Neurophysiological process - Circadian rhythm

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Circadian rhythm

Circadian rhythms are 24-h oscillations in behavior and physiology, which are internally generated and function to anticipate the environmental changes associated with the solar day. In mammals, the circadian system is organized in a hierarchical manner, in which a master pacemaker in the suprachiasmatic nucleus (SCN) regulates downstream oscillators in peripheral tissues [1]. The clock mechanism in the SCN consists of a network of transcriptional-translational feedback loops that drive rhythmic 24-h expression patterns of core clock components. The positive feedback loop includes the key circadian rhythm regulators Clock homolog (CLOCK) and Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) [2], [3]. BMAL1 forms heterodimers with CLOCK and Neuronal PAS domain protein 2 (NPAS2) and drives transcription of Period homologs 1, 2, 3 (PER1, PER2, PER3) and Cryptochromes 1 and 2 (CRY1, CRY2) [4], [5], [6]. Negative feedback is achieved by PER:CRY heterodimers that translocate from the cytoplasm to the nucleus to repress their own transcription by acting on the CLOCK:BMAL1 complex [1], [7], [8].

The 24-h molecular clock is governed by post-translational modifications of the key "clock" genes. Casein kinase I delta and Casein kinase I epsilon phosphorylate PER1, PER2, PER3 in the cytoplasm and promote PER1, PER2 and PER3 proteosomal degradation [9], [10], [11]. CRY1 and CRY2 are also phosphorylated by Casein kinase I epsilon [12]. In addition, Casein kinase I epsilon phosphorylates BMAL1 and stimulates its transcriptional activity [12].

Another regulatory loop is induced by CLOCK:BMAL1 heterodimers activating transcription of Nuclear receptor subfamily 1, group D, member 1 (REV-ERB alpha) and RAR-related orphan receptor A (ROR-alpha). REV-ERB alpha and ROR-alpha bind the same elements (ROREs) present in the BMAL1 promoter. ROR-alpha activates transcription of BMAL1, whereas REV-ERB alpha represses the transcription process [1], [13], [14], [15].

Basic helix-loop-helix family, members e40 and e41 (DEC1 (Stra13), DEC2) are another set of circadian rhythm regulators expressed in the suprachiasmic nucleus in a circadian fashion, with a peak in the subjective day. BMAL1 induces DEC1 (Stra13) expression, and DEC1 (Stra13) and DEC2 repress CLOCK: BMAL1-induced transactivation of the PER1 promoter [16], [17].

Expression of the main "clock" genes is mainly regulated by light and changes in metabolic state. Photic entrainment promotes release of L-Glutamic acid and Adenylate cyclase activating polypeptide 1 (PACAP) from the rethinohypothalamic tract. L-Glutamic acid binds to the Glutamate receptor, ionotropic, N-methyl D-aspartate 1 (NMDA receptor) and stimulates Ca('2+) influx in neurons. Elevated Ca('2+) levels promote Calcium/calmodulin-dependent protein kinase II (CaMK II) activation via Calmodulin 2 (Calmodulin). CaMK II phosphorylates cAMP responsive element binding protein 1 (CREB1), which induces PER1 and PER2 transcription [4], [18], [19], [20], [21]. In addition, CAMK II activates the V-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ mitogen-activated protein kinase kinases 1, 2 (MEK1(MAP2K1), MEK2(MAP2K2))/ mitogen-activated protein kinases 1-3 (ERK1/2) pathway [22], [23]. ERK1/2 activation leads to CREB1 phosphorylation, most likely via Ribosomal protein S6 kinase, 90kDa (p90Rsk) [24], [25], [26]. In addition, L-Glutamic acid -induced Ca('2+) increase promotes Nitric oxide synthase 1 (nNOS) activation via Calmodulin binding or probably via CAMK II phosphorylation of nNOS [27], [28]. Released NO activates Guanylate cyclase 1, soluble, which promotes Cyclic GMP production. Cyclic GMP activates Protein kinase, cGMP-dependent, type II (Protein kinase G 2), which phosphorylates CLOCK, thus promoting PER1 expression [29], [30], [31], [32]. Light-induced PACAP signaling also leads to CREB1 phosphorylation and PER1 transcription [33], [34], [35]. NO also activates RAS, dexamethasone-induced 1 (Dexras1). Dexras1 in turn activates ERK1/2 through an unknown mechanism [36], [37].

