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Volumn 265, Issue 3, 1999, Pages 1043-1055

The responses of rat hepatocytes to glucagon and adrenaline. Application of quantified elasticity analysis

Author keywords

Adrenaline; Control analysis; Glucagon; Hepatocyte metabolism; Regulation analysis

Indexed keywords

ADENOSINE TRIPHOSPHATE; ADRENALIN; GLUCAGON; GLUCOSE; GLUCOSE 6 PHOSPHATE; GLYCOGEN; LACTIC ACID; NICOTINAMIDE ADENINE DINUCLEOTIDE; PROTON; PYRUVIC ACID; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE;

EID: 0033231404     PISSN: 00142956     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1432-1327.1999.00820.x     Document Type: Article
Times cited : (30)

References (60)
  • 3
    • 0018527496 scopus 로고
    • Molecular democracy; who shares the controls?
    • 3. Kacser, H. & Burns, J.A. (1979) Molecular democracy; who shares the controls? Biochem. Soc. Trans. 7, 1149-1160.
    • (1979) Biochem. Soc. Trans. , vol.7 , pp. 1149-1160
    • Kacser, H.1    Burns, J.A.2
  • 4
    • 0026802334 scopus 로고
    • Metabolic control analysis, a survey of its theoretical and experimental development
    • 4. Fell, D.A. (1992) Metabolic control analysis, a survey of its theoretical and experimental development. Biochem. J. 286, 313-330.
    • (1992) Biochem. J. , vol.286 , pp. 313-330
    • Fell, D.A.1
  • 6
    • 0024295194 scopus 로고
    • How do external parameters control fluxes and concentrations of metabolites?
    • 6. Kholodenko, B.N. (1988) How do external parameters control fluxes and concentrations of metabolites? FEBS Lets. 232, 383-386.
    • (1988) FEBS Lett. , vol.232 , pp. 383-386
    • Kholodenko, B.N.1
  • 7
    • 0030898874 scopus 로고    scopus 로고
    • Regulation analysis of energy metabolism
    • 7. Brand, M.D. (1997) Regulation analysis of energy metabolism. J. Exp. Biol. 200, 193-202.
    • (1997) J. Exp. Biol. , vol.200 , pp. 193-202
    • Brand, M.D.1
  • 8
    • 0025822783 scopus 로고
    • Quantitative assessment of regulation in metabolic systems
    • 8. Hofmeyr, J.H.S. & Cornish-Bowden, A. (1991) Quantitative assessment of regulation in metabolic systems. Eur. J. Biochem. 200, 223-236.
    • (1991) Eur. J. Biochem. , vol.200 , pp. 223-236
    • Hofmeyr, J.H.S.1    Cornish-Bowden, A.2
  • 9
    • 0027605597 scopus 로고
    • The regulatory strength: How to be precise about regulation and homeostasis
    • 9. Kahn, D. & Westerhoff, H.V. (1993) The regulatory strength: how to be precise about regulation and homeostasis. Acta Biotheoretica 41, 85-96.
    • (1993) Acta Biotheoretica , vol.41 , pp. 85-96
    • Kahn, D.1    Westerhoff, H.V.2
  • 10
    • 0032969639 scopus 로고    scopus 로고
    • Quantifying elasticity analysis - How external effectors cause changes to metabolic systems
    • 10. Ainscow, E.K. & Brand, M.D. (1999) Quantifying elasticity analysis -how external effectors cause changes to metabolic systems. Biosystems 49, 151-159.
    • (1999) Biosystems , vol.49 , pp. 151-159
    • Ainscow, E.K.1    Brand, M.D.2
  • 11
    • 0031661513 scopus 로고    scopus 로고
    • Top-down elasticity analysis and its application to energy metabolism in isolated mitochondria and intact cells
    • 11. Brand, M.D. (1998) Top-down elasticity analysis and its application to energy metabolism in isolated mitochondria and intact cells. Mol. Cell. Biochem. 184, 13-20.
    • (1998) Mol. Cell. Biochem. , vol.184 , pp. 13-20
    • Brand, M.D.1
  • 12
    • 0030574107 scopus 로고    scopus 로고
    • Top down metabolic control analysis
    • 12. Brand, M.D. (1996) Top down metabolic control analysis. J. Theor. Biol. 182, 351-360.
