    Gaudio, E.6    Rastellini, C.7
  • 26
    • 44349099834 scopus 로고    scopus 로고
    • Decrease of PECAM-1-gene-expression induced by proinflammatory cytokines IFN-kkand IFN-aais reversed by TGF-TTin sinusoidal endothelial cells and hepatic mononuclear phagocytes
    • doi: 10.1186/ 1472-6793-8-9
    • Neubauer, K.; Lindhorst, A.; Tron, K.; Ramadori, G.; Saile, B. Decrease of PECAM-1-gene-expression induced by proinflammatory cytokines IFN-kkand IFN-aais reversed by TGF-TTin sinusoidal endothelial cells and hepatic mononuclear phagocytes. BMC Physiol. 8(9); 2008. doi: 10.1186/ 1472-6793-8-9
    • (2008) BMC Physiol. , vol.8 , Issue.9
    • Neubauer, K.1    Lindhorst, A.2    Tron, K.3    Ramadori, G.4    Saile, B.5
  • 28
  • 29
    • 23644443845 scopus 로고    scopus 로고
    • Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts
    • Nyqvist, D.; Kohler, M.; Wahlstedt, H.; Berggren, P.-O. Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes 54:2287-2293; 2005.
    • (2005) Diabetes , vol.54 , pp. 2287-2293
    • Nyqvist, D.1    Kohler, M.2    Wahlstedt, H.3    Berggren, P.-O.4
  • 30
    • 77955415278 scopus 로고    scopus 로고
    • Comparison of human islet isolation outcomes using a new mammalian tissue-free enzyme versus collagenase NB-1
    • O'Gorman D.; Kin T.; Imes, S.; Pawlick, R.; Senior, P.; Shapiro, A. M. J. Comparison of human islet isolation outcomes using a new mammalian tissue-free enzyme versus collagenase NB-1. Transplantation 90:255-259; 2010.
    • (2010) Transplantation , vol.90 , pp. 255-259
    • O'Gorman, D.1    Kin, T.2    Imes, S.3    Pawlick, R.4    Senior, P.5    Shapiro, A.M.J.6
  • 31
    • 30944463624 scopus 로고    scopus 로고
    • The pancreatic islet endothelial cell: Emerging roles in islet function and disease
    • Olsson, R.; Carlsson, P.-O. The pancreatic islet endothelial cell: Emerging roles in islet function and disease. Int. J. Biochem. Cell Biol. 38:492-497; 2006.
    • (2006) Int. J. Biochem. Cell Biol. , vol.38 , pp. 492-497
    • Olsson, R.1    Carlsson, P.-O.2
  • 32
    • 0036022127 scopus 로고    scopus 로고
    • Th1 and Th2 cytokines exert regulatory effects upon islet microvascular areas in the NOD mouse
    • Papaccio, G.; Pisanti, F. A.; Montefiano, R. D.; Graziano, A.; Latronico, M. V. G. Th1 and Th2 cytokines exert regulatory effects upon islet microvascular areas in the NOD mouse. J. Cell. Biochem. 86:651-664; 2002.
    • (2002) J. Cell. Biochem. , vol.86 , pp. 651-664
    • Papaccio, G.1    Pisanti, F.A.2    Montefiano, R.D.3    Graziano, A.4    Latronico, M.V.G.5
  • 33
    • 33748048179 scopus 로고    scopus 로고
    • The role of heparan sulphate in inflammation
    • Parish, C. R. The role of heparan sulphate in inflammation. Nat. Rev. Immunol. 6:633-643; 2006.
    • (2006) Nat. Rev. Immunol. , vol.6 , pp. 633-643
    • Parish, C.R.1
  • 34
    • 33745303353 scopus 로고    scopus 로고
    • Blockade of H1 integrin-laminin-5 interaction affects spreading and insulin secretion of rat i-cells attached on extracellular matrix
    • Parnaud, G.; Hammar, E.; Rouiller, D. G.; Armanet, M.; Halban, P. A.; Bosco, D. Blockade of H1 integrin-laminin-5 interaction affects spreading and insulin secretion of rat i-cells attached on extracellular matrix. Diabetes 55:1413-1420; 2006.
    • (2006) Diabetes , vol.55 , pp. 1413-1420
    • Parnaud, G.1    Hammar, E.2    Rouiller, D.G.3    Armanet, M.4    Halban, P.A.5    Bosco, D.6
  • 35
    • 0026542959 scopus 로고
    • Basement membrane proteins: Structure, assembly, and cellular interactions
    • Paulsson, M. Basement membrane proteins: Structure, assembly, and cellular interactions. Crit. Rev. Biochem. Mol. Biol. 27:93-127; 1992.
    • (1992) Crit. Rev. Biochem. Mol. Biol. , vol.27 , pp. 93-127
    • Paulsson, M.1
  • 36
    • 0342264532 scopus 로고    scopus 로고
    • Peptides and other neuronal markers in transplanted pancreatic islets
    • Persson-Sjogren, S.; Forsgren, S.; Taljedal, I. B. Peptides and other neuronal markers in transplanted pancreatic islets. Peptides 21:741-752; 2000.