Changes in metabolic states also regulate the circadian machine. Changes in the ratio of NAD('+) and NADH alter the binding affinity of both CLOCK:BMAL1 and NPAS2:BMAL1 to their DNA recognition sites. The reduced form NADH strongly enhances DNA binding of the CLOCK:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized form NAD('+) -inhibits binding [38]. In addition, NPAS:BMAL1 heterodimers regulate transcription of Lactate dehydrogenase A (LDHA), which catalyzes conversion of Pyruvic acid into (S)-Lactic acid with consumption of NADH and release of NAD('+). Thus, cofactors could be part of a feedback mechanism controlling the molecular clock [5].

References:

  1. Ko CH, Takahashi JS
    Molecular components of the mammalian circadian clock. Human molecular genetics 2006 Oct 15;15 Spec No 2:R271-7
  2. Hogenesch JB, Gu YZ, Jain S, Bradfield CA
    The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proceedings of the National Academy of Sciences of the United States of America 1998 May 12;95(10):5474-9
  3. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA
    Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 2000 Dec 22;103(7):1009-17
  4. Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P
    Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proceedings of the National Academy of Sciences of the United States of America 2002 May 28;99(11):7728-33
  5. Wang GK, Sehgal A
    Signaling components that drive circadian rhythms. Current opinion in neurobiology 2002 Jun;12(3):331-8
  6. Dudley CA, Erbel-Sieler C, Estill SJ, Reick M, Franken P, Pitts S, McKnight SL
    Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science (New York, N.Y.) 2003 Jul 18;301(5631):379-83
  7. Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM
    mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 1999 Jul 23;98(2):193-205
  8. Kondratov RV, Chernov MV, Kondratova AA, Gorbacheva VY, Gudkov AV, Antoch MP
    BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes & development 2003 Aug 1;17(15):1921-32
  9. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM
    Posttranslational mechanisms regulate the mammalian circadian clock. Cell 2001 Dec 28;107(7):855-67
  10. Miyazaki K, Mezaki M, Ishida N
    The role of phosphorylation and degradation of hPER protein oscillation in normal human fibroblasts. Novartis Foundation symposium 2003;253:238-48; discussion 249
  11. Miyazaki K, Nagase T, Mesaki M, Narukawa J, Ohara O, Ishida N
    Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. The Biochemical journal 2004 May 15;380(Pt 1):95-103
  12. Eide EJ, Vielhaber EL, Hinz WA, Virshup DM
    The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. The Journal of biological chemistry 2002 May 10;277(19):17248-54
  13. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U
    The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 2002 Jul 26;110(2):251-60
  14. Yin L, Lazar MA
    The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Molecular endocrinology (Baltimore, Md.) 2005 Jun;19(6):1452-9
  15. Guillaumond F, Dardente H, Giguère V, Cermakian N
    Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. Journal of biological rhythms 2005 Oct;20(5):391-403
  16. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K
    Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 2002 Oct 24;419(6909):841-4
  17. Sato F, Kawamoto T, Fujimoto K, Noshiro M, Honda KK, Honma S, Honma K, Kato Y
    Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation. Interaction with BMAL1. European journal of biochemistry / FEBS 2004 Nov;271(22):4409-19
  18. Yokota S, Yamamoto M, Moriya T, Akiyama M, Fukunaga K, Miyamoto E, Shibata S
    Involvement of calcium-calmodulin protein kinase but not mitogen-activated protein kinase in light-induced phase delays and Per gene expression in the suprachiasmatic nucleus of the hamster. Journal of neurochemistry 2001 Apr;77(2):618-27
  19. Akiyama M, Minami Y, Nakajima T, Moriya T, Shibata S
