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Volumn 6, Issue 1, 2011, Pages

MCT expression and lactate influx/efflux in tanycytes involved in glia-neuron metabolic interaction

Author keywords

[No Author keywords available]

Indexed keywords

LACTIC ACID; MONOCARBOXYLATE TRANSPORTER; MONOCARBOXYLATE TRANSPORTER 1; MONOCARBOXYLATE TRANSPORTER 4; COTRANSPORTER; GLUCOSE; LACTIC ACID DERIVATIVE; MCT4 PROTEIN, RAT; MONOCARBOXYLATE TRANSPORT PROTEIN 1; MUSCLE PROTEIN;

EID: 79551571718     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0016411     Document Type: Article
Times cited : (67)

References (49)
  • 2
    • 0032967165 scopus 로고    scopus 로고
    • Brain glucose sensing and body energy homeostasis: Role in obesity and diabetes
    • Levin BE, Dunn-Meynell AA, Routh VH (1999) Brain glucose sensing and body energy homeostasis: role in obesity and diabetes. Am J Physiol 276: R1223-1231.
    • (1999) Am J Physiol , vol.276
    • Levin, B.E.1    Dunn-Meynell, A.A.2    Routh, V.H.3
  • 3
    • 0014683812 scopus 로고
    • Glucose and osmosensitive neurones of the rat hypothalamus
    • Oomura Y, Ono T, Ooyama H, Wayner MJ (1969) Glucose and osmosensitive neurones of the rat hypothalamus. Nature 222: 282-284.
    • (1969) Nature , vol.222 , pp. 282-284
    • Oomura, Y.1    Ono, T.2    Ooyama, H.3    Wayner, M.J.4
  • 4
    • 12144275681 scopus 로고    scopus 로고
    • Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus
    • Song Z, Routh VH (2005) Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54: 15-22.
    • (2005) Diabetes , vol.54 , pp. 15-22
    • Song, Z.1    Routh, V.H.2
  • 5
    • 3242765290 scopus 로고    scopus 로고
    • The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides
    • Wang R, Liu X, Hentges ST, Dunn-Meynell AA, Levin BE, et al. (2004) The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 53: 1959-1965.
    • (2004) Diabetes , vol.53 , pp. 1959-1965
    • Wang, R.1    Liu, X.2    Hentges, S.T.3    Dunn-Meynell, A.A.4    Levin, B.E.5
  • 6
    • 0032829063 scopus 로고    scopus 로고
    • Hypothalamic glucose sensor: Similarities to and differences from pancreatic beta-cell mechanisms
    • Yang XJ, Kow LM, Funabashi T, Mobbs CV (1999) Hypothalamic glucose sensor: similarities to and differences from pancreatic beta-cell mechanisms. Diabetes 48: 1763-1772.
    • (1999) Diabetes , vol.48 , pp. 1763-1772
    • Yang, X.J.1    Kow, L.M.2    Funabashi, T.3    Mobbs, C.V.4
  • 8
    • 58149307894 scopus 로고    scopus 로고
    • Dissociation between sensing and metabolism of glucose in sugar sensing neurones
    • Gonzalez JA, Reimann F, Burdakov D (2009) Dissociation between sensing and metabolism of glucose in sugar sensing neurones. J Physiol 587: 41-48.
    • (2009) J Physiol , vol.587 , pp. 41-48
    • Gonzalez, J.A.1    Reimann, F.2    Burdakov, D.3
  • 9
    • 0037107408 scopus 로고    scopus 로고
    • Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: Evidence for ATP-independent control of ATP-sensitive K(+) channels
    • Ainscow EK, Mirshamsi S, Tang T, Ashford ML, Rutter GA (2002) Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K(+) channels. J Physiol 544: 429-445.
