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Mice with Chimeric Human Livers and Their Applications

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Hepatitis C Virus Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1911))

Abstract

The complete life cycle of the hepatitis C virus (HCV) can be recapitulated in vivo using immunodeficient mice that have had their livers extensively repopulated with human hepatocytes. These human liver chimeric mouse models have enabled the study of many aspects of the HCV life cycle, including antiviral interventions that have helped to shape the curative landscape that is available today. The first human liver chimeric mouse model capable of supporting the HCV life cycle was generated in SCID-uPA mice. Although other human liver chimeric mouse models have since been developed, the SCID-uPA mouse model remains one of the most robust in vivo systems available for HCV studies. This chapter reviews development, validation and application of the SCID-uPA mouse model, and discusses their potential application for studying other liver-centric diseases and pathogens and for the design and testing of vaccine candidates for the eradication of HCV.

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References

  1. Alter MJ (1997) Epidemiology of hepatitis C. Hepatology 26:62S–65S

    Article  CAS  Google Scholar 

  2. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A et al (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7:927–933

    Article  CAS  Google Scholar 

  3. Bukh J (2012) Animal models for the study of hepatitis C virus infection and related liver disease. Gastroenterology 142(1279–1287):e1273

    Google Scholar 

  4. Walters KA, Joyce MA, Thompson JC, Smith MW, Yeh MM, Proll S et al (2006) Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model: role of the innate antiviral immune response. PLoS Pathog 2:e59

    Article  Google Scholar 

  5. Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z et al (2008) Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 14:25–27

    Article  CAS  Google Scholar 

  6. Brown RJ, Hudson N, Wilson G, Rehman SU, Jabbari S, Hu K et al (2012) Hepatitis C virus envelope glycoprotein fitness defines virus population composition following transmission to a new host. J Virol 86:11956–11966

    Article  CAS  Google Scholar 

  7. Hsu EC, Hsi B, Hirota-Tsuchihara M, Ruland J, Iorio C, Sarangi F et al (2003) Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers. Nat Biotechnol 21:519–525

    Article  CAS  Google Scholar 

  8. Kneteman NM, Asthana S, Lewis J, Dibben C, Douglas D, Nourbakhsh M et al (2012) Impact of calcineurin inhibitors with or without interferon on hepatitis C virus titers in a chimeric mouse model of hepatitis C virus infection. Liver Transpl 18:38–44

    Article  Google Scholar 

  9. Kneteman NM, Howe AY, Gao T, Lewis J, Pevear D, Lund G et al (2009) HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity in vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus. Hepatology 49:745–752

    Article  CAS  Google Scholar 

  10. Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    Article  CAS  Google Scholar 

  11. Bitzegeio J, Bankwitz D, Hueging K, Haid S, Brohm C, Zeisel MB et al (2010) Adaptation of hepatitis C virus to mouse CD81 permits infection of mouse cells in the absence of human entry factors. PLoS Pathog 6:e1000978

    Article  Google Scholar 

  12. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP et al (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457:882–886

    Article  CAS  Google Scholar 

  13. Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K et al (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature 474:208–211

    Article  CAS  Google Scholar 

  14. Chen J, Zhao Y, Zhang C, Chen H, Feng J, Chi X et al (2014) Persistent hepatitis C virus infections and hepatopathological manifestations in immune-competent humanized mice. Cell Res 24:1050–1066

    Article  CAS  Google Scholar 

  15. Bartosch B, Dubuisson J, Cosset FL (2003) Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J Exp Med 197:633–642

    Article  CAS  Google Scholar 

  16. Hsu M, Zhang J, Flint M, Logvinoff C, Cheng-Mayer C, Rice CM et al (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A 100:7271–7276

    Article  CAS  Google Scholar 

  17. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC et al (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626

    Article  CAS  Google Scholar 

  18. Lindenbach BD, Meuleman P, Ploss A, Vanwolleghem T, Syder AJ, McKeating JA et al (2006) Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci U S A 103:3805–3809

    Article  CAS  Google Scholar 

  19. Wakita T, Kato T (2006) Development of an infectious HCV cell culture system. Horizon Bioscience, Norfolk

    Google Scholar 

  20. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z et al (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796

    Article  CAS  Google Scholar 

  21. Zhong J, Gastaminza P, Cheng G, Kapadia S, Kato T, Burton DR et al (2005) Robust hepatitis C virus infection in vitro. Proc Natl Acad Sci U S A 102:9294–9299

    Article  CAS  Google Scholar 

  22. Zhong J, Gastaminza P, Chung J, Stamataki Z, Isogawa M, Cheng G et al (2006) Persistent hepatitis C virus infection in vitro: coevolution of virus and host. J Virol 80:11082–11093