    Calcium and pituitary adenylate cyclase-activating polypeptide induced expression of circadian clock gene mPer1 in the mouse cerebellar granule cell culture. Journal of neurochemistry 2001 Aug;78(3):499-508
  20. Gau D, Lemberger T, von Gall C, Kretz O, Le Minh N, Gass P, Schmid W, Schibler U, Korf HW, Schütz G
    Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock. Neuron 2002 Apr 11;34(2):245-53
  21. Tischkau SA, Mitchell JW, Tyan SH, Buchanan GF, Gillette MU
    Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. The Journal of biological chemistry 2003 Jan 10;278(2):718-23
  22. Butcher GQ, Doner J, Dziema H, Collamore M, Burgoon PW, Obrietan K
    The p42/44 mitogen-activated protein kinase pathway couples photic input to circadian clock entrainment. The Journal of biological chemistry 2002 Aug 16;277(33):29519-25
  23. Coogan AN, Piggins HD
    MAP kinases in the mammalian circadian system--key regulators of clock function. Journal of neurochemistry 2004 Aug;90(4):769-75
  24. Obrietan K, Impey S, Storm DR
    Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature neuroscience 1998 Dec;1(8):693-700
  25. Dziema H, Oatis B, Butcher GQ, Yates R, Hoyt KR, Obrietan K
    The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. The European journal of neuroscience 2003 Apr;17(8):1617-27
  26. Butcher GQ, Lee B, Hsieh F, Obrietan K
    Light- and clock-dependent regulation of ribosomal S6 kinase activity in the suprachiasmatic nucleus. The European journal of neuroscience 2004 Feb;19(4):907-15
  27. Agostino PV, Ferreyra GA, Murad AD, Watanabe Y, Golombek DA
    Diurnal, circadian and photic regulation of calcium/calmodulin-dependent kinase II and neuronal nitric oxide synthase in the hamster suprachiasmatic nuclei. Neurochemistry international 2004 Jun;44(8):617-25
  28. Golombek DA, Agostino PV, Plano SA, Ferreyra GA
    Signaling in the mammalian circadian clock: the NO/cGMP pathway. Neurochemistry international 2004 Nov;45(6):929-36
  29. Weber ET, Gannon RL, Rea MA
    cGMP-dependent protein kinase inhibitor blocks light-induced phase advances of circadian rhythms in vivo. Neuroscience letters 1995 Sep 15;197(3):227-30
  30. Ferreyra GA, Golombek DA
    Rhythmicity of the cGMP-related signal transduction pathway in the mammalian circadian system. American journal of physiology. Regulatory, integrative and comparative physiology 2001 May;280(5):R1348-55
  31. Tischkau SA, Weber ET, Abbott SM, Mitchell JW, Gillette MU
    Circadian clock-controlled regulation of cGMP-protein kinase G in the nocturnal domain. The Journal of neuroscience : the official journal of the Society for Neuroscience 2003 Aug 20;23(20):7543-50
  32. Tischkau SA, Mitchell JW, Pace LA, Barnes JW, Barnes JA, Gillette MU
    Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock. Neuron 2004 Aug 19;43(4):539-49
  33. Kopp M, Meissl H, Korf HW
    The pituitary adenylate cyclase-activating polypeptide-induced phosphorylation of the transcription factor CREB (cAMP response element binding protein) in the rat suprachiasmatic nucleus is inhibited by melatonin. Neuroscience letters 1997 May 23;227(3):145-8
  34. von Gall C, Duffield GE, Hastings MH, Kopp MD, Dehghani F, Korf HW, Stehle JH
    CREB in the mouse SCN: a molecular interface coding the phase-adjusting stimuli light, glutamate, PACAP, and melatonin for clockwork access. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998 Dec 15;18(24):10389-97
  35. Hannibal J
    Neurotransmitters of the retino-hypothalamic tract. Cell and tissue research 2002 Jul;309(1):73-88
  36. Cismowski MJ, Ma C, Ribas C, Xie X, Spruyt M, Lizano JS, Lanier SM, Duzic E
    Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration. The Journal of biological chemistry 2000 Aug 4;275(31):23421-4
  37. Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH
    Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 2000 Oct;28(1):183-93
  38. Rutter J, Reick M, Wu LC, McKnight SL
    Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science (New York, N.Y.) 2001 Jul 20;293(5529):510-4

