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Hormonal Regulation of Cerebellar Development and Its Disorders

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Development of the Cerebellum from Molecular Aspects to Diseases

Part of the book series: Contemporary Clinical Neuroscience ((CCNE))

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Abstract

Cerebellar development and plasticity involves in various epigenetic processes that activate specific genes at different time points. Such epigenetic influences include hormonal signals from endocrine cells. Various hormone receptors are expressed in the cerebellum, and cerebellar function is greatly influenced by hormonal status. The aim of this chapter is to introduce several key features of hormones and their receptors involved in the regulation of cerebellar development and plasticity. Furthermore, cerebellar developmental disorders caused by aberrant hormonal status are also discussed. This chapter also covers the effect of endocrine-disrupting chemicals that may alter hormone functions in the cerebellum.

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References

  1. Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, Hoshino M, Joyner AL, Kano M, Kilpatrick DL, Koibuchi N, Marino S, Martinez S, Millen KJ, Millner TO, Miyata T, Parmigiani E, Schilling K, Sekerková G, Sillitoe RV, Sotelo C, Uesaka N, Wefers A, Wingate RJ, Hawkes R. Consensus paper: cerebellar development. Cerebellum. 2016;15:789–828.

    Article  PubMed  Google Scholar 

  2. Suzuki T, Abe T. Thyroid hormone transporters in the brain. Cerebellum. 2008;7:75–83.

    Article  CAS  PubMed  Google Scholar 

  3. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tetel MJ, Auger AP, Charlier TD. Who’s in charge? Nuclear receptor coactivator and corepressor function in brain and behavior. Front Neuroendocrinol. 2009;30:328–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006;126:789–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Qin J, Suh JM, Kim BJ, Yu CT, Tanaka T, Kodama T, Tsai MJ, Tsai SY. The expression pattern of nuclear receptors during cerebellar development. Dev Dyn. 2007;236:810–20.

    Article  CAS  PubMed  Google Scholar 

  7. Koibuchi N, Chin WW. Thyroid hormone action and brain development. Trends Endocrinol Metab. 2000;11:123–8.

    Article  CAS  PubMed  Google Scholar 

  8. Koibuchi N, Jingu H, Iwasaki T, Chin WW. Current perspectives on the role of thyroid hormone in growth and development of cerebellum. Cerebellum. 2003;2:279–89.

    Article  CAS  PubMed  Google Scholar 

  9. Koibuchi N. The role of thyroid hormone on functional organization in the cerebellum. Cerebellum. 2013;12:304–6.

    Article  CAS  PubMed  Google Scholar 

  10. Wassner AJ, Brown RS. Hypothyroidism in the newborn pariod. Curr Opin Endocrinol Diates Obes. 2013;20:449–54.

    Article  CAS  Google Scholar 

  11. Hedges VL, Ebner TJ, Meisel RL, Mermelstein PG. The cerebellum as a target for estrogen action. Front Neuroendocrinol. 2012;33:403–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tsutsui K. Neurosteroid biosynthesis and action during cerebellar development. Cerebellum. 2012;11:414–5.

    Article  CAS  PubMed  Google Scholar 

  13. Constantinof A, Moisiadis VG, Matthews SG. Programming of stress pathways: a transgenerational perspective. J Steroid Biochem Mol Biol. 2016;160:175–80.

    Article  CAS  PubMed  Google Scholar 

  14. Schutter DJLG. The cerebello-hypothalamic-pituitary-adrenal axis dysregulation hypothesis in depressive disorder. Med Hypotheses. 2012;79:779–83.

    Article  CAS  PubMed  Google Scholar 

  15. Ibhazehiebo K, Koibuchi N. Impact of endocrine disrupting chemicals on thyroid function and brain development. Expert Rev Endocr Metab. 2014;9:579–91.

