메뉴 건너뛰기




Volumn 11, Issue 8, 2010, Pages 972-984

Effect of ionic stress on apoptosis and the expression of TRPM2 in human olfactory neuroepithelial-derived progenitors

Author keywords

Bipolar disorder; calcium; cellular model; lithium; sodium

Indexed keywords

CALCIUM; CASPASE 3; CASPASE 7; CATION CHANNEL; CLUSTERIN; ION CHANNEL; IONOPHORE; LITHIUM; MONENSIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; SODIUM;

EID: 78549244112     PISSN: 15622975     EISSN: 18141412     Source Type: Journal    
DOI: 10.3109/15622975.2010.507784     Document Type: Article
Times cited : (13)

References (65)
  • 2
    • 33746208812 scopus 로고    scopus 로고
    • Toward a biaxial model of "bipolar" affective disorders: further exploration of genetic, molecular and cellular substrates
    • Askland K. 2006. Toward a biaxial model of "bipolar" affective disorders: further exploration of genetic, molecular and cellular substrates. J Affect Disord 94:35-66.
    • (2006) J Affect Disord , vol.94 , pp. 35-66
    • Askland, K.1
  • 3
    • 0034982569 scopus 로고    scopus 로고
    • Neuroanatomical studies on bipolar disorder
    • Baumann B, Bogerts B. 2001. Neuroanatomical studies on bipolar disorder. Br J Psychiatry 41:s142-147.
    • (2001) Br J Psychiatry , vol.41
    • Baumann, B.1    Bogerts, B.2
  • 4
    • 33644622093 scopus 로고    scopus 로고
    • The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia
    • Benes FM, Matzilevich D, Burke RE,Walsh J. 2006. The expression of proapoptosis genes is increased in bipolar disorder, but not in schizophrenia. Mol Psychiatry 11:241-251.
    • (2006) Mol Psychiatry , vol.11 , pp. 241-251
    • Benes, F.M.1    Matzilevich, D.2    Burke, R.E.3    Walsh, J.4
  • 5
    • 0032801648 scopus 로고    scopus 로고
    • Sodium/calcium exchange: Its physiological implications
    • Blaustein MP, Lederer WJ. 1999. Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763-854.
    • (1999) Physiol Rev , vol.79 , pp. 763-854
    • Blaustein, M.P.1    Lederer, W.J.2
  • 6
    • 2342511431 scopus 로고    scopus 로고
    • Mood stabilizers: Protecting the mood.protecting the brain
    • Brunello N. 2004. Mood stabilizers: protecting the mood.protecting the brain. J Affect Disord 79(Suppl 1):S15-20.
    • (2004) J Affect Disord 79(Suppl 1):S15-20
    • Brunello, N.1
  • 7
    • 9744238838 scopus 로고    scopus 로고
    • Neuroprotective and neurotrophic actions of the mood stabilizer lithium: Can it be used to treat neurodegenerative diseases?
    • Chuang DM. 2004. Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol 16:83-90.
    • (2004) Crit Rev Neurobiol , vol.16 , pp. 83-90
    • Chuang, D.M.1
  • 8
    • 28844475505 scopus 로고    scopus 로고
    • The antiapoptotic actions of mood stabilizers: Molecular mechanisms and therapeutic potentials
    • Chuang DM. 2005. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann NY Acad Sci 1053:195-204.
    • (2005) Ann NY Acad Sci , vol.1053 , pp. 195-204
    • Chuang, D.M.1
  • 9
    • 0347504835 scopus 로고    scopus 로고
    • TRP channels as cellular sensors
    • Clapham DE. 2003. TRP channels as cellular sensors. Nature 426:517-524.
    • (2003) Nature , vol.426 , pp. 517-524
    • Clapham, D.E.1
  • 12
    • 0026558672 scopus 로고
    • Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients
    • Dubovsky SL, Murphy J, Thomas M, Rademacher J. 1992. Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients. Am J Psychiatry 149:118-120.
    • (1992) Am J Psychiatry , vol.149 , pp. 118-120
    • Dubovsky, S.L.1    Murphy, J.2    Thomas, M.3    Rademacher, J.4
  • 14
    • 0027375452 scopus 로고
    • +) -ATPase the link between phosphoinositide metabolism and bipolar disorder?
    • +)-ATPase the link between phosphoinositide metabolism and bipolar disorder? J Neuropsychiatry Clin Neurosci 5:361-368.
