Journal of Pediatrics Review

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Endolysins of Bacteriophages as an Anti-Methicillin Resistant Staphylococcus aureus Infection in Children: A Narrative Review

Golnar Rahimzadeh 1 , 2 , Pooria Gill 3 and Mohammad Sadegh Rezai 1 , *
Authors Information
1 Pediatric Infectious Diseases Research Center, Mazandaran University of Medical Sciences, Sari, IR Iran
2 Student Research Committee, Mazandaran University of Medical Sciences, Sari, IR Iran
3 Nanomedicine Group, Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, IR Iran
Article information
  • Journal of Pediatrics Review: January 2018, 6 (1); e11562
  • Published Online: October 10, 2017
  • Article Type: Review Article
  • Received: March 30, 2017
  • Revised: July 10, 2017
  • Accepted: July 17, 2017
  • DOI: 10.5812/jpr.11562

To Cite: Rahimzadeh G, Gill P, Rezai M S. Endolysins of Bacteriophages as an Anti-Methicillin Resistant Staphylococcus aureus Infection in Children: A Narrative Review, J Pediatr Rev. 2018 ;6(1):e11562. doi: 10.5812/jpr.11562.

Copyright © 2017, Journal of Pediatrics Review. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Context
2. Evidence Acquisition
3. Results
4. Conclusions
  • 1. Rezai MS, Pourmousa R, Dadashzadeh R, Ahangarkani F. Multidrug resistance pattern of bacterial agents isolated from patient with chronic sinusitis. Caspian J Intern Med. 2016;7(2):114-9. [PubMed: 27386063].
  • 2. McCaskill ML, Mason EJ, Kaplan SL, Hammerman W, Lamberth LB, Hulten KG. Increase of the USA300 clone among community-acquired methicillin-susceptible Staphylococcus aureus causing invasive infections. Pediatr Infect Dis J. 2007;26(12):1122-7. doi: 10.1097/INF.0b013e31814536e0. [PubMed: 18043449].
  • 3. Rezai MS, Salehifar E, Rafiei A, Langaee T, Rafati M, Shafahi K, et al. Characterization of multidrug resistant extended-spectrum beta-lactamase-producing Escherichia coli among uropathogens of pediatrics in North of Iran. BioMed Res Int. 2015;2015.
  • 4. Jansen WT, van der Bruggen JT, Verhoef J, Fluit AC. Bacterial resistance: a sensitive issue complexity of the challenge and containment strategy in Europe. Drug Resist Updat. 2006;9(3):123-33. doi: 10.1016/j.drup.2006.06.002. [PubMed: 16807066].
  • 5. Croft AC, D'Antoni AV, Terzulli SL. Update on the antibacterial resistance crisis. Med Sci Monit. 2007;13(6):RA103-18. [PubMed: 17534243].
  • 6. Grisaru-Soen G, Sweed Y, Lerner-Geva L, Hirsh-Yechezkel G, Boyko V, Vardi A, et al. Nosocomial bloodstream infections in a pediatric intensive care unit: 3-year survey. Med Sci Monit. 2007;13(6):CR251-7. [PubMed: 17534230].
  • 7. Shea KM, American Academy of Pediatrics Committee on Environmental H, American Academy of Pediatrics Committee on Infectious D. Nontherapeutic use of antimicrobial agents in animal agriculture: implications for pediatrics. Pediatrics. 2004;114(3):862-8. doi: 10.1542/peds.2004-1233. [PubMed: 15342867].
  • 8. Zetola N, Francis JS, Nuermberger EL, Bishai WR. Community-acquired meticillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis. 2005;5(5):275-86. doi: 10.1016/S1473-3099(05)70112-2. [PubMed: 15854883].
  • 9. Johnson AP, Pearson A, Duckworth G. Surveillance and epidemiology of MRSA bacteraemia in the UK. J Antimicrob Chemother. 2005;56(3):455-62. doi: 10.1093/jac/dki266. [PubMed: 16046464].
  • 10. Jado I, Lopez R, Garcia E, Fenoll A, Casal J, Garcia P, et al. Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model. J Antimicrob Chemother. 2003;52(6):967-73. doi: 10.1093/jac/dkg485. [PubMed: 14613958].
  • 11. Rashel M, Uchiyama J, Ujihara T, Uehara Y, Kuramoto S, Sugihara S, et al. Efficient elimination of multidrug-resistant Staphylococcus aureus by cloned lysin derived from bacteriophage phi MR11. J Infect Dis. 2007;196(8):1237-47. doi: 10.1086/521305. [PubMed: 17955443].
  • 12. Doss J, Culbertson K, Hahn D, Camacho J, Barekzi N. A Review of Phage Therapy against Bacterial Pathogens of Aquatic and Terrestrial Organisms. Viruses. 2017;9(3). doi: 10.3390/v9030050. [PubMed: 28335451].
  • 13. Sybesma W, Zbinden R, Chanishvili N, Kutateladze M, Chkhotua A, Ujmajuridze A, et al. Bacteriophages as Potential Treatment for Urinary Tract Infections. Front Microbiol. 2016;7:465. doi: 10.3389/fmicb.2016.00465. [PubMed: 27148173].
  • 14. Galtier M, De Sordi L, Maura D, Arachchi H, Volant S, Dillies MA, et al. Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition. Environ Microbiol. 2016;18(7):2237-45. doi: 10.1111/1462-2920.13284. [PubMed: 26971586].
