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Volumn 59, Issue 4, 2011, Pages 456-464

13N as a tracer for studying glutamate metabolism

Author keywords

Alanine aminotransferase; Aspartate aminotransferase; Branched chain amino acid aminotransferase; Glutamate dehydrogenase; Glutamine cycle; Nitrogen flux; Transdeamination; Transreamination; Urea cycle

Indexed keywords

AMMONIA; ASPARTATE AMINOTRANSFERASE; GLUTAMATE DEHYDROGENASE; GLUTAMIC ACID; NITROGEN; NITROGEN 13; NITROGEN 15; DIAGNOSTIC AGENT; TRACER;

EID: 80052263625     PISSN: 01970186     EISSN: 18729754     Source Type: Journal    
DOI: 10.1016/j.neuint.2010.11.011     Document Type: Short Survey
Times cited : (56)

References (62)
  • 1
    • 3042737335 scopus 로고    scopus 로고
    • Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis
    • DOI 10.1002/hep.20290
    • B. Ahl, K. Weissenborn, J. van den Hoff, D. Fischer-Wasels, H. Köstler, H. Hecker, and W. Burchert Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis Hepatology 40 2004 73 79 (Pubitemid 38868925)
    • (2004) Hepatology , vol.40 , Issue.1 , pp. 73-79
    • Ahl, B.1    Weissenborn, K.2    Van Den Hoff, J.3    Fischer-Wasels, D.4    Kostler, H.5    Hecker, H.6    Burchert, W.7
  • 2
    • 0016746875 scopus 로고
    • Metabolism of amino acids and ammonia in rat brain cortex slices in vitro: A possible role of ammonia in brain function
    • A.M. Benjamin, and J.H. Quastel Metabolism of amino acids and ammonia in rat brain cortex slices in vitro: a possible role of ammonia in brain function J. Neurochem. 25 1975 197 206
    • (1975) J. Neurochem. , vol.25 , pp. 197-206
    • Benjamin, A.M.1    Quastel, J.H.2
  • 3
    • 73049161747 scopus 로고
    • Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver
    • S. Berl, G. Takagaki, D.D. Clarke, and H. Waelsch Metabolic compartments in vivo. Ammonia and glutamic acid metabolism in brain and liver J. Biol. Chem. 237 1962 2562 2569
    • (1962) J. Biol. Chem. , vol.237 , pp. 2562-2569
    • Berl, S.1    Takagaki, G.2    Clarke, D.D.3    Waelsch, H.4
  • 5
    • 33750536032 scopus 로고    scopus 로고
    • Differential gene expression in periportal and perivenous mouse hepatocytes
    • DOI 10.1111/j.1742-4658.2006.05503.x
    • A. Braeuning, C. Ittrich, C. Köhle, S. Hailfinger, M. Bonin, A. Buchmann, and M. Schwarz Differential gene expression in periportal and perivenous mouse hepatocytes FASEB J. 273 2006 5051 5061 (Pubitemid 44673296)
    • (2006) FEBS Journal , vol.273 , Issue.22 , pp. 5051-5061
    • Braeuning, A.1    Ittrich, C.2    Kohle, C.3    Hailfinger, S.4    Bonin, M.5    Buchmann, A.6    Schwarz, M.7
  • 6
    • 6744270166 scopus 로고
    • Principal ways of assimilation & dissimilation of nitrogen in animals
    • French
    • A.E. Braunstein Principal ways of assimilation & dissimilation of nitrogen in animals Adv. Enzymol. Relat. Subj. Biochem. 19 1957 335 389 French
    • (1957) Adv. Enzymol. Relat. Subj. Biochem. , vol.19 , pp. 335-389
    • Braunstein, A.E.1
  • 7
    • 51149184039 scopus 로고
    • Formation of amino-acids by inter-molecular transfer of the amino group
    • A.E. Braunstein, and M.G. Kritzmann Formation of amino-acids by inter-molecular transfer of the amino group Nature 140 1937 503 504
    • (1937) Nature , vol.140 , pp. 503-504