    Article  CAS  Google Scholar 

  23. Heckel JL, Sandgren EP, Degen JL, Palmiter RD, Brinster RL (1990) Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator. Cell 62:447–456

    Article  CAS  Google Scholar 

  24. Sandgren EP, Palmiter RD, Heckel JL, Daugherty CC, Brinster RL, Degen JL (1991) Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell 66:245–256

    Article  CAS  Google Scholar 

  25. Rhim JA, Sandgren EP, Degen JL, Palmiter RD, Brinster RL (1994) Replacement of diseased mouse liver by hepatic cell transplantation. Science 263:1149–1152

    Article  CAS  Google Scholar 

  26. Rhim JA, Sandgren EP, Palmiter RD, Brinster RL (1995) Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci U S A 92:4942–4946

    Article  CAS  Google Scholar 

  27. Meuleman P, Vanlandschoot P, Leroux-Roels G (2003) A simple and rapid method to determine the zygosity of uPA-transgenic SCID mice. Biochem Biophys Res Commun 308:375–378

    Article  CAS  Google Scholar 

  28. Kneteman NM, Mercer DF (2005) Mice with chimeric human livers: who says supermodels have to be tall? Hepatology 41:703–706

    Article  CAS  Google Scholar 

  29. Kawahara T, Toso C, Douglas DN, Nourbakhsh M, Lewis JT, Tyrrell DL et al (2010) Factors affecting hepatocyte isolation, engraftment, and replication in an in vivo model. Liver Transpl 16:974–982

    Article  Google Scholar 

  30. Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT, Chisari FV et al (2010) Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest 120:924–930

    Article  CAS  Google Scholar 

  31. Meuleman P, Libbrecht L, De Vos R, de Hemptinne B, Gevaert K, Vandekerckhove J et al (2005) Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology 41:847–856

    Article  CAS  Google Scholar 

  32. Hiraga N, Imamura M, Tsuge M, Noguchi C, Takahashi S, Iwao E et al (2007) Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis C virus and its susceptibility to interferon. FEBS Lett 581:1983–1987

    Article  CAS  Google Scholar 

  33. Hiraga N, Imamura M, Abe H, Hayes CN, Kono T, Onishi M et al (2011) Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo. Hepatology 54:781–788

    Article  CAS  Google Scholar 

  34. Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, Hayes CN et al (2011) Impact of viral amino acid substitutions and host interleukin-28b polymorphism on replication and susceptibility to interferon of hepatitis C virus. Hepatology 54:764–771

    Article  CAS  Google Scholar 

  35. Tateno C, Yoshizane Y, Saito N, Kataoka M, Utoh R, Yamasaki C et al (2004) Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol 165:901–912

    Article  CAS  Google Scholar 

  36. Yoshitsugu H, Nishimura M, Tateno C, Kataoka M, Takahashi E, Soeno Y et al (2006) Evaluation of human CYP1A2 and CYP3A4 mRNA expression in hepatocytes from chimeric mice with humanized liver. Drug Metab Pharmacokinet 21:465–474

    Article  CAS  Google Scholar 

  37. Kawahara T, Douglas DN, Lewis J, Lund G, Addison W, Tyrrell DL et al (2010) Critical role of natural killer cells in the rejection of human hepatocytes after xenotransplantation into immunodeficient mice. Transpl Int 23:934–943

    CAS  PubMed  Google Scholar 

  38. Brezillon NM, DaSilva L, L'Hote D, Bernex F, Piquet J, Binart N et al (2008) Rescue of fertility in homozygous mice for the urokinase plasminogen activator transgene by the transplantation of mouse hepatocytes. Cell Transplant 17:803–812

    Article  Google Scholar 

  39. Douglas DN, Pu CH, Lewis JT, Bhat R, Anwar-Mohamed A, Logan M et al (2016) Oxidative stress attenuates lipid synthesis and increases mitochondrial fatty acid oxidation in hepatoma cells infected with hepatitis C virus. J Biol Chem 291:1974–1990

    Article  CAS  Google Scholar 

  40. Tateno C, Kataoka M, Utoh R, Tachibana A, Itamoto T, Asahara T, Miya F, Tsunoda T, Yoshizato K (2011) Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver. Endocrinology 152:1479–1491

    Article  CAS  Google Scholar 

  41. Tachibana S, Watanabe T (2007) Sexual differences in the crucial environmental factors for the timing of postdiapause development in the rice bug Leptocorisa chinensis. J Insect Physiol 53:1000–1007

    Article  CAS  Google Scholar 

  42. Katoh M, Matsui T, Nakajima M, Tateno C, Kataoka M, Soeno Y et al (2004) Expression of human cytochromes P450 in chimeric mice with humanized liver. Drug Metab Dispos 32:1402–1410