    Article  CAS  Google Scholar 

  16. Calvo R, Obregon MJ, de Ruiz OC, del Escobar RF, de Morreale Escobar G. Congenital hypothyroidism, as studied in rats. J Clin Invest. 1990;86:889–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guadano-Ferraz A, Obregon MJ, St Germain DL, Bernal J. The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci U S A. 1997;94:10391–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Heuer H, Maier MK, Iden S, Mittag J, Friesema ECH, Visser TJ, et al. The monocarboxylate transporter8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations. Endocrinology. 2005;146:1701–6.

    Article  CAS  PubMed  Google Scholar 

  19. Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev. 1993;14:184–93.

    CAS  PubMed  Google Scholar 

  20. Bradley DJ, Towle HC, Young WS III. Spatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system. J Neurosci. 1992;12:2288–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kilby MD, Gittoes N, McCabe C, Verhaeg J, Franklyn JA. Expression of thyroid receptor isoforms in the human fetal central nervous system and the effects of intrauterine growth restriction. Clin Endocrinol. 2000;53:469–77.

    Article  CAS  Google Scholar 

  22. Koibuchi N. Animal models to study thyroid hormone action in cerebellum. Cerebellum. 2009;8:89–97.

    Article  CAS  PubMed  Google Scholar 

  23. Portella AC, Carvalho F, Faustino L, Wondisford FE, OrtigaCarvalho TM, Gomes FC. Thyroid hormone receptor β mutation causes severe impairment of cerebellar development. Mol Cell Neurosci. 2010;44:68–77.

    Article  CAS  PubMed  Google Scholar 

  24. Venero C, Guadaño-Ferraz A, Herrero AI, Nordström K, Manzano J, de Escobar GM, Bernal J, Vennström B. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor α1 can be ameliorated by T3 treatment. Genes Dev. 2005;19:2152–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fauquier T, Chatonnet F, Picou F, Richard S, Fossat N, Aguilera N, Lamonerie T, Flamant F. Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development. Development. 2014;141:166–75.

    Article  CAS  PubMed  Google Scholar 

  26. Yu L, Iwasaki T, Xu M, Lesmana R, Xiong Y, Shimokawa N, Chin WW, Koibuchi N. Aberrant cerebellar development of transgenic mice expressing dominant-negative thyroid hormone receptor in cerebellar Purkinje cells. Endocrinology. 2015;156:1565–76.

    Article  CAS  PubMed  Google Scholar 

  27. Beck-Peccoz P, Chatterjee VKK. The variable clinica phenotype in thyroid hormone resistance syndrome. Thyroid. 1994;4:225–32.

    Article  CAS  PubMed  Google Scholar 

  28. Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nat Rev Endocrinol. 2014;10:582–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmahmann JD. The role of the cerebellum in cognition and emotion: personal reflections since 1982 on the Dysmetria of thought hypothesis, and its historical evolution from theory to therapy. Neuropsychol Rev. 2010;20:236–60.

    Article  PubMed  Google Scholar 

  30. Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE. Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet. 2005;77:41–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wirth EK, Schweizer U, Köhrle J. Transport of thyroid hormone in brain. Front Endocrinol. 2014;5:98.

    Article  Google Scholar 

  32. Delbaere J, Vancamp P, Van Herck SL, Bourgeois NM, Green MJ, Wingate RJ, Darras VM. MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development. J Endocrinol. 2017;232:259–72.

    Article  CAS  PubMed  Google Scholar 

  33. Hampl R, Bičíková M, Sosvorová L. Hormones and the blood-brain barrier. Horm Mol Biol Clin Investig. 2015;21:159–64.

    CAS  PubMed  Google Scholar 

  34. Wright CL, Schwarz JS, Dean SL, McCarthy MM. Cellular mechanisms of estradiol-mediated sexual differentiation of the brain. Trends Endocrinol Metab. 2010;21:553–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bakker J, Brock O. Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of oestradiol in female brain development. J Neuroendocrinol. 2010;22:728–35.