    • Braunstein, A.E.1    Kritzmann, M.G.2
  • 8
    • 77957073688 scopus 로고    scopus 로고
    • Astrocyte glutamine synthetase: Importance in hyperammonemic syndromes and potential target for therapy
    • S.W. Brusilow, R.C. Koehler, R.J. Traystman, and A.J.L. Cooper Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy Neurotherapeutics 7 2010 452 470
    • (2010) Neurotherapeutics , vol.7 , pp. 452-470
    • Brusilow, S.W.1    Koehler, R.C.2    Traystman, R.J.3    Cooper, A.J.L.4
  • 9
    • 0018416947 scopus 로고
    • The purification and properties of rat brain glutamate dehydrogenase
    • DOI 10.1111/j.1471-4159.1979.tb11705.x
    • P.Y. Chee, J.L. Dahl, and L.A. Fahien The purification and properties of rat brain glutamate dehydrogenase J. Neurochem. 33 1979 53 60 (Pubitemid 9233911)
    • (1979) Journal of Neurochemistry , vol.33 , Issue.1 , pp. 53-60
    • Chee, P.Y.1    Dahl, J.L.2    Fahien, L.A.3
  • 10
    • 0024590390 scopus 로고
    • Channeling of urea cycle intermediates in situ in permeabilized hepatocytes
    • C. Cheung, N.S. Cohen, and L. Raijman Channeling of urea cycle intermediates in situ in permeabilized hepatocytes J. Biol. Chem. 264 1989 4038 4044 (Pubitemid 19072295)
    • (1989) Journal of Biological Chemistry , vol.264 , Issue.7 , pp. 4038-4044
    • Cheung, C.-W.1    Cohen, N.S.2    Raijman, L.3
  • 12
    • 0023277382 scopus 로고
    • Biochemistry and physiology of brain ammonia
    • A.J.L. Cooper, and F. Plum Biochemistry and physiology of brain ammonia Physiol. Rev. 67 1987 440 519 (Pubitemid 17063608)
    • (1987) Physiological Reviews , vol.67 , Issue.2 , pp. 440-519
    • Cooper, A.J.L.1    Plum, F.2
  • 13
    • 0024373082 scopus 로고
    • An appreciation of Professor Alexander E. Braunstein. The discovery and scope of enzymatic transamination
    • A.J.L. Cooper, and A. Meister An appreciation of Professor Alexander E. Braunstein. The discovery and scope of enzymatic transamination Biochimie 71 1989 387 404 (Pubitemid 19135721)
    • (1989) Biochimie , vol.71 , Issue.4 , pp. 387-404
    • Cooper, A.J.L.1    Meister, A.2
  • 19
    • 0021826269 scopus 로고
    • Cerebral ammonia metabolism in hyperammonemic rats
    • DOI 10.1111/j.1471-4159.1985.tb07159.x
    • A.J.L. Cooper, S.N. Mora, N.F. Cruz, and A.S. Gelbard Cerebral ammonia metabolism in hyperammonemic rats J. Neurochem. 44 1985 1716 1723 (Pubitemid 15000274)
    • (1985) Journal of Neurochemistry , vol.44 , Issue.6 , pp. 1716-1723
    • Cooper, A.J.L.1    Mora, S.N.2    Cruz, N.F.3    Gelbard, A.S.4
  • 20
    • 0036981517 scopus 로고    scopus 로고
    • 1H magnetic resonance in the study of hepatic encephalopathy in humans
    • DOI 10.1023/A:1021926405944
    • 1H magnetic resonance in the study of hepatic encephalopathy in humans Metab. Brain Dis. 17 2002 415 429 (Pubitemid 36204770)
    • (2002) Metabolic Brain Disease , vol.17 , Issue.4 , pp. 415-429
    • Cordoba, J.1    Sanpedro, F.2    Alonso, J.3    Rovira, A.4
  • 21
    • 0000528617 scopus 로고
    • Artificial production of a new kind of radio-element
    • I. Curie, and F. Joliot Artificial production of a new kind of radio-element Nature 133 1934 201 202
    • (1934) Nature , vol.133 , pp. 201-202
    • Curie, I.1    Joliot, F.2
  • 22