    • (1996) J. Theor. Biol. , vol.182 , pp. 351-360
    • Brand, M.D.1
  • 13
    • 0025238865 scopus 로고
    • A 'top-down' approach to the determination of control coefficients in metabolic control theory
    • 13. Brown, G.C., Hafner, R.P. & Brand, M.D. (1990) A 'top-down' approach to the determination of control coefficients in metabolic control theory. Eur. J. Biochem. 188, 321-325.
    • (1990) Eur. J. Biochem. , vol.188 , pp. 321-325
    • Brown, G.C.1    Hafner, R.P.2    Brand, M.D.3
  • 14
    • 0033179481 scopus 로고    scopus 로고
    • Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes
    • 14. Ainscow, E.K. & Brand, M.D. (1999) Top-down control analysis of ATP turnover, glycolysis and oxidative phosphorylation in rat hepatocytes. Eur. J. Biochem. 263, 671-685.
    • (1999) Eur. J. Biochem. , vol.263 , pp. 671-685
    • Ainscow, E.K.1    Brand, M.D.2
  • 15
    • 0022979755 scopus 로고
    • The involvement of calcium in the stimulation of respiration in isolated rat hepatocytes by adrenergic agonists and glucagon
    • 15. Crompton, M. & Goldstone, T.P. (1986) The involvement of calcium in the stimulation of respiration in isolated rat hepatocytes by adrenergic agonists and glucagon. FEBS Lett. 204, 198-202.
    • (1986) FEBS Lett. , vol.204 , pp. 198-202
    • Crompton, M.1    Goldstone, T.P.2
  • 17
    • 0020972416 scopus 로고
    • Gluconeogenesis and related aspects of glycolysis
    • 17. Hers, H.-G. & Hue, L. (1983) Gluconeogenesis and related aspects of glycolysis. Annu. Rev. Biochem. 52, 617-653.
    • (1983) Annu. Rev. Biochem. , vol.52 , pp. 617-653
    • Hers, H.-G.1    Hue, L.2
  • 18
    • 0015811263 scopus 로고
    • Hormonal control of glycogenolysis and gluconeogenesis in isolated rat liver cells
    • 18. Garrison, J.C. & Haynes, R.C. Jr (1973) Hormonal control of glycogenolysis and gluconeogenesis in isolated rat liver cells. J. Biol Chem. 248, 5333-5343.
    • (1973) J. Biol Chem. , vol.248 , pp. 5333-5343
    • Garrison, J.C.1    Haynes R.C., Jr.2
  • 19
    • 0027363499 scopus 로고
    • Calcium: Its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists
    • 19. Bygrave, F.L. & Benedetti, A. (1993) Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists. Biochem. J. 296, 1-14.
    • (1993) Biochem. J. , vol.296 , pp. 1-14
    • Bygrave, F.L.1    Benedetti, A.2
  • 20
    • 0022537356 scopus 로고
    • Mobilization of intracellular calcium by glucagon and cyclic-AMP analogues in isolated rat hepatocytes
    • 20. Mauger, J.P. & Claret, M. (1986) Mobilization of intracellular calcium by glucagon and cyclic-AMP analogues in isolated rat hepatocytes. FEBS Lett. 195, 106-110.
    • (1986) FEBS Lett. , vol.195 , pp. 106-110
    • Mauger, J.P.1    Claret, M.2
  • 21
    • 0002114258 scopus 로고
    • Measurement of mitochondrial protonmotive force
    • (Brown, G.C. & Cooper, C.E., eds). Oxford University Press, Oxford
    • 21. Brand, M.D. (1995) Measurement of mitochondrial protonmotive force. In Bioenergetics, a Practical Approach (Brown, G.C. & Cooper, C.E., eds), pp. 39-62. Oxford University Press, Oxford.
    • (1995) Bioenergetics, A Practical Approach , pp. 39-62
    • Brand, M.D.1
  • 22
    • 0014082605 scopus 로고
    • The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver
    • 22. Williamson, D.H., Lund, P. & Krebs, H.A. (1967) The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem. J. 103, 514-527.