    CAS  PubMed  Google Scholar 

  36. Zuloaga DG, Puts DA, Jordan CL, Breedlove SM. The role of androgen receptors in the masculinization of brain and behavior: what we’ve learned from the testicular feminization mutation. Horm Behav. 2008;53:613–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gottfried-Blackmore A, Croft G, McEwen BS, Bulloch K. Transcriptional activity of estrogen receptors ERα and ERβ in the EtC.1 cerebellar granule cell line. Brain Res. 2007;1186:41–7.

    Article  CAS  PubMed  Google Scholar 

  38. Ikeda Y, Nagai A. Differential expression of the estrogen receptors alpha and beta during postnatal development of the rat cerebellum. Brain Res. 2006;1083:39–49.

    Article  CAS  PubMed  Google Scholar 

  39. Pérez SE, Chen EY, Mufson EJ. Distribution of estrogen receptor alpha and beta immunoreactive profiles in the postnatal rat brain. Brain Res Dev Brain Res. 2003;145:117–39.

    Article  PubMed  CAS  Google Scholar 

  40. Jakab RL, Wong JK, Belcher SM. Estrogen receptor-ß immunoreactivity in differentiating cells of the developing rat cerebellum. J Comp Neurol. 2001;430:396–409.

    Article  CAS  PubMed  Google Scholar 

  41. Belcher SM. Rapid signaling mechanisms of estrogens in the developing cerebellum. Brain Res Rev. 2008;57:481–92.

    Article  CAS  PubMed  Google Scholar 

  42. Sholl SA, Kim KL. Aromatase, 5-alpha-reductase, and androgen receptor levels in the fetal monkey brain during early development. Neuroendocrinology. 1990;52:94–8.

    Article  CAS  PubMed  Google Scholar 

  43. Lavaque E, Mayen A, Azoitia I, Tene-Sempere M, Garcia-Segura LM. Sex differences, developmental changes, response to injury and cAMP regulation of the mRNA levels of steroidogenic acute regulatory protein, chtochrome p450scc, and aromatase in the olivocerebellar system. J Neurobiol. 2006;66:308–18.

    Article  CAS  PubMed  Google Scholar 

  44. Sakamoto H, Mezaki Y, Shikimi H, Ukena K, Tsutusi K. Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. Endocrinology. 2003;144:4466–77.

    Article  CAS  PubMed  Google Scholar 

  45. Ukena K, Kohchi C, Tsutsui K. Expression and activity of 3beta-hydroxysteroid dehydrogenase/delta5-delta4-isomerase in the rat Pukinje neuron during neonatal life. Endocrinology. 1999;140:805–13.

    Article  CAS  PubMed  Google Scholar 

  46. Sakamoto H, Ukena K, Tsutsui K. Effects of progesterone synthesized de novo in the developing Purkinje cell on its dendritic growth and synaptogenesis. J Neurosci. 2001;21:6221–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abel JM, Witt DM, Rissman EF. Sex differences in the cerebellum and frontal cortex: roles of estrogen receptor alpha and sex chromosome genes. Neuroendocrinology. 2011;93:230–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Raz N, Gunning-Dixon F, Head D, Williamson A, Acker JD. Age and sex difference in the cerebellum and the ventral pons: a prospective MR study of healthy adults. Am J Neuroradiol. 2001;22:1161–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Giedd JN, Snell JW, Lange N, Rajapakse JC, Casey BJ, Kozuch PL, Vaituzis AC, Vauss YC, Hamburger SD, Kaysen D, Rapoport JL. Quantitative magnetic resonance imaging of human brain development: ages 4–18. Cereb Cortex. 1996;6:551–60.

    Article  CAS  PubMed  Google Scholar 

  50. Nopoulos P, Flaum M, O’Leary D, Andreason NC. Sexual dimorphism in the human brain: evaluation of tissue volume, tissue composition and surface anatomy using magnetic resonance imaging. Psychiatry Res. 2000;98:1–13.