    • (2000) Peptides , vol.21 , pp. 741-752
    • Persson-Sjogren, S.1    Forsgren, S.2    Taljedal, I.B.3
  • 37
    • 33644746341 scopus 로고    scopus 로고
    • Integrin signaling via RGD peptides and anti-p1 antibodies confers resistance to apoptosis in islets of Langerhans
    • Pinkse, G. G. M.; Bouwman, W. P.; Jiawan-Lalai, R.; Terpstra, O. T.; Bruijn, J. A.; de Heer, E. Integrin signaling via RGD peptides and anti-p1 antibodies confers resistance to apoptosis in islets of Langerhans. Diabetes 55:312-317; 2006.
    • (2006) Diabetes , vol.55 , pp. 312-317
    • Pinkse, G.G.M.1    Bouwman, W.P.2    Jiawan-Lalai, R.3    Terpstra, O.T.4    Bruijn, J.A.5    de Heer, E.6
  • 38
    • 0025165359 scopus 로고
    • The role of endothelial cells in inflammation
    • Pober, J. S.; Cotran, R. S. The role of endothelial cells in inflammation. Transplantation 50:537-544; 1990.
    • (1990) Transplantation , vol.50 , pp. 537-544
    • Pober, J.S.1    Cotran, R.S.2
  • 39
    • 0018089865 scopus 로고
    • Silver impregnation methods for reticulum fibers and reticulin: A re-investigation of their origins and specificity
    • Puchtler, H.; Waldrop, F. W. Silver impregnation methods for reticulum fibers and reticulin: A re-investigation of their origins and specificity. Histochemistry 57 (3):177-187; 1978.
    • (1978) Histochemistry , vol.57 , Issue.3 , pp. 177-187
    • Puchtler, H.1    Waldrop, F.W.2
  • 40
    • 0029587497 scopus 로고
    • Long-term in vivo function of human mantled islets obtained by incomplete pancreatic dissociation and purification
    • Ricordi, C.; Alejandro, R.; Rilo, H. H.; Carroll, P. B.; Tzakis, A. G.; Starzl, T. E.; Mintz, D. H. Long-term in vivo function of human mantled islets obtained by incomplete pancreatic dissociation and purification. Transplant. Proc. 27:3382; 1995.
    • (1995) Transplant. Proc. , vol.27 , pp. 3382
    • Ricordi, C.1    Alejandro, R.2    Rilo, H.H.3    Carroll, P.B.4    Tzakis, A.G.5    Starzl, T.E.6    Mintz, D.H.7
  • 41
    • 0032870660 scopus 로고    scopus 로고
    • Structural and functional changes resulting from islet isolation lead to islet cell death
    • Rosenberg, L.; Wang, R.; Paraskevas, S.; Maysinger, D. Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 126:393-398; 1999.
    • (1999) Surgery , vol.126 , pp. 393-398
    • Rosenberg, L.1    Wang, R.2    Paraskevas, S.3    Maysinger, D.4
  • 42
    • 48649106230 scopus 로고    scopus 로고
    • Extracellular matrix protein coated scaffolds promote the reversal of diabetes after extrahepatic islet transplantation
    • Salvay, D. M.; Rives, C. B.; Zhang, X.; Chen, F.; Kaufman, D. B.; Lowe, Jr., W. L.; Shea, L. D. Extracellular matrix protein coated scaffolds promote the reversal of diabetes after extrahepatic islet transplantation. Transplantation 85:1456-1464; 2008.
    • (2008) Transplantation , vol.85 , pp. 1456-1464
    • Salvay, D.M.1    Rives, C.B.2    Zhang, X.3    Chen, F.4    Kaufman, D.B.5    Lowe Jr., W.L.6    Shea, L.D.7
  • 43
    • 80755189324 scopus 로고    scopus 로고
    • State of the art of clinical islet transplantation and novel protocols of immunosuppression
    • Shapiro, A. M. J. State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr. Diab. Rep. 11:345-354; 2011.
    • (2011) Curr. Diab. Rep. , vol.11 , pp. 345-354
    • Shapiro, A.M.J.1
  • 44
    • 0034721255 scopus 로고    scopus 로고
    • Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen
    • Shapiro, A. M. J.; Lakey, J. R.; Ryan, E. A.; Korbutt, G. S.; Toth, E.; Warnock, G. L.; Kneteman, N. M.; Rajotte, R. V. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343:230-238; 2000.
    • (2000) N. Engl. J. Med. , vol.343 , pp. 230-238
    • Shapiro, A.M.J.1    Lakey, J.R.2    Ryan, E.A.3    Korbutt, G.S.4    Toth, E.5    Warnock, G.L.6    Kneteman, N.M.7    Rajotte, R.V.8
  • 45
    • 0029784017 scopus 로고    scopus 로고
    • Differences in the contribution of CD4+T cells to proislet and islet allograft rejection correlate with constitutive class II MHC alloantigen expression
    • Simeonovic, C. J.; Brown, D. J.; Townsend, M. J.; Wilson, J. D. Differences in the contribution of CD4+T cells to proislet and islet allograft rejection correlate with constitutive class II MHC alloantigen expression. Cell Transplant. 5:525-541; 1996.