    • (1967) Biochem. J. , vol.103 , pp. 514-527
    • Williamson, D.H.1    Lund, P.2    Krebs, H.A.3
  • 23
    • 0021836615 scopus 로고
    • The effect of glucagon and adrenergic agonists on intracellular pH in isolated hepatocytes
    • 23. Deutsch, C.J., Kashiwagura, T., Taylor, J., Wilson, D.F. & Erecinska, M. (1985) The effect of glucagon and adrenergic agonists on intracellular pH in isolated hepatocytes. J. Biol. Chem. 260, 6808-6810.
    • (1985) J. Biol. Chem. , vol.260 , pp. 6808-6810
    • Deutsch, C.J.1    Kashiwagura, T.2    Taylor, J.3    Wilson, D.F.4    Erecinska, M.5
  • 24
    • 0032555906 scopus 로고    scopus 로고
    • Errors associated with metabolic control analysis. Application of Monte-Carlo simulation of experimental data
    • 24. Ainscow, E.K. & Brand, M.D. (1998) Errors associated with metabolic control analysis. Application of Monte-Carlo simulation of experimental data. J. Theor. Biol. 194, 233-243.
    • (1998) J. Theor. Biol. , vol.194 , pp. 233-243
    • Ainscow, E.K.1    Brand, M.D.2
  • 25
    • 0028029801 scopus 로고
    • Quantitative determination of the regulation of oxidative phosphorylation by cadmium in potato tuber mitochondria
    • 25. Kesseler, A. & Brand, M.D. (1994) Quantitative determination of the regulation of oxidative phosphorylation by cadmium in potato tuber mitochondria. Eur. J. Biochem. 225, 923-935.
    • (1994) Eur. J. Biochem. , vol.225 , pp. 923-935
    • Kesseler, A.1    Brand, M.D.2
  • 26
    • 0032494282 scopus 로고    scopus 로고
    • Control analysis of systems with reaction blocks that 'cross-talk'
    • 26. Ainscow, E.K. & Brand, M.D. (1998) Control analysis of systems with reaction blocks that 'cross-talk'. Biochim. Biophys. Acta 1366, 284-290.
    • (1998) Biochim. Biophys. Acta , vol.1366 , pp. 284-290
    • Ainscow, E.K.1    Brand, M.D.2
  • 27
  • 28
    • 0025769502 scopus 로고
    • Regulation of liver cell volume and proteolysis by glucagon and insulin
    • 28. Vom Dahl, S., Hallbrucker, C., Lang, F., Gerok, W. & Haussinger, D. (1991) Regulation of liver cell volume and proteolysis by glucagon and insulin. Biochem. J. 278, 771-777.
    • (1991) Biochem. J. , vol.278 , pp. 771-777
    • Vom Dahl, S.1    Hallbrucker, C.2    Lang, F.3    Gerok, W.4    Haussinger, D.5
  • 31
    • 0020317588 scopus 로고
    • The influences of glucagon, epinephrine and adrenergic agents of glycogen phosphorylase-alpha and pyruvate-kinase activities in hepatocytes from juvenile and adult-rabbits
    • 31. Yorek, M.A., Blair, J.B. & Ray, P.D. (1982) The influences of glucagon, epinephrine and adrenergic agents of glycogen phosphorylase-alpha and pyruvate-kinase activities in hepatocytes from juvenile and adult-rabbits. Biochim. Biophys. Acta 717, 143-148.
    • (1982) Biochim. Biophys. Acta , vol.717 , pp. 143-148
    • Yorek, M.A.1    Blair, J.B.2    Ray, P.D.3
  • 32
    • 0018190607 scopus 로고
    • Studies on α-andrenergic activation of hepatic glucose output
    • 32. Blackmore, P.F., Brumley, F.T., Marks, J.L. & Exton, J.H. (1978) Studies on α-andrenergic activation of hepatic glucose output. J. Biol. Chem. 253, 4851-4858.