    • 0036306987 scopus 로고    scopus 로고
    • Expression of the aspartate/glutamate mitochondrial carriers aralar1 and citrin during development and in adult rat tissues
    • DOI 10.1046/j.1432-1033.2002.03018.x
    • A. del Arco, J. Morcillo, J.R. Martínez-Morales, C. Galián, V. Martos, P. Bovolenta, and J. Satrústegui Expression of the aspartate/glutamate mitochondrial carriers aralar1 and citrin during development and in adult rat tissues Eur. J. Biochem. 269 2002 3313 3320 (Pubitemid 34748118)
    • (2002) European Journal of Biochemistry , vol.269 , Issue.13 , pp. 3313-3320
    • Del Arco, A.1    Morcillo, J.2    Martinez-Morales, J.R.3    Galian, C.4    Martos, V.5    Bovolenta, P.6    Satrustegui, J.7
  • 23
    • 0342314620 scopus 로고    scopus 로고
    • Effect of portacaval anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle
    • P. Desjardins, K.V. Rao, A. Michalak, C. Rose, and R.F. Butterworth Effect of portacaval anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle Metab. Brain Dis. 14 1999 273 280 (Pubitemid 30337701)
    • (1999) Metabolic Brain Disease , vol.14 , Issue.4 , pp. 273-280
    • Desjardins, P.1    Rama Rao, K.V.2    Michalak, A.3    Rose, C.4    Butterworth, R.F.5
  • 24
    • 0015548985 scopus 로고
    • Uptake of individual amino acids by the human brain
    • P. Felig, J. Wahren, and G. Ahlborg Uptake of individual amino acids by the human brain Proc. Soc. Exp. Biol. Med. 142 1973 230 231
    • (1973) Proc. Soc. Exp. Biol. Med. , vol.142 , pp. 230-231
    • Felig, P.1    Wahren, J.2    Ahlborg, G.3
  • 25
    • 33847709986 scopus 로고    scopus 로고
    • Widespread neuronal expression of branched-chain aminotransferase in the CNS: Implications for leucine/glutamate metabolism and for signaling by amino acids
    • DOI 10.1111/j.1471-4159.2006.04332.x
    • M.A. García-Espinosa, R. Wallin, S.M. Hutson, and A.J. Sweatt Widespread neuronal expression of branched-chain aminotransferase in the CNS: implications for leucine/glutamate metabolism and for signaling by amino acids J. Neurochem. 100 2007 1458 1468 (Pubitemid 46376212)
    • (2007) Journal of Neurochemistry , vol.100 , Issue.6 , pp. 1458-1468
    • Garcia-Espinosa, M.A.1    Wallin, R.2    Hutson, S.M.3    Sweatt, A.J.4
  • 27
    • 0018934586 scopus 로고
    • Imaging of the human heart after administration of L-(N-13)glutamate
    • A.S. Gelbard, R.S. Benua, R.E. Reiman, J.M. McDonald, J.J. Vomero, and J.S. Laughlin Imaging of the human heart after administration of l-(N-13)glutamate J. Nucl. Med. 21 1980 988 991 (Pubitemid 10010848)
    • (1980) Journal of Nuclear Medicine , vol.21 , Issue.10 , pp. 988-991
    • Gelbard, A.S.1    Benua, R.S.2    Reiman, R.E.3
  • 29
    • 0025356216 scopus 로고
    • Methods for the enzymatic synthesis of tyrosine and phenylalanine labeled with nitrogen-13
    • DOI 10.1016/0883-2889(90)90114-V
    • A.S. Gelbard, A.J.L. Cooper, Y. Asano, E. Nieves, S. Filc-DeRicco, and K.C. Rosenspire Methods for the enzymatic synthesis of tyrosine and phenylalanine labeled with nitrogen-13 Appl. Radiat. Isot. Int. J. Radiat. Appl. Instrum. A 41 1990 229 233 (Pubitemid 20103492)
    • (1990) Applied Radiation and Isotopes , vol.41 , Issue.2 , pp. 229-233
    • Gelbard, A.S.1    Cooper, A.J.L.2    Asano, Y.3    Nieves, E.4    Filc-Dericco, S.5    Rosenspire, K.C.6