    Article  CAS  Google Scholar 

  43. Katoh M, Matsui T, Nakajima M, Tateno C, Soeno Y, Horie T et al (2005) In vivo induction of human cytochrome P450 enzymes expressed in chimeric mice with humanized liver. Drug Metab Dispos 33:754–763

    Article  CAS  Google Scholar 

  44. Katoh M, Matsui T, Okumura H, Nakajima M, Nishimura M, Naito S et al (2005) Expression of human phase II enzymes in chimeric mice with humanized liver. Drug Metab Dispos 33:1333–1340

    Article  CAS  Google Scholar 

  45. Katoh M, Sawada T, Soeno Y, Nakajima M, Tateno C, Yoshizato K et al (2007) In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J Pharm Sci 96:428–437

    Article  CAS  Google Scholar 

  46. Nishimura M, Yoshitsugu H, Yokoi T, Tateno C, Kataoka M, Horie T et al (2005) Evaluation of mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mouse with humanized liver. Xenobiotica 35:877–890

    Article  CAS  Google Scholar 

  47. Nishimura M, Yokoi T, Tateno C, Kataoka M, Takahashi E, Horie T et al (2005) Induction of human CYP1A2 and CYP3A4 in primary culture of hepatocytes from chimeric mice with humanized liver. Drug Metab Pharmacokinet 20:121–126

    Article  CAS  Google Scholar 

  48. Dandri M, Burda MR, Torok E, Pollok JM, Iwanska A, Sommer G et al (2001) Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology 33:981–988

    Article  CAS  Google Scholar 

  49. Suemizu H, Hasegawa M, Kawai K, Taniguchi K, Monnai M, Wakui M et al (2008) Establishment of a humanized model of liver using NOD/Shi-scid IL2Rgnull mice. Biochem Biophys Res Commun 377:248–252

    Article  CAS  Google Scholar 

  50. Song X, Guo Y, Duo S, Che J, Wu C, Ochiya T et al (2009) A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation. Am J Pathol 175:1975–1983

    Article  CAS  Google Scholar 

  51. Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E et al (2007) Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 25:903–910

    Article  CAS  Google Scholar 

  52. Bissig KD, Le TT, Woods NB, Verma IM (2007) Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model. Proc Natl Acad Sci U S A 104:20507–20511

    Article  CAS  Google Scholar 

  53. Kosaka K, Hiraga N, Imamura M, Yoshimi S, Murakami E, Nakahara T et al (2013) A novel TK-NOG based humanized mouse model for the study of HBV and HCV infections. Biochem Biophys Res Commun 441:230–235

    Article  CAS  Google Scholar 

  54. Foquet L, Hermsen CC, Verhoye L, van Gemert GJ, Cortese R, Nicosia A et al (2015) Anti-CD81 but not anti-SR-BI blocks Plasmodium falciparum liver infection in a humanized mouse model. J Antimicrob Chemother 70:1784–1787

    CAS  PubMed  Google Scholar 

  55. Sacci JB Jr, Alam U, Douglas D, Lewis J, Tyrrell DL, Azad AF et al (2006) Plasmodium falciparum infection and exoerythrocytic development in mice with chimeric human livers. Int J Parasitol 36:353–360

    Article  CAS  Google Scholar 

  56. Meuleman P, Catanese MT, Verhoye L, Desombere I, Farhoudi A, Jones CT et al (2012) A human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo. Hepatology 55:364–372

    Article  CAS  Google Scholar 

  57. Kneteman NM, Weiner AJ, O'Connell J, Collett M, Gao T, Aukerman L et al (2006) Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology 43:1346–1353

    Article  CAS  Google Scholar 

  58. Takebe Y, Saucedo CJ, Lund G, Uenishi R, Hase S, Tsuchiura T et al (2013) Antiviral lectins from red and blue-green algae show potent in vitro and in vivo activity against hepatitis C virus. PLoS One 8:e64449

    Article  CAS  Google Scholar 

  59. Lin C, Gates CA, Rao BG, Brennan DL, Fulghum JR, Luong YP et al (2005) In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J Biol Chem 280:36784–36791

    Article  CAS  Google Scholar 

  60. Lin C, Lin K, Luong YP, Rao BG, Wei YY, Brennan DL et al (2004) In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 279:17508–17514

    Article  CAS  Google Scholar 

  61. Reiser M, Hinrichsen H, Benhamou Y, Reesink HW, Wedemeyer H, Avendano C et al (2005) Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 41:832–835

    Article  CAS  Google Scholar 

  62. Thibeault D, Bousquet C, Gingras R, Lagace L, Maurice R, White PW et al (2004) Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061. J Virol 78:7352–7359