    • (1978) J. Biol. Chem. , vol.253 , pp. 4851-4858
    • Blackmore, P.F.1    Brumley, F.T.2    Marks, J.L.3    Exton, J.H.4
  • 33
    • 0030687645 scopus 로고    scopus 로고
    • Generalization of the double-modulation method for in situ determination of elasticities
    • 33. Acerenza, L. & Cornish-Bowden, A. (1997) Generalization of the double-modulation method for in situ determination of elasticities. Biochem. J. 327, 217-224.
    • (1997) Biochem. J. , vol.327 , pp. 217-224
    • Acerenza, L.1    Cornish-Bowden, A.2
  • 35
    • 0023682777 scopus 로고
    • Sources of calcium mobilized by glucagon in isolated rat hepatocytes
    • 35. Mine, T., Kojima, I. & Ogata, E. (1988) Sources of calcium mobilized by glucagon in isolated rat hepatocytes. Acta Endocrin. 119, 301-306.
    • (1988) Acta Endocrin. , vol.119 , pp. 301-306
    • Mine, T.1    Kojima, I.2    Ogata, E.3
  • 37
    • 0025319665 scopus 로고
    • Role of calcium ions in regulation of mammalian intra-mitochondrial metabolism
    • 37. McCormack, J.G., Halestrap, A.P. & Denton, R.M. (1990) Role of calcium ions in regulation of mammalian intra-mitochondrial metabolism. Physiol. Rev. 70, 391-425.
    • (1990) Physiol. Rev. , vol.70 , pp. 391-425
    • McCormack, J.G.1    Halestrap, A.P.2    Denton, R.M.3
  • 38
    • 0026012979 scopus 로고
    • Frequency and amplitude enhancement of calcium transients by cyclic-AMP in hepatocytes
    • 38. Schofl, C., Sanchez-Bueno, A., Brabant, G., Cobbold, PH. & Cuthbertson, K.S.R. (1991) Frequency and amplitude enhancement of calcium transients by cyclic-AMP in hepatocytes. Biochem. J. 273, 799-802.
    • (1991) Biochem. J. , vol.273 , pp. 799-802
    • Schofl, C.1    Sanchez-Bueno, A.2    Brabant, G.3    Cobbold, P.H.4    Cuthbertson, K.S.R.5
  • 40
    • 0022481617 scopus 로고
    • Inactivation of basal glycogen-synthase by glucagon and epinephrine in hepatocytes from fed rats
    • 40. Bosch, F., Ciudad, C.J. & Guinovart, J.J. (1986) Inactivation of basal glycogen-synthase by glucagon and epinephrine in hepatocytes from fed rats. FEBS Lett. 200, 47-50.
    • (1986) FEBS Lett. , vol.200 , pp. 47-50
    • Bosch, F.1    Ciudad, C.J.2    Guinovart, J.J.3
  • 41
    • 0024195969 scopus 로고
    • The role of cyclic AMP in rapid and long-term regulation of gluconeogenesis and glycolysis
    • 41. Pilkis, S.J., Claus, T.H. & El-Maghrabi, M.R. (1988) The role of cyclic AMP in rapid and long-term regulation of gluconeogenesis and glycolysis. Adv. Sec. Mess. Phosphoprotein Res. 22, 175-191.
    • (1988) Adv. Sec. Mess. Phosphoprotein Res. , vol.22 , pp. 175-191
    • Pilkis, S.J.1    Claus, T.H.2    El-Maghrabi, M.R.3
  • 42
    • 0022521181 scopus 로고
    • Mechanism of glucagon stimulation of fructose-1,6-bisphosphatase in rat hepatocytes - Involvement of a low-M, activator
    • 42. Casteleijn, E., Van Rooij, H.C.J., Van Berkel, T.J.C. & Koster, J.F. (1986) Mechanism of glucagon stimulation of fructose-1,6-bisphosphatase in rat hepatocytes - involvement of a low-M, activator. FEBS Lett. 201, 193-197.
    • (1986) FEBS Lett. , vol.201 , pp. 193-197
    • Casteleijn, E.1    Van Rooij, H.C.J.2    Van Berkel, T.J.C.3    Koster, J.F.4
  • 43
    • 0021075427 scopus 로고
    • Control of gluconeogenesis - Kinetics of the individual enzymes and the effect of glucagon
    • 43. Groen, A.K., Vervoorn, R.C., Van der Meer, R. & Tager, J.M. (1982) Control of gluconeogenesis - kinetics of the individual enzymes and the effect of glucagon. J. Biol. Chem. 258, 14346-14353.