  • 32
    • 0025231570 scopus 로고
    • Nitrogen metabolism in liver: Structural and functional organization and physiological relevance
    • D. Häussinger Nitrogen metabolism in liver: structural and functional organization and physiological relevance Biochem. J. 267 1990 281 290 (Pubitemid 20136054)
    • (1990) Biochemical Journal , vol.267 , Issue.2 , pp. 281-290
    • Haussinger, D.1
  • 34
    • 0016733259 scopus 로고
    • Control of the redox state of the pyridine nucleotides in the rat cerebral cortex. Effect of electroshock-induced seizures
    • D.C. Howse, and T.E. Duffy Control of the redox state of the pyridine nucleotides in the rat cerebral cortex. Effect of electroshock-induced seizures J. Neurochem. 24 1975 935 940
    • (1975) J. Neurochem. , vol.24 , pp. 935-940
    • Howse, D.C.1    Duffy, T.E.2
  • 37
    • 0029800090 scopus 로고    scopus 로고
    • Zonation of parenchymal and nonparenchymal metabolism in liver
    • K. Jungermann, and T. Kietzmann Zonation of parenchymal and nonparenchymal metabolism in liver Annu. Rev. Nutr. 16 1996 179 203 (Pubitemid 26286852)
    • (1996) Annual Review of Nutrition , vol.16 , pp. 179-203
    • Jungermann, K.1    Kietzmann, T.2
  • 38
    • 0023176895 scopus 로고
    • Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy
    • J. Lavoie, J.F. Gigure, G.P. Layrargues, and R.F. Butterworth Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy J. Neurochem. 49 1987 692 697 (Pubitemid 17123714)
    • (1987) Journal of Neurochemistry , vol.49 , Issue.3 , pp. 692-697
    • Lavoie, J.1    Giguere, J.-F.2    Layrargues, G.P.3    Butterworth, R.F.4
  • 39
    • 0018393048 scopus 로고
    • The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia
    • A.H. Lockwood, J.M. McDonald, R.E. Reiman, A.S. Gelbard, J.S. Laughlin, T.E. Duffy, and F. Plum The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia J. Clin. Invest. 63 1979 449 460 (Pubitemid 9130208)
    • (1979) Journal of Clinical Investigation , vol.63 , Issue.3 , pp. 449-460
    • Lockwood, A.H.1    McDonald, J.M.2    Reiman, R.E.3
  • 40
    • 0018843027 scopus 로고
    • Factors that affect the uptake of ammonia by the brain: The blood-brain pH gradient
    • DOI 10.1016/0006-8993(80)90611-3
    • A.H. Lockwood, R.D. Finn, J.A. Campbell, and T.B. Richman Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient Brain Res. 181 1980 259 266 (Pubitemid 10130788)
    • (1980) Brain Research , vol.181 , Issue.2 , pp. 259-266
    • Lockwood, A.H.1    Finn, R.D.2    Campbell, J.A.3    Richman, T.B.4
  • 41
    • 0025979046 scopus 로고
    • Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy
    • A.H. Lockwood, E.W. Yap, and W.H. Wong Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy J. Cereb. Blood Flow Metab. 11 1991 337 341
    • (1991) J. Cereb. Blood Flow Metab. , vol.11 , pp. 337-341
    • Lockwood, A.H.1    Yap, E.W.2    Wong, W.H.3
  • 42
    • 0015317149 scopus 로고
    • Ammonia production in muscle and other tissues
    • J.M. Lowenstein Ammonia production in muscle and other tissues Physiol. Rev. 52 1972 382 414
    • (1972) Physiol. Rev. , vol.52 , pp. 382-414
    • Lowenstein, J.M.1
  • 43
    • 0018191855 scopus 로고
    • The purine nucleotide cycle in skeletal muscle
