Differential expression of immediate-early genes during synaptic plasticity, seizures and brain injury suggests specific functions for these molecules in brain neurons

  • M. Dragunow


Although the discovery of immediate-early gene expression in brain and spinal cord neurons occured over 6 years ago (Dragunow et al. 1987; Ruppert and Wille 1987; Dragunow and Robertson 1987; Hunt et al. 1987; Morgan et al. 1987; White et al. 1987; Saffen et al. 1988), the functional role of the sub-group that generates DNA-binding proteins (the immediate-early gene proteins, IEGPs) in neurons remains obscure. We have taken a number of approaches to discovering the functions of these proteins including describing the physiological and pathological conditions in which different IEGPs are expressed, and the biochemical pathways (e.g.: neurotransmitters, receptors, second messengers, etc) involved in their expression in particular brain regions after specific inducing stimuli. The goal of this work is to then focus on the functional role of particular IEGPs in particular systems. Using drugs which block IEGP expression by interfering with the biochemical pathway through which they are induced we can initially test the role of a particular IEGP in a non-specific fashion. Subsequently, using antisense DNA technology in vivo to inactivate specific genes (Chiasson et al. 1992), we can directly test the role of a particular IEGP in our test system.


Nerve Growth Factor Granule Cell Status Epilepticus Spinal Cord Neuron Dentate Granule Cell 
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  1. Abraham WC, Dragunow M, Tate WP (1991) The role of immediate-early genes in the stabilization of long-term potentiation. Molecular Neurobiol 5:297–314CrossRefGoogle Scholar
  2. Abraham WC, Mason SE, Demmer J, Williams JM, Richardson CL, Tate WP, Lawlor PA, Dragunow M, (1993) Correlations between immediate-early gene induction and the persistence of longterm potentiation. Neuroscience 56:717–727PubMedCrossRefGoogle Scholar
  3. Auwerx J, Sassone-Corsi P (1991) IP-1: A dominant inhibitor of fos/jun whose activity is modulated by phosphorylation. Cell 64:983–993PubMedCrossRefGoogle Scholar
  4. Baichwal VR, Park A, Tjian R (1991) v-Src and EJ Ras alleviate repression of c-Jun by a cell-specific inhibitor. Nature 352:165–168PubMedCrossRefGoogle Scholar
  5. Bissonnette RP, Echeverri F, Mahboubi A, Green DR (1992) Apoptotic cell death induced by c-myc is inhibited by bel-2. Nature 359:552–553PubMedCrossRefGoogle Scholar
  6. Blanar MA, Rutter WJ (1992) Interaction cloning: identification of a helix-loop-helix zipper protein that interacts with c-fos. Science 256:1014–1017PubMedCrossRefGoogle Scholar
  7. Cao X, Mahjendran R, Guy GR, Tan YH (1992) Protein phosphatase inhibitors induce the sustained expression of the Egr-1 gene and the hyperphosphorylation of its gene product. J Biol Chem 267:12991–12997PubMedGoogle Scholar
  8. Chiasson BJ, Hooper ML, Murphy PR, Robertson HA (1992) Antisense oligonucleotide eliminates in vivo expression of c-fos in mammalian brain. Eur J Pharmacol 227:451–453PubMedCrossRefGoogle Scholar
  9. Choi DW (1990) Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci 10, 8:2493–2451PubMedGoogle Scholar
  10. Demello SR, Jiang C, Lamberti C, Martin SC, Heinrich G (1992) Differential regulation of the nerve growth factor and brain-derived neurotrophic factor genes in L929 mouse fibroblasts. J Neurosci Res 33 4:419–526Google Scholar
  11. Demmer J, Dragunow M, Lawlor PA, Mason SE, Leah JD, Abraham WC, Tate WP (1992) Differential expression of immediate early genes after hippocampal long-term potentiation in awake rats. Mol Brain Res 17:279–286CrossRefGoogle Scholar
  12. Dessi F, Charriaut-Marlangue C, Ben-Ari Y (1992) Anisomycin and cycloheximide protect cerebellar neurons in culture from anoxia. Brain Res 581:323–326PubMedCrossRefGoogle Scholar
  13. Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249:1266–1271PubMedCrossRefGoogle Scholar