    • (1982) J. Biol. Chem. , vol.258 , pp. 14346-14353
    • Groen, A.K.1    Vervoorn, R.C.2    Van Der Meer, R.3    Tager, J.M.4
  • 44
    • 0022374494 scopus 로고
    • Studies on the activation of rat-liver pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase by adrenaline and glucagon
    • 44. McCormack, J.G. (1985) Studies on the activation of rat-liver pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase by adrenaline and glucagon. Biochem. J. 231, 597-608.
    • (1985) Biochem. J. , vol.231 , pp. 597-608
    • McCormack, J.G.1
  • 45
    • 0022533272 scopus 로고
    • Hormonal regulation of the tri-carboxylic acid cycle in the isolated perfused rat liver
    • 45. Patel, T.B. (1986) Hormonal regulation of the tri-carboxylic acid cycle in the isolated perfused rat liver. Eur. J. Biochem. 159, 15-22.
    • (1986) Eur. J. Biochem. , vol.159 , pp. 15-22
    • Patel, T.B.1
  • 46
    • 0023546694 scopus 로고
    • Hormonal regulation of fluxes through pyruvate dehydrogenase and the citric acid cycle in mammalian tissues
    • 46. Denton, R.M., McCormack, J.G., Midgley, P.J.W. & Rutter, G.A. (1987) Hormonal regulation of fluxes through pyruvate dehydrogenase and the citric acid cycle in mammalian tissues. Biochem. Soc. Symposium 54, 127-143.
    • (1987) Biochem. Soc. Symposium , vol.54 , pp. 127-143
    • Denton, R.M.1    McCormack, J.G.2    Midgley, P.J.W.3    Rutter, G.A.4
  • 47
    • 0022629939 scopus 로고
    • The stimulation of tri-carboxylic acid-cycle flux by α-adrenergic agonists in perfused rat liver
    • 47. Taylor, W.M., Van de Pol, E. & Bygrave, F.L. (1986) The stimulation of tri-carboxylic acid-cycle flux by α-adrenergic agonists in perfused rat liver. Biochem. J. 233, 321-324.
    • (1986) Biochem. J. , vol.233 , pp. 321-324
    • Taylor, W.M.1    Van De Pol, E.2    Bygrave, F.L.3
  • 48
    • 0025777572 scopus 로고
    • Differential effects of insulin, epinephrine and glucagon on rat hepatocyte mitochondrial activity
    • 48. Mohan, C., Memon, R.A. & Bessman, S.P. (1991) Differential effects of insulin, epinephrine and glucagon on rat hepatocyte mitochondrial activity. Arch. Biochem. Biophys. 287, 18-23.
    • (1991) Arch. Biochem. Biophys. , vol.287 , pp. 18-23
    • Mohan, C.1    Memon, R.A.2    Bessman, S.P.3
  • 49
    • 0023107237 scopus 로고
    • Glucagon treatment of rats activates the respiratory chain of liver at more than one site
    • 49. Halestrap, A.P. (1987) Glucagon treatment of rats activates the respiratory chain of liver at more than one site. Biochim. Biophys. Acta 927, 280-290.
    • (1987) Biochim. Biophys. Acta , vol.927 , pp. 280-290
    • Halestrap, A.P.1
  • 50
    • 0029062803 scopus 로고
    • Proportional activation coefficients during stimulation of oxidative phosphorylation by lactate and pyruvate or by vasopressin
    • 50. Korzeniewski, B., Harper, M.-E. & Brand, M.D. (1995) Proportional activation coefficients during stimulation of oxidative phosphorylation by lactate and pyruvate or by vasopressin. Biochim. Biophys. Acta 1229, 315-322.