  1. Ko CH, Takahashi JS
    Molecular components of the mammalian circadian clock. Human molecular genetics 2006 Oct 15;15 Spec No 2:R271-7
  2. Hogenesch JB, Gu YZ, Jain S, Bradfield CA
    The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proceedings of the National Academy of Sciences of the United States of America 1998 May 12;95(10):5474-9
  3. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA
    Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 2000 Dec 22;103(7):1009-17
  4. Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P
    Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proceedings of the National Academy of Sciences of the United States of America 2002 May 28;99(11):7728-33
  5. Wang GK, Sehgal A
    Signaling components that drive circadian rhythms. Current opinion in neurobiology 2002 Jun;12(3):331-8
  6. Dudley CA, Erbel-Sieler C, Estill SJ, Reick M, Franken P, Pitts S, McKnight SL
    Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science (New York, N.Y.) 2003 Jul 18;301(5631):379-83
  7. Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM
    mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 1999 Jul 23;98(2):193-205
  8. Kondratov RV, Chernov MV, Kondratova AA, Gorbacheva VY, Gudkov AV, Antoch MP
    BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes & development 2003 Aug 1;17(15):1921-32
  9. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM
    Posttranslational mechanisms regulate the mammalian circadian clock. Cell 2001 Dec 28;107(7):855-67
  10. Miyazaki K, Mezaki M, Ishida N
    The role of phosphorylation and degradation of hPER protein oscillation in normal human fibroblasts. Novartis Foundation symposium 2003;253:238-48; discussion 249
  11. Miyazaki K, Nagase T, Mesaki M, Narukawa J, Ohara O, Ishida N
    Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. The Biochemical journal 2004 May 15;380(Pt 1):95-103
  12. Eide EJ, Vielhaber EL, Hinz WA, Virshup DM
    The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon. The Journal of biological chemistry 2002 May 10;277(19):17248-54
  13. Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U
    The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 2002 Jul 26;110(2):251-60
  14. Yin L, Lazar MA
    The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. Molecular endocrinology (Baltimore, Md.) 2005 Jun;19(6):1452-9
  15. Guillaumond F, Dardente H, Giguère V, Cermakian N
    Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. Journal of biological rhythms 2005 Oct;20(5):391-403
  16. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K
    Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 2002 Oct 24;419(6909):841-4
  17. Sato F, Kawamoto T, Fujimoto K, Noshiro M, Honda KK, Honma S, Honma K, Kato Y
    Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation. Interaction with BMAL1. European journal of biochemistry / FEBS 2004 Nov;271(22):4409-19
  18. Yokota S, Yamamoto M, Moriya T, Akiyama M, Fukunaga K, Miyamoto E, Shibata S
    Involvement of calcium-calmodulin protein kinase but not mitogen-activated protein kinase in light-induced phase delays and Per gene expression in the suprachiasmatic nucleus of the hamster. Journal of neurochemistry 2001 Apr;77(2):618-27
  19. Akiyama M, Minami Y, Nakajima T, Moriya T, Shibata S
    Calcium and pituitary adenylate cyclase-activating polypeptide induced expression of circadian clock gene mPer1 in the mouse cerebellar granule cell culture. Journal of neurochemistry 2001 Aug;78(3):499-508
  20. Gau D, Lemberger T, von Gall C, Kretz O, Le Minh N, Gass P, Schmid W, Schibler U, Korf HW, Schütz G
    Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock. Neuron 2002 Apr 11;34(2):245-53