  14. Douglas RM, Dragunow M, Robertson HA (1988) High-frequency discharge of dentate granule cells, but not long-term potentiation, induces c-fos protein. Mol Brain Res 4:259–262CrossRefGoogle Scholar
  15. Dragunow M, Williams M, Faull RLM. (1990d) Haloperidol induces fos and related molecules in intrastriatal grafts derived from fetal striatal primordia. Brain Res 530:309–311PubMedCrossRefGoogle Scholar
  16. Dragunow M, Abraham WC, Goulding M, Mason SE, Robertson HA, Faull RLM (1989a) Longterm potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats. Neurosci Lett 101:274–280PubMedCrossRefGoogle Scholar
  17. Dragunow M, Robertson HA (1987a) Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus. Nature 329:441–442PubMedCrossRefGoogle Scholar
  18. Dragunow M, Robertson HA (1987b) Generalized seizures induce c-fos protein(s) in mammalian neurons. Neurosci Lett 82:157–161PubMedCrossRefGoogle Scholar
  19. Dragunow M, Faull RLM (1990) MK-801 induces c-fos protein in thalamic and neocortical neurons of rat brain. Neurosci Lett 113:144–150PubMedCrossRefGoogle Scholar
  20. Dragunow M (1992) Axotomized medial septal-diagonal band neurons express Jun-like immunoreactivity. Mol Brain Res 15:141–144PubMedCrossRefGoogle Scholar
  21. Dragunow M, Robertson HA (1988) Brain injury induces c-fos protein(s) in nerve and glial-like cells in adult mammalian brain. Brain Res 455:295–299PubMedCrossRefGoogle Scholar
  22. Dragunow M, Faull RLM, Jansen KLR (1990a) MK-801, an antagonist of NMDA receptors, inhibits injury-induced c-fos protein accumulation in rat brain. Neurosci Lett 109:128–133PubMedCrossRefGoogle Scholar
  23. Dragunow M, Goulding M, Faull RLM, Ralph R, Mee E, Frith R (1990b) Induction of c-fos mRNA and protein in neurons and glia after traumatic brain injury: pharmacological characterization. Exp Neurol 107:236–248PubMedCrossRefGoogle Scholar
  24. Dragunow M, de Castro D, Faull RLM (1990c) Induction of fos in glia-like cells after focal braininjury but not during wallerian degeneration. Brain Res 527:41–54PubMedCrossRefGoogle Scholar
  25. Dragunow M, Yamada N, Bilkey DK, Lawlor P (1992) Induction of immediate-early gene proteins in dentate granule cells and somatostatin interneurons after hippocampal seizures. Mol Brain Res 13:119–126PubMedCrossRefGoogle Scholar
  26. Dragunow M, Currie RW, Faull RLM, Robertson HA, Jansen K (1989b) Immediate-early genes, kindling and long-term potentiation. Neurosci Biobehav Rev 13 (4):301–313PubMedCrossRefGoogle Scholar
  27. Dragunow M (1990) Presence and induction of Fos B-like immunoreactivity in neural, but non-neural, cells in adult rat brain. Brain Res 553:324–328CrossRefGoogle Scholar
  28. Dragunow M, Faull RLM (1989) Rolipram induces c-fos protein-like immunoreactivity in ependymal and glial-like cells in adult rat brain. Brain Res 501:382–388PubMedCrossRefGoogle Scholar
  29. Dragunow M, Currie RW, Robertson HA, Faull RLM (1989c) Heat shock induces c-fos protein-like immunoreactivity in glial cells in adult rat brain. Exper Neurol 106:105–109CrossRefGoogle Scholar
  30. Dragunow M, Young D, Hughes P, MacGibbon G, Lawlor P, Singleton K, Sirimanne E, Beilharz E, Gluckman P (1993) Is c-jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? Brain Res Mol Brain Res 18:347–52PubMedCrossRefGoogle Scholar
  31. Dragunow M, Hughes P (1993) Differential expression of immediate-early proteins in non-nerve cells after focal brain injury. Int J Devi Neurosci 11:249–55CrossRefGoogle Scholar
  32. Dragunow M, Robertson HA, Robertson GS (1988) Amygdala kindling and c-fos protein(s). Exp Neurol 102:261–263PubMedCrossRefGoogle Scholar
  33. Dragunow M, Robertson GS, Faull RLM, Robertson HA, Jansen K (1990c) D2 dopamine receptor antagonists induce fos and related proteins in rat striatal neurons. Neurosci 37:287–294CrossRefGoogle Scholar
  34. Dragunow M, Logan B, Laverty R. (1991b) 3,4-Methylenedioxymethamphetamine induces Fos-like proteins in rat basal ganglia: reversal with MK 801. Eur J Pharmacol 206:255–258PubMedCrossRefGoogle Scholar