    • (2002) J Physiol , vol.544 , pp. 429-445
    • Ainscow, E.K.1    Mirshamsi, S.2    Tang, T.3    Ashford, M.L.4    Rutter, G.A.5
  • 10
    • 0028909335 scopus 로고
    • CDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1
    • Garcia CK, Brown MS, Pathak RK, Goldstein JL (1995) CDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J Biol Chem 270: 1843-1849.
    • (1995) J Biol Chem , vol.270 , pp. 1843-1849
    • Garcia, C.K.1    Brown, M.S.2    Pathak, R.K.3    Goldstein, J.L.4
  • 11
    • 0033569442 scopus 로고    scopus 로고
    • The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation
    • Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2): 281-299.
    • (1999) Biochem J , vol.343 , Issue.PART 2 , pp. 281-299
    • Halestrap, A.P.1    Price, N.T.2
  • 12
    • 12244262261 scopus 로고    scopus 로고
    • Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain
    • Pellerin L, Bergersen LH, Halestrap AP, Pierre K (2005) Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res 79: 55-64.
    • (2005) J Neurosci Res , vol.79 , pp. 55-64
    • Pellerin, L.1    Bergersen, L.H.2    Halestrap, A.P.3    Pierre, K.4
  • 13
    • 0027939545 scopus 로고
    • CDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12
    • Garcia CK, Li X, Luna J, Francke U (1994) CDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12. Genomics 23: 500-503.
    • (1994) Genomics , vol.23 , pp. 500-503
    • Garcia, C.K.1    Li, X.2    Luna, J.3    Francke, U.4
  • 14
    • 1242340302 scopus 로고    scopus 로고
    • The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond
    • Halestrap AP, Meredith D (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 447: 619-628.
    • (2004) Pflugers Arch , vol.447 , pp. 619-628
    • Halestrap, A.P.1    Meredith, D.2
  • 15
    • 0034663601 scopus 로고    scopus 로고
    • The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells
    • Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350(Pt 1): 219-227.
    • (2000) Biochem J , vol.350 , Issue.PART 1 , pp. 219-227
    • Dimmer, K.S.1    Friedrich, B.2    Lang, F.3    Deitmer, J.W.4    Broer, S.5
  • 16
    • 0030774069 scopus 로고    scopus 로고
    • Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons
    • Broer S, Rahman B, Pellegri G, Pellerin L, Martin JL, et al. (1997) Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem 272: 30096-30102.
    • (1997) J Biol Chem , vol.272 , pp. 30096-30102
    • Broer, S.1    Rahman, B.2    Pellegri, G.3    Pellerin, L.4    Martin, J.L.5
  • 17
    • 0034041755 scopus 로고    scopus 로고
    • Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo
    • Hanu R, McKenna M, O'Neill A, Resneck WG, Bloch RJ (2000) Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo. Am J Physiol Cell Physiol 278: C921-930.
    • (2000) Am J Physiol Cell Physiol , vol.278
    • Hanu, R.1    McKenna, M.2    O'Neill, A.3    Resneck, W.G.4    Bloch, R.J.5
  • 19
    • 0033548527 scopus 로고    scopus 로고
    • Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: A quantitative electron microscopic immunogold study
    • Leino RL, Gerhart DZ, Drewes LR (1999) Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Brain Res Dev Brain Res 113: 47-54.
    • (1999) Brain Res Dev Brain Res , vol.113 , pp. 47-54
    • Leino, R.L.1    Gerhart, D.Z.2    Drewes, L.R.3
  • 20
    • 0034721575 scopus 로고    scopus 로고
    • Cellspecific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy
    • Pierre K, Pellerin L, Debernardi R, Riederer BM, Magistretti PJ (2000) Cellspecific localization of monocarboxylate transporters, MCT1 and MCT2, in the adult mouse brain revealed by double immunohistochemical labeling and confocal microscopy. Neuroscience 100: 617-627.