    Article  CAS  PubMed  Google Scholar 

  51. Werling DM. The role of sex-differential biology in risk for autism spectrum disorder. Biol Sex Differ. 2016;7:58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, Maravilla KR, Giedd JN, Munson J, Dawson G, Dager SR. Brain structural abnormalities in young children with autism spectrum disorder. Neurology. 2002;59:184–92.

    Article  CAS  PubMed  Google Scholar 

  53. Murakami JW, Courchesne E, Press GA, Yeung-Courchesne R, Hesselink JR. Reduced cerebellar hemisphere size and its relationship to vermal hypoplasia in autism. Arch Neurol. 1989;46:689–94.

    Article  CAS  PubMed  Google Scholar 

  54. Courchesne E. Neuroanatomic imaging in autism. Pediatrics. 1991;87:781–90.

    Article  CAS  PubMed  Google Scholar 

  55. Heh CW, Smith R, Wu J, Hazlett E, Russell A, Asarnow R, Tanguay P, Buchsbaum MS. Positron emission tomography of the cerebellum in autism. Am J Psychiatry. 1989;146:242–5.

    Article  CAS  PubMed  Google Scholar 

  56. Davies W. Sex differences in attention deficit hyperactivity disorder: candidate genetic and endocrine mechanisms. Front Neuroendocrinol. 2014;35:331–46.

    Article  CAS  PubMed  Google Scholar 

  57. Bledsoe J, Semrud-Clikeman M, Pliszka SR. A magnetic resonance imaging study of the cerebellar vermis in chronically treated and treatmentnaive children with attention-deficit/hyperactivity disorder combined type. Biol Psychiatry. 2009;65:620–4.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Lesmana R, Shimokawa N, Takatsuru Y, Iwasaki T, Koibuchi N. Lactational exposure to hydroxylated polychlorinated biphenyls (OH-PCB 106) causes hyperactivity in male rat pups by aberrant increase in dopamine and its receptor. Environ Toxicol. 2014;29:876–83.

    Article  CAS  PubMed  Google Scholar 

  59. Mueller SC, Wierckx K, Jackson K, T’Sjoen G. Circulating androgens correlate with resting-state MRI in transgender men. Psychoneuroendocrinology. 2016;73:91–8.

    Article  CAS  PubMed  Google Scholar 

  60. Simon L, Kozák LR, Simon V, Czobor P, Unoka Z, Szabó Á, Csukly G. Regional grey matter structure differences between transsexuals and healthy controls – a voxel based morphometry study. PLoS One. 2013;8:e83947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Rashid S, Lewis GF. The mechanisms of differential glucocorticoid and mineralocorticoid action in the brain and peripheral tissues. Clin Biochem. 2005;38:401–9.

    Article  CAS  PubMed  Google Scholar 

  62. Evanson NK, Herman JP, Sakai RR, Krause EG. Nongenomic actions of adrenal steroids in the central nervous system. J Neuroendocrinol. 2010;22:846–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Fowden AL, Li J, Forhead AJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc. 1998;57:113–22.

    Article  CAS  PubMed  Google Scholar 

  64. Diaz R, Brown RW, Seckl JR. Distinct ontogeny of glucocorticoid and mineralcoticoid receptor and 11b-hdroxysteriod dehydrogenase types I and II mRNAs in the fetal rat brain suggests acomplex control of glucocorticoid actions. J Neurosci. 1998;18:2570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lawson A, Ahima RS, Krozowski Z, Harlan RE. Postnatal development of corticosteroid receptor immunoreactivity in the rat cerebellum and brain stem. Neuroendocrinology. 1992;55:695–707.

    Article  CAS  PubMed  Google Scholar 

  66. Robson AC, Leckie CM, Seckl JR, Holms MC. 11beta-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain. Brain Res Mol Brain Res. 1998;61:1–10.

    Article  CAS  PubMed  Google Scholar 

  67. Rugerio-Vargas C, Ramírez-Escoto M, DelaRosa-Rugerio C, Rivas-Manzano P. Prenatal corticosterone influences the trajectory of neuronal development, delaying or accelerating aspects of the Purkinje cell differentiation. Histol Histopathol. 2007;22:963–9.