  35. Dragunow M, Leah JD, Faull RLM (1991a) Prolonged and selective induction of fos-related antigen(s) in striatal neurons after 6-hydroxydopamine lesions of the rat substantia nigra pars compacta. Mol Brain Res 10:355–358PubMedCrossRefGoogle Scholar
  36. Dragunow M, Peterson MR, Robertson HA (1987) Presence of c-fos-like immunoreactivity in the adult rat brain. Eur J Pharmacol 135:113–114PubMedCrossRefGoogle Scholar
  37. Ernfors P, Bengzon J, Kokaia Z, Persson H, Lindvall O (1991) Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis. Neuron 7:165–176PubMedCrossRefGoogle Scholar
  38. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69 1:119–128PubMedCrossRefGoogle Scholar
  39. Faden AI, Demediuk P, Scott Panter S, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–799PubMedCrossRefGoogle Scholar
  40. Falkenberg T, Mohammed AK, Henriksson B, Persson H, Winblad B, Lindefors N (1992) Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138:153–156PubMedCrossRefGoogle Scholar
  41. Fanidi A, Harrington EA, Evan GI (1992) Cooperative interaction between c-myc and bel-2 protooncogenes. Nature 359:554–556PubMedCrossRefGoogle Scholar
  42. Funder J (1993) Mineralocorticoids, glucocorticoids, receptors and response elements. Science 259:1132–1133PubMedCrossRefGoogle Scholar
  43. Gall CM, Isackson PJ (1989) Limbic seizures increase neuronal production of messenger RNA for nerve-growth factor. Science 245:758–761PubMedCrossRefGoogle Scholar
  44. Garcia I, Martinou I, Tsujimoto Y, Martinou J-C (1992) Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science 258:302–304PubMedCrossRefGoogle Scholar
  45. Gluckman P, Klempt N, Guan J, Mallard C, Sirimanne E, Dragunow M, Klempt M, Singh K, Williams C, Nikolics K. A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischaemic injury. Biochem Biophys Res Comm 182 (2):593–599Google Scholar
  46. Goc A, Norman SA, Puchacz E, Stachowiak EK, Lukas RJ, Stachowiak MK (1992) A 5′-Flanking region of the bovine tyrosine hydroxylase gene is involved in cell-specific expression, activation of gene transcription by phorbol ester, and transactivation by c-fos and c-jun. Mol and Cell Neurosci 3:383–394CrossRefGoogle Scholar
  47. Goto K, Ishige A, Sekiguchi K, Iizuka S, Sugimoto A, Yuzurihara M, Aburada M, Hosoya E, Kogure K (1990) Effects of cycloheximide on delayed neuronal death in rat hippocampus. Brain Res 534:299–302PubMedCrossRefGoogle Scholar
  48. Gunn AJ, Dragunow M, Faull RLM, Gluckman PD (1990) Effects of hypoxia-ischemia and seizures on neuronal and glial-like c-fos protein levels in the infant rat. Brain Res 531:105–116PubMedCrossRefGoogle Scholar
  49. Hai T, Curran T (1991) Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88:3720–3724PubMedCrossRefGoogle Scholar
  50. Hengerer B, Lindholm D, Heumann R, Rüther U, Wagner EF, Thoenen H (1990). Lesion-induced increase in nerve growth factor mRNA is mediated by c-fos. Proc Natl Acad Sci USA 87:3899–3903PubMedCrossRefGoogle Scholar
  51. Hughes P, Young D, Dragunow M (1993a) MK-801 sensitizes rats to pilocarpine induced limbic seizures and status epilepticus. Neuroreport 4: 314–316PubMedCrossRefGoogle Scholar
  52. Hughes P, Dragunow M (1993) Muscarinic receptor mediated induction of Fos protein in rat brain. Neurosci Lett 150:122–126PubMedCrossRefGoogle Scholar
  53. Hughes P, Lawlor P, Dragunow M (1992) Basal expression of Fos, Fos-related, Jun, and Krox-24 proteins in rat hippocampus. Mol Brain Res 13:355–357PubMedCrossRefGoogle Scholar
  54. Hughes P, Dragunow M, Beilharz E, Lawlor P, Gluckman P (1993b) MK-801 induces immediate-early gene proteins and BDNF mRNA in rat cerebrocortical neurons. Neuroreport 4:183–186PubMedCrossRefGoogle Scholar
  55. Hughes P, Beilharz E, Gluckman P, Dragunow M (1993c) Brain-derived neurotrophic factor is induced as an immediate-early gene following N-methyl-D-aspartate receptor activation. Neuroscience 57:319–328PubMedCrossRefGoogle Scholar
  56. Hunt SP, Pini A, Evan G (1987) Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 328:632–634PubMedCrossRefGoogle Scholar