    • (2000) Neuroscience , vol.100 , pp. 617-627
    • Pierre, K.1    Pellerin, L.2    Debernardi, R.3    Riederer, B.M.4    Magistretti, P.J.5
  • 21
    • 0035114149 scopus 로고    scopus 로고
    • A novel postsynaptic density protein: The monocarboxylate transporter MCT2 is colocalized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses
    • Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P, et al. (2001) A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is colocalized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res 136: 523-534.
    • (2001) Exp Brain Res , vol.136 , pp. 523-534
    • Bergersen, L.1    Waerhaug, O.2    Helm, J.3    Thomas, M.4    Laake, P.5
  • 22
    • 0037963512 scopus 로고    scopus 로고
    • Cellspecific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures
    • Debernardi R, Pierre K, Lengacher S, Magistretti PJ, Pellerin L (2003) Cellspecific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures. J Neurosci Res 73: 141-155.
    • (2003) J Neurosci Res , vol.73 , pp. 141-155
    • Debernardi, R.1    Pierre, K.2    Lengacher, S.3    Magistretti, P.J.4    Pellerin, L.5
  • 23
    • 21344444566 scopus 로고    scopus 로고
    • Monocarboxylate transporters in the central nervous system: Distribution, regulation and function
    • Pierre K, Pellerin L (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J Neurochem 94: 1-14.
    • (2005) J Neurochem , vol.94 , pp. 1-14
    • Pierre, K.1    Pellerin, L.2
  • 24
    • 0034525940 scopus 로고    scopus 로고
    • Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle
    • Manning Fox JE, Meredith D, Halestrap AP (2000) Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol 529(Pt 2): 285-293.
    • (2000) J Physiol , vol.529 , Issue.PART 2 , pp. 285-293
    • Manning, F.J.E.1    Meredith, D.2    Halestrap, A.P.3
  • 25
    • 0242485280 scopus 로고    scopus 로고
    • Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain
    • Rafiki A, Boulland JL, Halestrap AP, Ottersen OP, Bergersen L (2003) Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain. Neuroscience 122: 677-688.
    • (2003) Neuroscience , vol.122 , pp. 677-688
    • Rafiki, A.1    Boulland, J.L.2    Halestrap, A.P.3    Ottersen, O.P.4    Bergersen, L.5
  • 26
    • 0029038308 scopus 로고
    • Transected axons of adult hypothalamo-neurohypophysial neurons regenerate along tanycytic processes
    • Chauvet N, Parmentier ML, Alonso G (1995) Transected axons of adult hypothalamo-neurohypophysial neurons regenerate along tanycytic processes. J Neurosci Res 41: 129-144.
    • (1995) J Neurosci Res , vol.41 , pp. 129-144
    • Chauvet, N.1    Parmentier, M.L.2    Alonso, G.3
  • 27
    • 0022293260 scopus 로고
    • Tanycytes: Morphology and functions: A review
    • Flament-Durand J, Brion JP (1985) Tanycytes: morphology and functions: a review. Int Rev Cytol 96: 121-155.
    • (1985) Int Rev Cytol , vol.96 , pp. 121-155
    • Flament-Durand, J.1    Brion, J.P.2
  • 28
    • 0035140305 scopus 로고    scopus 로고
    • Elevated expression of glucose transporter-1 in hypothalamic ependymal cells not involved in the formation of the brain-cerebrospinal fluid barrier
    • Garcia MA, Carrasco M, Godoy A, Reinicke K, Montecinos VP, et al. (2001) Elevated expression of glucose transporter-1 in hypothalamic ependymal cells not involved in the formation of the brain-cerebrospinal fluid barrier. J Cell Biochem 80: 491-503.
    • (2001) J Cell Biochem , vol.80 , pp. 491-503
    • Garcia, M.A.1    Carrasco, M.2    Godoy, A.3    Reinicke, K.4    Montecinos, V.P.5
  • 29
    • 0042303943 scopus 로고    scopus 로고
    • Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing
    • Garcia MA, Millan C, Balmaceda-Aguilera C, Castro T, Pastor P, et al. (2003) Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem 86: 709-724.