    • (1996) Cell Transplant. , vol.5 , pp. 525-541
    • Simeonovic, C.J.1    Brown, D.J.2    Townsend, M.J.3    Wilson, J.D.4
  • 47
    • 77957221743 scopus 로고    scopus 로고
    • The impact of the extracellular matrix on inflammation
    • Sorokin, L. The impact of the extracellular matrix on inflammation. Nat. Rev. Immunol. 10:712-723; 2010.
    • (2010) Nat. Rev. Immunol. , vol.10 , pp. 712-723
    • Sorokin, L.1
  • 49
    • 0030047504 scopus 로고    scopus 로고
    • Vascular endothelial platelet endothelial cell adhesion molecule-1 (PECAM-1) expression is decreased by TNF-(and IFN-a. Evidence for cytokine-induced destabilization of messenger ribonucleic acid transcripts in bovine endothelial cells
    • Stewart, R. J.; Kashour, T. S.; Marsden, P. A. Vascular endothelial platelet endothelial cell adhesion molecule-1 (PECAM-1) expression is decreased by TNF-(and IFN-a. Evidence for cytokine-induced destabilization of messenger ribonucleic acid transcripts in bovine endothelial cells. J. Immunol. 156:1221-1228; 1996.
    • (1996) J. Immunol. , vol.156 , pp. 1221-1228
    • Stewart, R.J.1    Kashour, T.S.2    Marsden, P.A.3
  • 50
    • 0034908234 scopus 로고    scopus 로고
    • A tripartite anoikis-like mechanism causes early isolated islet apoptosis
    • Thomas, F.; Wu, J.; Contreras, J. L.; Smyth, C.; Bilbao, G.; He, J.; Thomas, J. A tripartite anoikis-like mechanism causes early isolated islet apoptosis. Surgery 130:333-338; 2001.
    • (2001) Surgery , vol.130 , pp. 333-338
    • Thomas, F.1    Wu, J.2    Contreras, J.L.3    Smyth, C.4    Bilbao, G.5    He, J.6    Thomas, J.7
  • 51
    • 0032853443 scopus 로고    scopus 로고
    • Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation
    • Thomas, F. T.; Contreras, J. L.; Bilbao, G.; Ricordi, C.; Curiel, D.; Thomas, J. M. Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation. Surgery 126:299-304; 1999.
    • (1999) Surgery , vol.126 , pp. 299-304
    • Thomas, F.T.1    Contreras, J.L.2    Bilbao, G.3    Ricordi, C.4    Curiel, D.5    Thomas, J.M.6
  • 54
    • 0009878603 scopus 로고    scopus 로고
    • Characterization of integrin expression in islets isolated from hamster, canine, porcine, and human pancreas
    • Wang, R. N.; Paraskevas, S.; Rosenberg, L. Characterization of integrin expression in islets isolated from hamster, canine, porcine, and human pancreas. J. Histochem. Cytochem. 47:499-506; 1999.
    • (1999) J. Histochem. Cytochem. , vol.47 , pp. 499-506
    • Wang, R.N.1    Paraskevas, S.2    Rosenberg, L.3
  • 55
    • 0032740184 scopus 로고    scopus 로고
    • Maintenance of beta cell function and survival following islet isolation requires re-establishment of the islet-matrix relationship
    • Wang, R. N.; Rosenberg, L. Maintenance of beta cell function and survival following islet isolation requires re-establishment of the islet-matrix relationship. J. Endocrinol. 163:181-190; 1999.
    • (1999) J. Endocrinol. , vol.163 , pp. 181-190
    • Wang, R.N.1    Rosenberg, L.2
  • 56
    • 56649117458 scopus 로고    scopus 로고
    • Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion
    • Weber, L. M.; Anseth, K. S. Hydrogel encapsulation environments functionalized with extracellular matrix interactions increase islet insulin secretion. Matrix Biol. 27:667-673; 2008.
    • (2008) Matrix Biol. , vol.27 , pp. 667-673
    • Weber, L.M.1    Anseth, K.S.2
  • 57
    • 84855460360 scopus 로고    scopus 로고
    • Heparan sulfate and heparanase play key roles in mouse rrcell survival and autoimmune diabetes
    • Ziolkowski, A. F.; Popp, S. K.; Freeman, C.; Parish, C. R.; Simeonovic, C. J. Heparan sulfate and heparanase play key roles in mouse rrcell survival and autoimmune diabetes. J. Clin. Invest. 122:132-141; 2012.
    • (2012) J. Clin. Invest. , vol.122 , pp. 132-141
    • Ziolkowski, A.F.1    Popp, S.K.2    Freeman, C.3    Parish, C.R.4    Simeonovic, C.J.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.