    Article  CAS  Google Scholar 

  63. Vanwolleghem T, Meuleman P, Libbrecht L, Roskams T, De Vos R, Leroux-Roels G (2007) Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse. Gastroenterology 133:1144–1155

    Article  CAS  Google Scholar 

  64. Viropharma (2006) Viropharma announces presentation of HCV 796 phase Ib data at digestive disease week. Viropharma, Harrisburg, PA

    Google Scholar 

  65. Ohara E, Hiraga N, Imamura M, Iwao E, Kamiya N, Yamada I et al (2011) Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice. J Hepatol 54:872–878

    Article  CAS  Google Scholar 

  66. Gopalsamy A, Aplasca A, Ciszewski G, Park K, Ellingboe JW, Orlowski M et al (2006) Design and synthesis of 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran derivatives as non-nucleoside inhibitors of HCV NS5B RNA dependent RNA polymerase. Bioorg Med Chem Lett 16:457–460

    Article  CAS  Google Scholar 

  67. Viropharma (2003) Viropharma announces results of hepatitis C Phase Ib study. Viropharma, Harrisburg, PA

    Google Scholar 

  68. Neumann-Haefelin C, Thimme R (2013) Adaptive immune responses in hepatitis C virus infection. Curr Top Microbiol Immunol 369:243–262

    CAS  PubMed  Google Scholar 

  69. Dahari H, Feinstone SM, Major ME (2010) Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins. Gastroenterology 139:965–974

    Article  CAS  Google Scholar 

  70. Meunier JC, Gottwein JM, Houghton M, Russell RS, Emerson SU, Bukh J et al (2011) Vaccine-induced cross-genotype reactive neutralizing antibodies against hepatitis C virus. J Infect Dis 204:1186–1190

    Article  CAS  Google Scholar 

  71. Meuleman P, Bukh J, Verhoye L, Farhoudi A, Vanwolleghem T, Wang RY et al (2011) In vivo evaluation of the cross-genotype neutralizing activity of polyclonal antibodies against hepatitis C virus. Hepatology 53:755–762

    Article  CAS  Google Scholar 

  72. Vanwolleghem T, Bukh J, Meuleman P, Desombere I, Meunier JC, Alter H et al (2008) Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver-chimeric mice from infection with a homologous hepatitis C virus strain. Hepatology 47:1846–1855

    Article  CAS  Google Scholar 

  73. Meuleman P, Hesselgesser J, Paulson M, Vanwolleghem T, Desombere I, Reiser H et al (2008) Anti-CD81 antibodies can prevent a hepatitis C virus infection in vivo. Hepatology 48:1761–1768

    Article  CAS  Google Scholar 

  74. WHO (2015) Hepatitis B. WHO, Geneva http://www.who.int/mediacentre/factsheets/fs204/en/

    Google Scholar 

  75. Lok AS (2004) Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 127:S303–S309

    Article  Google Scholar 

  76. Douglas DN, Kneteman NM (2015) Generation of improved mouse models for the study of hepatitis C virus. Eur J Pharmacol 759:313–325

    Article  CAS  Google Scholar 

  77. Keng CT, Sze CW, Zheng D, Zheng Z, Yong KS, Tan SQ et al (2016) Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection. Gut 65:1744–1753

    Article  CAS  Google Scholar 

  78. Wilson EM, Bial J, Tarlow B, Bial G, Jensen B, Greiner DL et al (2014) Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Res 13:404–412

    Article  CAS  Google Scholar 

  79. Gutti TL, Knibbe JS, Makarov E, Zhang J, Yannam GR, Gorantla S et al (2014) Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice. Am J Pathol 184:101–109

    Article  CAS  Google Scholar 

  80. Strick-Marchand H, Dusseaux M, Darche S, Huntington ND, Legrand N, Masse-Ranson G et al (2015) A novel mouse model for stable engraftment of a human immune system and human hepatocytes. PLoS One 10:e0119820

    Article  Google Scholar 

  81. Bility MT, Zhang L, Washburn ML, Curtis TA, Kovalev GI, Su L (2012) Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis. Nat Protoc 7:1608–1617

    Article  CAS  Google Scholar 

  82. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA et al (2011) A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140:1334–1344

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada

    Donna N. Douglas & Norman M. Kneteman

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  1. Donna N. Douglas
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  2. Norman M. Kneteman
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Correspondence to Norman M. Kneteman .

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  1. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA

    Mansun Law

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Douglas, D.N., Kneteman, N.M. (2019). Mice with Chimeric Human Livers and Their Applications. In: Law, M. (eds) Hepatitis C Virus Protocols . Methods in Molecular Biology, vol 1911. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8976-8_32

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  • DOI: https://doi.org/10.1007/978-1-4939-8976-8_32

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