  21. Tischkau SA, Mitchell JW, Tyan SH, Buchanan GF, Gillette MU
    Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. The Journal of biological chemistry 2003 Jan 10;278(2):718-23
  22. Butcher GQ, Doner J, Dziema H, Collamore M, Burgoon PW, Obrietan K
    The p42/44 mitogen-activated protein kinase pathway couples photic input to circadian clock entrainment. The Journal of biological chemistry 2002 Aug 16;277(33):29519-25
  23. Coogan AN, Piggins HD
    MAP kinases in the mammalian circadian system--key regulators of clock function. Journal of neurochemistry 2004 Aug;90(4):769-75
  24. Obrietan K, Impey S, Storm DR
    Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature neuroscience 1998 Dec;1(8):693-700
  25. Dziema H, Oatis B, Butcher GQ, Yates R, Hoyt KR, Obrietan K
    The ERK/MAP kinase pathway couples light to immediate-early gene expression in the suprachiasmatic nucleus. The European journal of neuroscience 2003 Apr;17(8):1617-27
  26. Butcher GQ, Lee B, Hsieh F, Obrietan K
    Light- and clock-dependent regulation of ribosomal S6 kinase activity in the suprachiasmatic nucleus. The European journal of neuroscience 2004 Feb;19(4):907-15
  27. Agostino PV, Ferreyra GA, Murad AD, Watanabe Y, Golombek DA
    Diurnal, circadian and photic regulation of calcium/calmodulin-dependent kinase II and neuronal nitric oxide synthase in the hamster suprachiasmatic nuclei. Neurochemistry international 2004 Jun;44(8):617-25
  28. Golombek DA, Agostino PV, Plano SA, Ferreyra GA
    Signaling in the mammalian circadian clock: the NO/cGMP pathway. Neurochemistry international 2004 Nov;45(6):929-36
  29. Weber ET, Gannon RL, Rea MA
    cGMP-dependent protein kinase inhibitor blocks light-induced phase advances of circadian rhythms in vivo. Neuroscience letters 1995 Sep 15;197(3):227-30
  30. Ferreyra GA, Golombek DA
    Rhythmicity of the cGMP-related signal transduction pathway in the mammalian circadian system. American journal of physiology. Regulatory, integrative and comparative physiology 2001 May;280(5):R1348-55
  31. Tischkau SA, Weber ET, Abbott SM, Mitchell JW, Gillette MU
    Circadian clock-controlled regulation of cGMP-protein kinase G in the nocturnal domain. The Journal of neuroscience : the official journal of the Society for Neuroscience 2003 Aug 20;23(20):7543-50
  32. Tischkau SA, Mitchell JW, Pace LA, Barnes JW, Barnes JA, Gillette MU
    Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock. Neuron 2004 Aug 19;43(4):539-49
  33. Kopp M, Meissl H, Korf HW
    The pituitary adenylate cyclase-activating polypeptide-induced phosphorylation of the transcription factor CREB (cAMP response element binding protein) in the rat suprachiasmatic nucleus is inhibited by melatonin. Neuroscience letters 1997 May 23;227(3):145-8
  34. von Gall C, Duffield GE, Hastings MH, Kopp MD, Dehghani F, Korf HW, Stehle JH
    CREB in the mouse SCN: a molecular interface coding the phase-adjusting stimuli light, glutamate, PACAP, and melatonin for clockwork access. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998 Dec 15;18(24):10389-97
  35. Hannibal J
    Neurotransmitters of the retino-hypothalamic tract. Cell and tissue research 2002 Jul;309(1):73-88
  36. Cismowski MJ, Ma C, Ribas C, Xie X, Spruyt M, Lizano JS, Lanier SM, Duzic E
    Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration. The Journal of biological chemistry 2000 Aug 4;275(31):23421-4
  37. Fang M, Jaffrey SR, Sawa A, Ye K, Luo X, Snyder SH
    Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON. Neuron 2000 Oct;28(1):183-93
  38. Rutter J, Reick M, Wu LC, McKnight SL
    Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science (New York, N.Y.) 2001 Jul 20;293(5529):510-4

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