    • (1993) J Neuropsychiatry Clin Neurosci , vol.5 , pp. 361-368
    • El-Mallakh, R.S.1    Li, R.2
  • 15
    • 0028966044 scopus 로고
    • The Na,K-ATPase hypothesis for bipolar illness
    • El-Mallakh RS, Wyatt RJ. 1995. The Na,K-ATPase hypothesis for bipolar illness. Biol Psychiatry 37:235-244.
    • (1995) Biol Psychiatry , vol.37 , pp. 235-244
    • El-Mallakh, R.S.1    Wyatt, R.J.2
  • 16
    • 0030997903 scopus 로고    scopus 로고
    • High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar i disorder
    • Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A, et al. 1997. High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder. Am J Psychiatry 154:976-982.
    • (1997) Am J Psychiatry , vol.154 , pp. 976-982
    • Emamghoreishi, M.1    Schlichter, L.2    Li, P.P.3    Parikh, S.4    Sen, J.5    Kamble, A.6
  • 17
    • 0036366102 scopus 로고    scopus 로고
    • Antiepilep-tic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity
    • Farber NB, Jiang XP, Heinkel C, Nemmers B. 2002. Antiepilep-tic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry 7: 726-733.
    • (2002) Mol Psychiatry , vol.7 , pp. 726-733
    • Farber, N.B.1    Jiang, X.P.2    Heinkel, C.3    Nemmers, B.4
  • 18
    • 50449089356 scopus 로고    scopus 로고
    • Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder
    • Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. 2008. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40(9):1042-1044.
    • (2008) Nat Genet , vol.40 , Issue.9 , pp. 1042-1044
    • Ferreira, M.A.1    O'Donovan, M.C.2    Meng, Y.A.3    Jones, I.R.4    Ruderfer, D.M.5    Jones, L.6
  • 19
    • 7644238945 scopus 로고    scopus 로고
    • The TRPM ion channel subfamily: Molecular, biophysical and functional features
    • Fleig A, Penner R. 2004. The TRPM ion channel subfamily: molecular, biophysical and functional features. Trends Pharmacol Sci 25:633-639.
    • (2004) Trends Pharmacol Sci , vol.25 , pp. 633-639
    • Fleig, A.1    Penner, R.2
  • 20
    • 0021895138 scopus 로고
    • + indicators with greatly improved fluorescence properties
    • + indicators with greatly improved fluorescence properties. J Biol Chem 260:3440-3450.
    • (1985) J Biol Chem , vol.260 , pp. 3440-3450
    • Grynkiewicz, G.1    Poenie, M.2    Tsien, R.Y.3
  • 24
    • 0024950179 scopus 로고
    • Deficient erythrocyte NaK-ATPase activity in different affective states in bipolar affective disorder and normalization by lithium therapy
    • Hokin-Neaverson M, Jefferson JW 1989. Deficient erythrocyte NaK-ATPase activity in different affective states in bipolar affective disorder and normalization by lithium therapy. Neu-ropsychobiology 22:18-25.
    • (1989) Neu-ropsychobiology , vol.22 , pp. 18-25
    • Hokin-Neaverson, M.1    Jefferson, J.W.2
  • 25
    • 0034280095 scopus 로고    scopus 로고
    • Serum lithium levels and the outcome of maintenance therapy of bipolar disorder
    • Hopkins HS, Gelenberg AJ. 2000. Serum lithium levels and the outcome of maintenance therapy of bipolar disorder. Bipolar Disord 2:174-179.
    • (2000) Bipolar Disord , vol.2 , pp. 174-179
    • Hopkins, H.S.1    Gelenberg, A.J.2
  • 27
    • 34047273052 scopus 로고    scopus 로고
    • Lithium normalizes elevated intracellular sodium
    • Huang X, Lei Z, El-Mallakh RS. 2007. Lithium normalizes elevated intracellular sodium. Bipolar Disord 9:298-300.
    • (2007) Bipolar Disord , vol.9 , pp. 298-300
    • Huang, X.1    Lei, Z.2    El-Mallakh, R.S.3
  • 29
    • 37749045368 scopus 로고    scopus 로고
    • Comprehensive gene expression analysis in bipolar disorder
    • Kato T, Kakiuchi C, Iwamoto K. 2007. Comprehensive gene expression analysis in bipolar disorder. Can J Psychiatry 52:763-771.