    • (2003) J Neurochem , vol.86 , pp. 709-724
    • Garcia, M.A.1    Millan, C.2    Balmaceda-Aguilera, C.3    Castro, T.4    Pastor, P.5
  • 30
    • 77956257822 scopus 로고    scopus 로고
    • Glial glucokinase expression in adult and post-natal development of the hypothalamic region
    • Millan C, Martinez F, Cortes-Campos C, Lizama I, Yanez MJ, et al. (2010) Glial glucokinase expression in adult and post-natal development of the hypothalamic region. ASN Neuro 2: e00035.
    • (2010) ASN Neuro , vol.2
    • Millan, C.1    Martinez, F.2    Cortes-Campos, C.3    Lizama, I.4    Yanez, M.J.5
  • 31
    • 0017754686 scopus 로고
    • Morphological aspects of the hypothalamichypophyseal system. VII. The tanycytes: Their relation to the hypophyseal adrenocorticotrophic function. An ultrastructural study
    • Akmayev IG, Popov AP (1977) Morphological aspects of the hypothalamichypophyseal system. VII. The tanycytes: Their relation to the hypophyseal adrenocorticotrophic function. An ultrastructural study. Cell Tissue Res 180:263-282.
    • (1977) Cell Tissue Res , vol.180 , pp. 263-282
    • Akmayev, I.G.1    Popov, A.P.2
  • 32
  • 33
    • 2342510308 scopus 로고    scopus 로고
    • Third ventricular alloxan reversibly impairs glucose counterregulatory responses
    • Sanders NM, Dunn-Meynell AA, Levin BE (2004) Third ventricular alloxan reversibly impairs glucose counterregulatory responses. Diabetes 53: 1230-1236.
    • (2004) Diabetes , vol.53 , pp. 1230-1236
    • Sanders, N.M.1    Dunn-Meynell, A.A.2    Levin, B.E.3
  • 34
    • 23244458439 scopus 로고    scopus 로고
    • Regulation of blood glucose by hypothalamic pyruvate metabolism
    • Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L (2005) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309: 943-947.
    • (2005) Science , vol.309 , pp. 943-947
    • Lam, T.K.1    Gutierrez-Juarez, R.2    Pocai, A.3    Rossetti, L.4
  • 35
    • 0030837750 scopus 로고    scopus 로고
    • Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats
    • Gerhart DZ, Enerson BE, Zhdankina OY, Leino RL, Drewes LR (1997) Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats. Am J Physiol 273: E207-213.
    • (1997) Am J Physiol , vol.273
    • Gerhart, D.Z.1    Enerson, B.E.2    Zhdankina, O.Y.3    Leino, R.L.4    Drewes, L.R.5
  • 37
    • 0032130554 scopus 로고    scopus 로고
    • Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons
    • Hahn TM, Breininger JF, Baskin DG, Schwartz MW (1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1: 271-272.
    • (1998) Nat Neurosci , vol.1 , pp. 271-272
    • Hahn, T.M.1    Breininger, J.F.2    Baskin, D.G.3    Schwartz, M.W.4
  • 38
    • 0033515710 scopus 로고    scopus 로고
    • Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y
    • Muroya S, Yada T, Shioda S, Takigawa M (1999) Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci Lett 264: 113-116.
    • (1999) Neurosci Lett , vol.264 , pp. 113-116
    • Muroya, S.1    Yada, T.2    Shioda, S.3    Takigawa, M.4
  • 39
    • 0037387207 scopus 로고    scopus 로고
    • Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels
    • Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, et al. (2003) Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144: 1331-1340.
    • (2003) Endocrinology , vol.144 , pp. 1331-1340
    • Ibrahim, N.1    Bosch, M.A.2    Smart, J.L.3    Qiu, J.4    Rubinstein, M.5
  • 40
    • 34548604499 scopus 로고    scopus 로고
    • Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity
    • Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, et al. (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449: 228-232.