  57. Hunter T, Karin M (1992) The regulation of transcription by phosphorylation. Cell 70:375–387PubMedCrossRefGoogle Scholar
  58. Jeffery KJ, Abraham WC, Dragunow M, Mason SE (1990) Induction of fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanesthetized rats. Mol Brain Res 8:267–274PubMedCrossRefGoogle Scholar
  59. Joseph R, Li W, Han E (1993) Neuronal death, cytoplasmic calcium and internucleosomal DNA fragmentation: evidence for DNA fragments being released from cells. Mol Brain Res 17:70–76PubMedCrossRefGoogle Scholar
  60. Kerpolla TK, Curran T (1991) Fos-Jun heterodimers and jun homodimers bend DNA in opposite directions: implications for transcription factor cooperativity. Cell 66:317–326CrossRefGoogle Scholar
  61. Koh J-Y, Cotman CW (1992) Programmed cell death: its possible contribution to neurotoxicity mediated by calcium channel antagonists. Brain Res 587:233–240PubMedCrossRefGoogle Scholar
  62. Kovary K, Bravo R (1991) Expression of different jun and fos proteins during the G0-to-G1 transition in mouse fibroblasts: in vitro and in vivo associations. Mol & Cell Biol 11:2451–2459Google Scholar
  63. Kromer LF (1986) Nerve growth factor treatment after brain injury prevents neuronal death. Science 235:214–216CrossRefGoogle Scholar
  64. Leah JD, Herdegen T, Dragunow M, Murahov A, Bravo R (1993) Expression of immediate-early gene proteins following axotomy and inhibition of axonal transport in the rat CNS. Neuroscience 57:53–66PubMedCrossRefGoogle Scholar
  65. Lerea LS, Butler LS, McNamara JO (1992) NMDA and Non-NMDA Receptor-mediated increase of c-fos mRNA in dentate gyrus neurons involves calcium influx via different routes. J Neurosci 12(8):2973–2981PubMedGoogle Scholar
  66. MacGibbon G, Lawlor P, Bravo R, Dragunow M (1994) Clozapine and haloperidol produce a differential pattern of immediate-early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of calleja. Mol Brain Res 23:21–32PubMedCrossRefGoogle Scholar
  67. Martin DP, Schmidt RE, DeStefano PS, Lowry OH, Carter JG, Johnson EM Jr. (1988) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol 106:829–844PubMedCrossRefGoogle Scholar
  68. Moochetti I, De Bemardi MA, Szekely AM, Alho H, Brooker G, Costa E (1989) Regulation of nerve growth factor biosynthesis by beta-adrenergic receptor activation in astrocytoma cells: a potential role of c-fos protein. Proc Natl Acad Sci USA 86:3891–3895CrossRefGoogle Scholar
  69. Morgan JI, Cohen DR, Hampstead JL, Curran T (1987) Mapping patterns of c-fos expression in the CNS after seizure. Science 237:192–197PubMedCrossRefGoogle Scholar
  70. Morgan JI, Curran T (1991) Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Ann Rev Neurosci 14:421–451PubMedCrossRefGoogle Scholar
  71. Nakabeppu Y, Nathans D (1991) A naturally occurring truncated form of FosB that inhibits Fos/Jun transcriptional activity. Cell 64: 751–759PubMedCrossRefGoogle Scholar
  72. Najilerahim A, Showeil DGL, Pearson RCA (1991) Transient increase in glutamic acid decarboxylase mRNA in the cerebral cortex following focal cortical lesion in the rat. Exp Brain Res 87:113–118Google Scholar
  73. Olenik C, Lais A, Meyer DK (1991) Effects of unilateral cortex lesions on gene expression of rat cortical cholecystokinin neurons. Mol Brain Res 10:259–265PubMedCrossRefGoogle Scholar
  74. Papas S, Crépel V, Hasboun D, Jorquera I, Chinestra P, Ben-Ari Y (1992) Cycloheximide reduces the effects of anoxic insult in vivo and in vitro. Eur J Neurosci 4:758–765PubMedCrossRefGoogle Scholar
  75. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR (1991) Phosphorylation of c-jun mediated by MAP kinases. Nature 353:345–349CrossRefGoogle Scholar
  76. Riabowol KT, Vosatka RJ, Ziff EB, Lamb NJ, Feramisco JR (1988) Microinjection of fos-specific antibodies blocks DNA synthesis in fibroblast cells. Mol Cell Biol 8:1670–1676PubMedGoogle Scholar
  77. Richardson CL, Tate WP, Mason SE, Lawlor PA, Dragunow M, Abraham WC (1992) Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus. Brain Res 580:147–154PubMedCrossRefGoogle Scholar