    • J.M. Lowenstein, and M.N. Goodman The purine nucleotide cycle in skeletal muscle Fed. Proc. 37 1978 2308 2312 (Pubitemid 8373663)
    • (1978) Federation Proceedings , vol.37 , Issue.9 , pp. 2308-2312
    • Lowenstein, J.M.1    Goodman, M.N.2
  • 44
    • 0141815496 scopus 로고    scopus 로고
    • Mathematical modelling of the urea cycle. A numerical investigation into substrate channelling
    • DOI 10.1046/j.1432-1033.2003.03783.x
    • A.D. Maher, P.W. Kuchel, F. Ortega, P. de Atauri, J. Centelles, and M. Cascante Mathematical modelling of the urea cycle. A numerical investigation into substrate channelling Eur. J. Biochem. 270 2003 3953 3961 (Pubitemid 37193872)
    • (2003) European Journal of Biochemistry , vol.270 , Issue.19 , pp. 3953-3961
    • Maher, A.D.1    Kuchel, P.W.2    Ortega, F.3    De Atauri, P.4    Centelles, J.5    Cascante, M.6
  • 45
    • 0017579832 scopus 로고
    • Glutamine synthetase: Glial localization in brain
    • A. Martinez-Hernandez, K.P. Bell, and M.D. Norenberg Glutamine synthetase: glial localization in brain Science 195 1977 1356 1358 (Pubitemid 8056735)
    • (1977) Science , vol.195 , Issue.4284 , pp. 1356-1358
    • Martinez Hernandez, A.1    Bell, K.P.2    Norenberg, M.D.3
  • 46
    • 0028051606 scopus 로고
    • Hepatic glutaminase mRNA is confined to part of the urea cycle domain in the adult rodent liver lobule
    • DOI 10.1016/0014-5793(94)01230-X
    • A.F.M. Moorman, P.A. de Boer, M. Watford, M.A. Dingemanse, and W.H. Lamers Hepatic glutaminase mRNA is confined to part of the urea cycle domain in the adult rodent liver lobule FEBS Lett. 356 1994 76 80 (Pubitemid 24374036)
    • (1994) FEBS Letters , vol.356 , Issue.1 , pp. 76-80
    • Moorman, A.F.M.1
  • 47
    • 0018382256 scopus 로고
    • Fine structural localization of glutamine synthetase in astrocytes of rat brain
    • DOI 10.1016/0006-8993(79)90071-4
    • M.D. Norenberg, and A. Martinez-Hernandez Fine structural localization of glutamine synthetase in astrocytes of rat brain Brain Res 161 1979 303 310 (Pubitemid 9087410)
    • (1979) Brain Research , vol.161 , Issue.2 , pp. 303-310
    • Norenberg, M.D.1    Martinez-Hernandez, A.2
  • 48
    • 0002726753 scopus 로고
    • Studies on the mechanism of glutamine synthesis; Isolation and properties of the enzyme from sheep brain
    • V. Pamiljans, P.R. Krishnaswamy, G. Dumville, and A. Meister Studies on the mechanism of glutamine synthesis; isolation and properties of the enzyme from sheep brain Biochemistry 1 1962 153 158
    • (1962) Biochemistry , vol.1 , pp. 153-158
    • Pamiljans, V.1    Krishnaswamy, P.R.2    Dumville, G.3    Meister, A.4
  • 50
    • 0019581651 scopus 로고
    • 13N-ammonia from blood to brain. A new regional residue detection model
    • 13N-ammonia from blood to brain. A new regional residue detection model Circ. Res. 48 1981 913 937 (Pubitemid 11126080)
    • (1981) Circulation Research , vol.48 , Issue.6 , pp. 913-937
    • Raichle, M.E.1    Larson, K.B.2
  • 52
    • 54249128893 scopus 로고    scopus 로고
    • MR imaging findings in hepatic encephalopathy
    • A. Rovira, J. Alonso, and J. Córdoba MR imaging findings in hepatic encephalopathy Am. J. Neuroradiol. 29 2008 1612 1621
    • (2008) Am. J. Neuroradiol. , vol.29 , pp. 1612-1621