    CAS  PubMed  Google Scholar 

  68. Pavlik A, Buresova M. The neonatal cerebellum: the highest level of glucocorticoid receptors in the brain. Brain Res. 1984;314:13–21.

    Article  CAS  PubMed  Google Scholar 

  69. Velazquez PN, Romano MC. Corticosterone therapy during gestation: effects on the development of rat cerebellum. Int J Dev Neurosci. 1987;5:189–94.

    Article  CAS  PubMed  Google Scholar 

  70. Bohn MC, Lauder JM. Cerebellar granule cell genesis in the hydrocortisone-treated rats. Dev Neurosci. 1980;3:81–9.

    Article  CAS  PubMed  Google Scholar 

  71. Ahlbom E, Gogvadze V, Chen M, Celsi G, Ceccatelli S. Prenatal exposure to high levels of glucocorticoids increases the susceptibility of cerebellar granule cells to oxidative stress-induced cell death. Proc Natl Acad Sci U S A. 2000;97:14726–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Carson R, Mnaghan-Nichols AP, DeFranco DB, Rudine AC. Effects of antenatal glucocorticoids on the developing brain. Steroids. 2016;114:25–32.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Noguchi KK. Gucocorticoid induced cerebellar toxicity in the developing neonate: implication for glucocorticoid therapy during bronchopulmonary dyspasia. Cell. 2014;3:36–52.

    Article  CAS  Google Scholar 

  74. Babenko O, Kovalchuk I, Metz GA. Stress-induced perinatal and transgenerational epgenetic programming of brain development and mental health. Neurosci Biobehav Res. 2015;48:70–91.

    Article  Google Scholar 

  75. Shutter DLJG. The cerebello-hypothalamic-pituitary-adrenal axis dysregulation hypothesis in depressive disorder. Med Hypotheses. 2012;79:779–83.

    Article  CAS  Google Scholar 

  76. Llorente R, Gallardo ML, Berzal AL, Prada C, Garcia-Segura LM, Viveros MP. Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells. Int J Dev Neurosci. 2009;27:233–2341.

    Article  CAS  PubMed  Google Scholar 

  77. Miki T, Yokoyama T, Kusaka T, Suzuki S, Ohta K, Warita K, Wang ZY, Ueki M, Sumitani K, Bellinger FP, Tamai M, Liu JQ, Yakura T, Takeuchi Y. Early postnatal repeated maternal deprivation causes a transient increase in OMpg and BDNF in rat cerebellum suggesting precocious myelination. J Neurol Sci. 2014;336:62–7.

    Article  CAS  PubMed  Google Scholar 

  78. IPCS. Global assessment of the sate-of-the-science of endocrine disruptors. http://www.who.int/ipcs/publicatios/new_issues/endocrine_disruptors/en/.

  79. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, Gore AC. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009;30:293–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, Toppari J, Zoeller RT. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015;36:E1–E150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014;13:330–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ibhazehiebo K, Iwasaki T, Kimura-Kuroda J, Miyazaki W, Shimokawa N, Koibuchi N. Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced Purkinje cell dendrite arborization by polybrominated diphenyl ethers. Env Health Perspect. 2011;119:168–75.

    Article  CAS  Google Scholar 

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  1. Department of Integrative Physiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan

    Noriyuki Koibuchi

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Correspondence to Noriyuki Koibuchi .

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  1. Department of Human Anatomy and Cell Science, The Children’s Hospital Research Institute of Manitoba (CHRIM), Max Rady College of Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, MB, Canada

    Hassan Marzban

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Koibuchi, N. (2017). Hormonal Regulation of Cerebellar Development and Its Disorders. In: Marzban, H. (eds) Development of the Cerebellum from Molecular Aspects to Diseases. Contemporary Clinical Neuroscience. Springer, Cham. https://doi.org/10.1007/978-3-319-59749-2_11

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