    • (2007) Can J Psychiatry , vol.52 , pp. 763-771
    • Kato, T.1    Kakiuchi, C.2    Iwamoto, K.3
  • 32
    • 61449223631 scopus 로고    scopus 로고
    • Convergent functional genomics of genome-wide association data for bipolar disorder: Comprehensive identification of candidate genes, pathways and mechanisms
    • Le-Niculescu H, Patel SD, Bhat M, Kuczenski R, Faraone SV, Tsuang MT, et al. 2009. Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms. Am J Med Genet B Neuropsychiatr Genet 150B:155-181.
    • (2009) Am J Med Genet B Neuropsychiatr Genet , vol.150 B , pp. 155-181
    • Le-Niculescu, H.1    Patel, S.D.2    Bhat, M.3    Kuczenski, R.4    Faraone, S.V.5    Tsuang, M.T.6
  • 33
    • 57149126371 scopus 로고    scopus 로고
    • Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder
    • Liu L Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, et al. 2008. Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder. Psychiatr Genet 18:267-274.
    • (2008) Psychiatr Genet , vol.18 , pp. 267-274
    • Liu Foroud, L.T.1    Xuei, X.2    Berrettini, W.3    Byerley, W.4    Coryell, W.5
  • 34
    • 0034666355 scopus 로고    scopus 로고
    • Signaling: Cellular insights into the pathophysiology of bipolar disorder
    • Manji HK, Lenox RH. 2000. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry 48:518-530.
    • (2000) Biol Psychiatry , vol.48 , pp. 518-530
    • Manji, H.K.1    Lenox, R.H.2
  • 35
    • 19444369409 scopus 로고    scopus 로고
    • Human adult olfactory neuroepithelial derived progenitors retain telomerase activity and lack apoptotic activity
    • Marshall CT, Guo Z, Lu C, Klueber KM, Khalyfa A, Cooper NG, et al. 2005. Human adult olfactory neuroepithelial derived progenitors retain telomerase activity and lack apoptotic activity. Brain Res 1045:45-56.
    • (2005) Brain Res , vol.1045 , pp. 45-56
    • Marshall, C.T.1    Guo, Z.2    Lu, C.3    Klueber, K.M.4    Khalyfa, A.5    Cooper, N.G.6
  • 37
    • 33344472348 scopus 로고    scopus 로고
    • Cell cycle alterations in biopsied olfactory neuroepi-thelium in schizophrenia and bipolar i disorder using cell culture and gene expression analyses
    • McCurdy RD, Feron F, Perry C, Chant DC, McLean D, Matigian N, et al. 2006. Cell cycle alterations in biopsied olfactory neuroepi-thelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res 82:163-173.
    • (2006) Schizophr Res , vol.82 , pp. 163-173
    • McCurdy, R.D.1    Feron, F.2    Perry, C.3    Chant, D.C.4    McLean, D.5    Matigian, N.6
  • 39
    • 31544472602 scopus 로고    scopus 로고
    • Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3
    • McQuillin A, Bass NJ, Kalsi G, Lawrence J, Puri V, Choudhury K, et al. 2006. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Mol Psychiatry 11:134-142.
    • (2006) Mol Psychiatry , vol.11 , pp. 134-142
    • McQuillin, A.1    Bass, N.J.2    Kalsi, G.3    Lawrence, J.4    Puri, V.5    Choudhury, K.6
  • 40
    • 33646554494 scopus 로고    scopus 로고
    • The role of TRP channels in oxidative stress-induced cell death
    • Mller BA. 2006. The role of TRP channels in oxidative stress-induced cell death. J Membr Biol 209:31-41.
    • (2006) J Membr Biol , vol.209 , pp. 31-41
    • Mller, B.A.1
  • 42
    • 0015011593 scopus 로고
    • Changes in erythrocyte sodium and potassium on recovery from a depressive illness
    • Naylor GJ, McNamee HB, Moody JP. 1971. Changes in erythrocyte sodium and potassium on recovery from a depressive illness. Br J Psychiatry 118:219-223.
    • (1971) Br J Psychiatry , vol.118 , pp. 219-223
    • Naylor, G.J.1    McNamee, H.B.2    Moody, J.P.3
  • 43
  • 44
    • 0035978751 scopus 로고    scopus 로고
    • ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology
    • Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, et al. 2001. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411:595-599.
    • (2001) Nature , vol.411 , pp. 595-599
    • Perraud, A.L.1    Fleig, A.2    Dunn, C.A.3    Bagley, L.A.4    Launay, P.5    Schmitz, C.6
  • 45
    • 0036102199 scopus 로고    scopus 로고
    • Cell pathology in bipolar disorder
    • Rajkowska G. 2002. Cell pathology in bipolar disorder. Bipolar Disord 4:105-116.
    • (2002) Bipolar Disord , vol.4 , pp. 105-116
    • Rajkowska, G.1
  • 47
    • 77950807141 scopus 로고    scopus 로고
    • Effect of dopamine on intracellular sodium: A common pathway for pharmacological mechanism of action in bipolar illness
    • Roberts RJ, Repass R, El-Mallakh RS. 2010. Effect of dopamine on intracellular sodium: A common pathway for pharmacological mechanism of action in bipolar illness. World J Biol Psychiatry 11:181-187.
    • (2010) World J Biol Psychiatry , vol.11 , pp. 181-187
    • Roberts, R.J.1    Repass, R.2    El-Mallakh, R.S.3
  • 48
    • 36749009604 scopus 로고    scopus 로고
    • Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis
    • Roche S, Cassidy F, Zhao C, Badger J, Claffey E, Mooney L, et al. 2007. Candidate gene analysis of 21q22: Support for S100B as a susceptibility gene for bipolar affective disorder with psychosis. Am J Med Genet B Neuropsychiatr Genet 144B(8):1094-1096
    • (2007) Am J Med Genet B Neuropsychiatr Genet , vol.144 B , Issue.8 , pp. 1094-1096
    • Roche, S.1    Cassidy, F.2    Zhao, C.3    Badger, J.4    Claffey, E.5    Mooney, L.6
  • 49
    • 3142774111 scopus 로고    scopus 로고
    • The neurobiology of antiepilep-tic drugs for the treatment of nonepileptic conditions
    • Rogawski MA, Loscher W. 2004. The neurobiology of antiepilep-tic drugs for the treatment of nonepileptic conditions. Nat Med 10:685-692.
    • (2004) Nat Med , vol.10 , pp. 685-692
    • Rogawski, M.A.1    Loscher, W.2
  • 51
    • 4344600690 scopus 로고    scopus 로고
    • Anticonvulsants as mood stabilizers and adjuncts to antipsychotics: Valproate, lamotrigine, carbamazepine, and oxcarbazepine and actions at voltage-gated sodium channels
    • Stahl SM. 2004. Anticonvulsants as mood stabilizers and adjuncts to antipsychotics: valproate, lamotrigine, carbamazepine, and oxcarbazepine and actions at voltage-gated sodium channels. J Clin Psychiatry 65:738-739.
    • (2004) J Clin Psychiatry , vol.65 , pp. 738-739
    • Stahl, S.M.1
  • 53
    • 0036115945 scopus 로고    scopus 로고
    • Volumetric MRI studies of mood disorders: Do they distinguish unipolar and bipolar disorder?
    • Strakowski SM, Adler CM, DelBello MP. 2002. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder? Bipolar Disord 4:80-88.
    • (2002) Bipolar Disord , vol.4 , pp. 80-88
    • Strakowski, S.M.1    Adler, C.M.2    Delbello, M.P.3
  • 54
    • 0035015584 scopus 로고    scopus 로고
    • Effect of lithium and sodium valproate ions on resting membrane potentials in neurons: An hypothesis
    • Thiruvengadam A. 2001. Effect of lithium and sodium valproate ions on resting membrane potentials in neurons: an hypothesis. J Affect Disorders 65:95-99.
    • (2001) J Affect Disorders , vol.65 , pp. 95-99
    • Thiruvengadam, A.1
  • 56
    • 0037189484 scopus 로고    scopus 로고
    • Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose
    • Wehage E, Eisfeld J, Heiner I, Jungling E, Zitt C, Luckhoff A. 2002. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem 277:23150-23156.
    • (2002) J Biol Chem , vol.277 , pp. 23150-23156
    • Wehage, E.1    Eisfeld, J.2    Heiner, I.3    Jungling, E.4    Zitt, C.5    Luckhoff, A.6
  • 57
    • 15544372896 scopus 로고    scopus 로고
    • Endoscopic biopsy of human olfactory epithelium as a source of progenitor cells