  78. Robertson GS, Herrera DG, Dragunow M, Robertson HA (1989) L-dopa activates c-fos in the striatum ipsilateral to a 6-hydroxydopamine lesion of the substantia nigra. Eur J Pharmacol 159:99–100PubMedCrossRefGoogle Scholar
  79. Rosen JB, Cain CJ, Weiss S, Post RM (1992) Alterations in mRNA of enkephalin, dynorphin and thyrotropin releasing hormone during amygdala kindling: an in situ hybridization study. Mol Brain Res 15:247–255PubMedCrossRefGoogle Scholar
  80. Ruppert C, Wille W (1987) Proto-oncogene c-fos is highly induced by disruption of neonatal but not of mature brain tissue. Mol Brain Res 2:51–56CrossRefGoogle Scholar
  81. Saffen DW, Cole AJ, Worley PF, Christy BA, Ryder K, Baraban JM (1988) Convulsant-induced increase in transcription factor messenger RNAs in rat brain. Proc Natl Acad Sci USA 85:7795–7799PubMedCrossRefGoogle Scholar
  82. Schreiber SS, Najm I, Tocco G, Baudry M (1992) Cycloheximide treatment prevents neurotoxicity and c-fos expression in adult rat brain following kainic acid treatment. Society for Neurose, Abstracts 18:81Google Scholar
  83. Schüle R, Rangarajan P, Yang N, Kliewer S, Ransone LJ, Bolado J, Verma IM, Evans RM (1991) Retinoic acid is a negative regulator of AP-1-responsive genes. Proc Natl Acad Sci USA 88:6092–6096PubMedCrossRefGoogle Scholar
  84. Seyfert VL, McMahon SB, Glenn WD, Yellen AJ, Sukhatme VP, Cao X, Monroe JG (1990) Methylation of an immediate-early inducible gene as a mechanism for B Cell tolerance induction. Science 250:797–799PubMedCrossRefGoogle Scholar
  85. Shi Y, Glynn JM, Guilbert LJ, Cotter TG, Bissonnette RP, Green DR (1992) Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257:212–217PubMedCrossRefGoogle Scholar
  86. Shigeno T, Yamasaki Y, Kato G, Kusaka K, Mima T, Takakura K, Graham DI, Furukawa S (1990) Reduction of delayed neuronal death by inhibition of protein synthesis. Neurosci Lett 120:117–119PubMedCrossRefGoogle Scholar
  87. Shigeno T, Mima T, Takakura K, Graham DI, Kato G, Hashimoto Y, Furukawa S (1991) Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci 11(9):2914–2919PubMedGoogle Scholar
  88. Sonnenberg JL, Rauscher FJ (III), Morgan JI, Curran T (1989) Regulation of proenkephalin by Fos and Jun. Science 246:1622–1624PubMedCrossRefGoogle Scholar
  89. Sutula T, Cavazos J, Golarai G (1992) Alteration of long-lasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital. J Neurosci 12(11):4173–4187PubMedGoogle Scholar
  90. Weiser M, Baker H, Wessel TC, Joh TH (1993) Axotomy-induced differential gene induction in neurons of the locus ceruleus and substantia nigra. Mol Brain Res 17:319–327PubMedCrossRefGoogle Scholar
  91. Wetmore C, Cao Y, Petterson RF, Olson L (1991) Brain-derived neurotrophic factor: Subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies. Proc Natl Acad Sci USA 88:9843–9847PubMedCrossRefGoogle Scholar
  92. Williams J, Dragunow M, Lawlor P, Mason B, Abraham W, Leah J, Bravo R, Demmer J, Tate W (1994) Krox 20 may play a key role in the stabilization of long-term potentiation. Mol Brain Res (in press)Google Scholar
  93. White JD, Gall CM (1987) Differential regulation of neuropeptide and proto-oncogene mRNA content in the hippocampus following recurrent seizures. Mol Brain Res 3:21–29CrossRefGoogle Scholar
  94. Xanthoudakis S, Curran T (1992) Identification and characterization of Ref-1, a nuclear protein that facilitates AP-1 DNA-binding activity. EMBO J 11:653–665PubMedGoogle Scholar
  95. Young D, Dragunow M (1993) Non-NMDA glutamate receptors are involved in the maintenance of status epilepticus. Neuroreport 5:81–83PubMedCrossRefGoogle Scholar
  96. Zhang X-K, Wills KN, Husmann M, Hermann T, Pfahl M (1991) Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities. Mol and Cell Biol 11:6016–6025Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • M. Dragunow
    • 1
  1. 1.Department of Pharmacology, School of MedicineThe University of AucklandAucklandNew Zealand

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