    • (2007) Nature , vol.449 , pp. 228-232
    • Parton, L.E.1    Ye, C.P.2    Coppari, R.3    Enriori, P.J.4    Choi, B.5
  • 42
    • 0032522384 scopus 로고    scopus 로고
    • Ependymal and choroidal cells in culture: Characterization and functional differentiation
    • Gabrion JB, Herbute S, Bouille C, Maurel D, Kuchler-Bopp S, et al. (1998) Ependymal and choroidal cells in culture: characterization and functional differentiation. Microsc Res Tech 41: 124-157.
    • (1998) Microsc Res Tech , vol.41 , pp. 124-157
    • Gabrion, J.B.1    Herbute, S.2    Bouille, C.3    Maurel, D.4    Kuchler-Bopp, S.5
  • 43
    • 0039351371 scopus 로고    scopus 로고
    • Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes
    • Broer S, Broer A, Schneider HP, Stegen C, Halestrap AP, et al. (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341(Pt 3): 529-535.
    • (1999) Biochem J , vol.341 , Issue.PART 3 , pp. 529-535
    • Broer, S.1    Broer, A.2    Schneider, H.P.3    Stegen, C.4    Halestrap, A.P.5
  • 44
    • 7144253117 scopus 로고    scopus 로고
    • Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter isoform MCT3
    • Wilson MC, Jackson VN, Heddle C, Price NT, Pilegaard H, et al. (1998) Lactic acid efflux from white skeletal muscle is catalyzed by the monocarboxylate transporter isoform MCT3. J Biol Chem 273: 15920-15926.
    • (1998) J Biol Chem , vol.273 , pp. 15920-15926
    • Wilson, M.C.1    Jackson, V.N.2    Heddle, C.3    Price, N.T.4    Pilegaard, H.5
  • 45
    • 0028080101 scopus 로고
    • Glutamate uptake into astrocytes stimulates aerobic glycolysis: A mechanism coupling neuronal activity to glucose utilization
    • Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91: 10625-10629.
    • (1994) Proc Natl Acad Sci U S A , vol.91 , pp. 10625-10629
    • Pellerin, L.1    Magistretti, P.J.2
  • 46
    • 0345700729 scopus 로고    scopus 로고
    • Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation
    • Borg MA, Tamborlane WV, Shulman GI, Sherwin RS (2003) Local lactate perfusion of the ventromedial hypothalamus suppresses hypoglycemic counterregulation. Diabetes 52: 663-666.
    • (2003) Diabetes , vol.52 , pp. 663-666
    • Borg, M.A.1    Tamborlane, W.V.2    Shulman, G.I.3    Sherwin, R.S.4
  • 47
    • 0027104001 scopus 로고
    • Dynamics of three-dimensional replication patterns during the S-phase, analysed by double labelling of DNA and confocal microscopy
    • Manders EM, Stap J, Brakenhoff GJ, van Driel R, Aten JA (1992) Dynamics of three-dimensional replication patterns during the S-phase, analysed by double labelling of DNA and confocal microscopy. J Cell Sci 103(Pt 3): 857-862.
    • (1992) J Cell Sci , vol.103 , Issue.PART 3 , pp. 857-862
    • Manders, E.M.1    Stap, J.2    Brakenhoff, G.J.3    van Driel, R.4    Aten, J.A.5
  • 48
    • 20244388980 scopus 로고    scopus 로고
    • Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells
    • Garcia M, Salazar K, Millan C, Rodriguez F, Montecinos H, et al. (2005) Sodium vitamin C cotransporter SVCT2 is expressed in hypothalamic glial cells. Glia 50: 32-47.
    • (2005) Glia , vol.50 , pp. 32-47
    • Garcia, M.1    Salazar, K.2    Millan, C.3    Rodriguez, F.4    Montecinos, H.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.