    • (1995) Biochim. Biophys. Acta , vol.1229 , pp. 315-322
    • Korzeniewski, B.1    Harper, M.-E.2    Brand, M.D.3
  • 51
    • 0022973622 scopus 로고
    • Control of mitochondrial content of adenine nucleotides by submicromolar calcium concentrations and its relationship to hormonal effects
    • 51. Haynes, R.C. Jr, Picking, R.A. & Zaks, W.J. (1986) Control of mitochondrial content of adenine nucleotides by submicromolar calcium concentrations and its relationship to hormonal effects. J. Biol. Chem. 261, 16121-16125.
    • (1986) J. Biol. Chem. , vol.261 , pp. 16121-16125
    • Haynes R.C., Jr.1    Picking, R.A.2    Zaks, W.J.3
  • 52
    • 0022375606 scopus 로고
    • Contribution of the translocator of adenine nucleotides and the ATP synthase to the control of oxidative phosphorylation and arsenylation in liver mitochondria
    • 52. Moreno-Sanchez, R. (1985) Contribution of the translocator of adenine nucleotides and the ATP synthase to the control of oxidative phosphorylation and arsenylation in liver mitochondria. J. Biol. Chem. 260, 12554-12560.
    • (1985) J. Biol. Chem. , vol.260 , pp. 12554-12560
    • Moreno-Sanchez, R.1
  • 53
    • 0022273551 scopus 로고
    • 2+-binding properties of a unique ATPase inhibitor protein isolated from mitochondria of bovine heart and rat skeletal muscle
    • 2+-binding properties of a unique ATPase inhibitor protein isolated from mitochondria of bovine heart and rat skeletal muscle. Cell Calcium 6, 469-479.
    • (1985) Cell Calcium , vol.6 , pp. 469-479
    • Yamada, E.W.1    Huzel, N.J.2
  • 54
    • 0018632933 scopus 로고
    • The stimulation of mitochondrial uncoupler-dependent ATPase in isolated hepatocytes by catecholamines and glucagon and its relationship to gluconeogenesis
    • 54. Titheredge, M.A., Stringer, J.L. & Haynes, R.C. Jr (1979) The stimulation of mitochondrial uncoupler-dependent ATPase in isolated hepatocytes by catecholamines and glucagon and its relationship to gluconeogenesis. Eur. J. Biochem. 102, 117-124.
    • (1979) Eur. J. Biochem. , vol.102 , pp. 117-124
    • Titheredge, M.A.1    Stringer, J.L.2    Haynes R.C., Jr.3
  • 56
    • 0029094167 scopus 로고
    • Physiological control of metabolic flux: The requirement for multisite modulation
    • 56. Fell, D.A. & Thomas, S. (1995) Physiological control of metabolic flux: the requirement for multisite modulation. Biochem. J. 311, 35-39.
    • (1995) Biochem. J. , vol.311 , pp. 35-39
    • Fell, D.A.1    Thomas, S.2
  • 57
    • 0027301842 scopus 로고
    • A universal method of achieving increases in metabolite production
    • 57. Kacser, H. & Acerenza, L. (1993) A universal method of achieving increases in metabolite production. Eur. J. Biochem. 216, 361-367.
    • (1993) Eur. J. Biochem. , vol.216 , pp. 361-367
    • Kacser, H.1    Acerenza, L.2
  • 58
    • 0027241092 scopus 로고
    • Control of the effective P/O ratio of oxidative phosphorylation in liver-mitochondria and hepatocytes
    • 58. Brand, M.D., Harper, M.-E. & Taylor, H.C. (1993) Control of the effective P/O ratio of oxidative phosphorylation in liver-mitochondria and hepatocytes. Biochem. J. 291, 739-748.
    • (1993) Biochem. J. , vol.291 , pp. 739-748
    • Brand, M.D.1    Harper, M.-E.2    Taylor, H.C.3
  • 59
    • 0027234486 scopus 로고
    • Control of oxidative phosphorylation in liver mitochondria and hepatocytes
    • 59. Brand, M.D., Chien, L.-F. & Rolfe, D.F.S. (1993) Control of oxidative phosphorylation in liver mitochondria and hepatocytes. Biochem. Soc. Trans. 21, 757-762.
    • (1993) Biochem. Soc. Trans. , vol.21 , pp. 757-762
    • Brand, M.D.1    Chien, L.-F.2    Rolfe, D.F.S.3


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