    • Rovira, A.1    Alonso, J.2    Córdoba, J.3
  • 53
    • 0014806328 scopus 로고
    • Identification of l-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine
    • W.B. Rowe, and A. Meister Identification of l-methionine-S-sulfoximine as the convulsant isomer of methionine sulfoximine Proc. Natl. Acad. Sci. U.S.A. 66 1970 500 506
    • (1970) Proc. Natl. Acad. Sci. U.S.A. , vol.66 , pp. 500-506
    • Rowe, W.B.1    Meister, A.2
  • 55
    • 0017804298 scopus 로고
    • The purine nucleotide cycle. Studies of ammonia production and interconversions of adenine and hypoxanthine nucleotides and nucleosides by rat brain in situ
    • V. Schultz, and J.M. Lowenstein The purine nucleotide cycle. Studies of ammonia production and interconversions of adenine and hypoxanthine nucleotides and nucleosides by rat brain in situ J. Biol. Chem. 253 1978 1938 1943 (Pubitemid 8299519)
    • (1978) Journal of Biological Chemistry , vol.253 , Issue.6 , pp. 1938-1943
    • Schultz, V.1    Lowenstein, J.M.2
  • 57
    • 60449086224 scopus 로고    scopus 로고
    • Backflux of ammonia from brain to blood in human subjects with and without hepatic encephalopathy
    • M. Sørensen, O.L. Munk, and S. Keiding Backflux of ammonia from brain to blood in human subjects with and without hepatic encephalopathy Metab. Brain Dis. 24 2009 237 242
    • (2009) Metab. Brain Dis. , vol.24 , pp. 237-242
    • Sørensen, M.1    Munk, O.L.2    Keiding, S.3
  • 58
    • 77955283331 scopus 로고    scopus 로고
    • On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndrome
    • J.R. Treberg, M.E. Brosnan, M. Watford, and J.T. Brosnan On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndrome Adv. Enzyme. Reg. 50 2010 34 43
    • (2010) Adv. Enzyme. Reg. , vol.50 , pp. 34-43
    • Treberg, J.R.1    Brosnan, M.E.2    Watford, M.3    Brosnan, J.T.4
  • 59
    • 0026298781 scopus 로고
    • The urea cycle: A two-compartment system
    • M. Watford The urea cycle: a two-compartment system Essays Biochem. 26 1991 49 58
    • (1991) Essays Biochem. , vol.26 , pp. 49-58
    • Watford, M.1
  • 60
    • 0025348055 scopus 로고
    • Distribution of hepatic glutaminase activity and mRNA in perivenous and periportal rat hepatocytes
    • M. Watford, and E.M. Smith Distribution of hepatic glutaminase activity and mRNA in perivenous and periportal rat hepatocytes Biochem. J. 267 1990 265 267 (Pubitemid 20122667)
    • (1990) Biochemical Journal , vol.267 , Issue.1 , pp. 265-267
    • Watford, M.1    Smith, E.M.2
  • 61
    • 0014082605 scopus 로고
    • The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver
    • D.H. Williamson, P. Lund, and H.A. Krebs The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver Biochem. J. 103 1967 514 527
    • (1967) Biochem. J. , vol.103 , pp. 514-527
    • Williamson, D.H.1    Lund, P.2    Krebs, H.A.3
  • 62
    • 35448961690 scopus 로고    scopus 로고
    • The anaplerotic flux and ammonia detoxification in hepatic encephalopathy
    • DOI 10.1007/s11011-007-9069-y
    • C. Zwingmann The anaplerotic flux and ammonia detoxification in hepatic encephalopathy Metab. Brain Dis. 22 2007 235 249 (Pubitemid 47624321)
    • (2007) Metabolic Brain Disease , vol.22 , Issue.3-4 , pp. 235-249
    • Zwingmann, C.1


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