    • Winstead W, Marshall CT, Lu CL, Klueber KM, Roisen FJ. 2005. Endoscopic biopsy of human olfactory epithelium as a source of progenitor cells. Am J Rhinol 19:83-90.
    • (2005) Am J Rhinol , vol.19 , pp. 83-90
    • Winstead, W.1    Marshall, C.T.2    Lu, C.L.3    Klueber, K.M.4    Roisen, F.J.5
  • 58
    • 30344479721 scopus 로고    scopus 로고
    • Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder
    • Xu C, Macciardi F, Li PP, Yoon IS, Cooke RG, Hughes B, et al. 2006. Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 141:36-43.
    • (2006) Am J Med Genet B Neuropsychiatr Genet , vol.141 , pp. 36-43
    • Xu, C.1    MacCiardi, F.2    Li, P.P.3    Yoon, I.S.4    Cooke, R.G.5    Hughes, B.6
  • 59
    • 35548993594 scopus 로고    scopus 로고
    • Lithium inhibits function of voltage-dependent sodium channels and catecholamine secretion independent of glycogen synthase kinase-3 in adrenal chromaffin cells
    • Yanagita T, Maruta T, Uezono Y, Satoh S, Yoshikawa N, Nemoto T, et al. 2007. Lithium inhibits function of voltage-dependent sodium channels and catecholamine secretion independent of glycogen synthase kinase-3 in adrenal chromaffin cells. Neuropharmacology 53:881-889.
    • (2007) Neuropharmacology , vol.53 , pp. 881-889
    • Yanagita, T.1    Maruta, T.2    Uezono, Y.3    Satoh, S.4    Yoshikawa, N.5    Nemoto, T.6
  • 61
    • 0038521288 scopus 로고    scopus 로고
    • A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death
    • Zhang W, Chu X, Tong Q, Cheung JY, Conrad K, Masker K, et al. 2003. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J Biol Chem 278:16222-16229.
    • (2003) J Biol Chem , vol.278 , pp. 16222-16229
    • Zhang, W.1    Chu, X.2    Tong, Q.3    Cheung, J.Y.4    Conrad, K.5    Masker, K.6
  • 62
    • 15544376966 scopus 로고    scopus 로고
    • Induction of oligodendrocytes from adult human olfactory epithelial-derived progenitors by transcription factors
    • Zhang X, Cai J, Klueber KM, Guo Z, Lu C, Qiu M, et al. 2005. Induction of oligodendrocytes from adult human olfactory epithelial-derived progenitors by transcription factors. Stem Cells 23:442-453.
    • (2005) Stem Cells , vol.23 , pp. 442-453
    • Zhang, X.1    Cai, J.2    Klueber, K.M.3    Guo, Z.4    Lu, C.5    Qiu, M.6
  • 63
    • 33646415942 scopus 로고    scopus 로고
    • TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage
    • Zhang W, Hirschler-Laszkiewicz I, Tong Q, Conrad K, Sun SC, Penn L, et al. 2006a. TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. Am J Physiol 290:C1146-1159.
    • (2006) Am J Physiol , vol.290
    • Zhang, W.1    Hirschler-Laszkiewicz, I.2    Tong, Q.3    Conrad, K.4    Sun, S.C.5    Penn, L.6
  • 64
    • 33746889825 scopus 로고    scopus 로고
    • Role of transcription factors in motoneuron differentiation of adult human olfactory neuroepithelial-derived progenitors
    • Zhang X, Cai J, Klueber KM, Guo Z, Lu C, Winstead WI, et al. 2006b. Role of transcription factors in motoneuron differentiation of adult human olfactory neuroepithelial-derived progenitors. Stem Cells 24:434-442.
    • (2006) Stem Cells , vol.24 , pp. 434-442
    • Zhang, X.1    Cai, J.2    Klueber, K.M.3    Guo, Z.4    Lu, C.5    Winstead, W.I.6
  • 65
    • 33645016905 scopus 로고    scopus 로고
    • Induction of neuronal differentiation of adult human olfactory neuroepithelial-derived progenitors
    • Zhang X, Klueber KM, Guo Z, Cai J, Lu C, Winstead WI, et al. 2006c. Induction of neuronal differentiation of adult human olfactory neuroepithelial-derived progenitors. Brain Res 1073-1074:109-119.
    • (2006) Brain Res , vol.1073-1074 , pp. 109-119
    • Zhang, X.1    Klueber, K.M.2    Guo, Z.3    Cai, J.4    Lu, C.5    Winstead, W.I.6


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.