  • 15. Rahmani R, Zarrini G, Sheikhzadeh F, Aghamohammadzadeh N. Effective Phages as Green Antimicrobial Agents Against Antibiotic-Resistant Hospital Escherichia coli. Jundishapur J Microbiol. 2015;8(2). e17744. doi: 10.5812/jjm.17744. [PubMed: 25834712].
  • 16. Revazishvili T, Kotetishvili M, Stine OC, Kreger AS, Morris JJ, Sulakvelidze A. Comparative analysis of multilocus sequence typing and pulsed-field gel electrophoresis for characterizing Listeria monocytogenes strains isolated from environmental and clinical sources. J Clin Microbiol. 2004;42(1):276-85. [PubMed: 14715765].
  • 17. Summers WC. Bacteriophage research: early history. Bacteriophages Biol Applications. 2005:5-27.
  • 18. Sulakvelidze A, Alavidze Z, Morris JJ. Bacteriophage therapy. Antimicrob Agents Chemother. 2001;45(3):649-59. doi: 10.1128/AAC.45.3.649-659.2001. [PubMed: 11181338].
  • 19. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011;1(2):66-85. doi: 10.4161/bact.1.2.15845. [PubMed: 22334863].
  • 20. Yoong P, Schuch R, Nelson D, Fischetti VA. Identification of a broadly active phage lytic enzyme with lethal activity against antibiotic-resistant Enterococcus faecalis and Enterococcus faecium. J Bacteriol. 2004;186(14):4808-12. doi: 10.1128/JB.186.14.4808-4812.2004. [PubMed: 15231813].
  • 21. Lopez R, Garcia E. Recent trends on the molecular biology of pneumococcal capsules, lytic enzymes, and bacteriophage. FEMS Microbiol Rev. 2004;28(5):553-80. doi: 10.1016/j.femsre.2004.05.002. [PubMed: 15539074].
  • 22. Fischetti VA. Bacteriophage lysins as effective antibacterials. Curr Opin Microbiol. 2008;11(5):393-400. doi: 10.1016/j.mib.2008.09.012. [PubMed: 18824123].
  • 23. Fischetti VA. Bacteriophage endolysins: a novel anti-infective to control Gram-positive pathogens. Int J Med Microbiol. 2010;300(6):357-62. doi: 10.1016/j.ijmm.2010.04.002. [PubMed: 20452280].
  • 24. Keary R, Sanz-Gaitero M, van Raaij MJ, O'Mahony J, Fenton M, McAuliffe O, et al. Characterization of a Bacteriophage-Derived Murein Peptidase for Elimination of Antibiotic-Resistant Staphylococcus aureus. Curr Protein Pept Sci. 2016;17(2):183-90. [PubMed: 26521950].
  • 25. Elbreki M, Ross RP, Hill C, O'Mahony J, McAuliffe O, Coffey A. Bacteriophages and their derivatives as biotherapeutic agents in disease prevention and treatment. J Viruses. 2014;2014.
  • 26. Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol. 2013;8(6):769-83. doi: 10.2217/fmb.13.47. [PubMed: 23701332].
  • 27. Herpers BL, Leeson N. Endolysins: redefining antibacterial therapy. Future Microbiol. 2015;10(3):309-11. doi: 10.2217/fmb.14.142. [PubMed: 25812452].
  • 28. Richman PB, Garra G, Eskin B, Nashed AH, Cody R. Oral antibiotic use without consulting a physician: a survey of ED patients. Am J Emerg Med. 2001;19(1):57-60. doi: 10.1053/ajem.2001.20035. [PubMed: 11146021].
  • 29. Schuch R, Lee HM, Schneider BC, Sauve KL, Law C, Khan BK, et al. Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia. J Infect Dis. 2014;209(9):1469-78. doi: 10.1093/infdis/jit637. [PubMed: 24286983].
  • 30. Pritchard DG, Dong S, Kirk MC, Cartee RT, Baker JR. LambdaSa1 and LambdaSa2 prophage lysins of Streptococcus agalactiae. Appl Environ Microbiol. 2007;73(22):7150-4. doi: 10.1128/AEM.01783-07. [PubMed: 17905888].
  • 31. Singh PK, Donovan DM, Kumar A. Intravitreal injection of the chimeric phage endolysin Ply187 protects mice from Staphylococcus aureus endophthalmitis. Antimicrob Agents Chemother. 2014;58(8):4621-9. doi: 10.1128/AAC.00126-14. [PubMed: 24890598].
  • 32. Rodriguez-Rubio L, Martinez B, Rodriguez A, Donovan DM, Gotz F, Garcia P. The phage lytic proteins from the Staphylococcus aureus bacteriophage vB_SauS-phiIPLA88 display multiple active catalytic domains and do not trigger staphylococcal resistance. PLoS One. 2013;8(5). e64671. doi: 10.1371/journal.pone.0064671. [PubMed: 23724076].
  • 33. Pritchard DG, Dong S, Baker JR, Engler JA. The bifunctional peptidoglycan lysin of Streptococcus agalactiae bacteriophage B30. Microbiology. 2004;150(Pt 7):2079-87. doi: 10.1099/mic.0.27063-0. [PubMed: 15256551].
  • 34. Becker SC, Dong S, Baker JR, Foster-Frey J, Pritchard DG, Donovan DM. LysK CHAP endopeptidase domain is required for lysis of live staphylococcal cells. FEMS Microbiol Lett. 2009;294(1):52-60. doi: 10.1111/j.1574-6968.2009.01541.x. [PubMed: 19493008].
  • 35. Fenton M, Ross P, McAuliffe O, O'Mahony J, Coffey A. Recombinant bacteriophage lysins as antibacterials. Bioeng Bugs. 2010;1(1):9-16. doi: 10.4161/bbug.1.1.9818. [PubMed: 21327123].
  • 36. Sass P, Bierbaum G. Lytic activity of recombinant bacteriophage phi11 and phi12 endolysins on whole cells and biofilms of Staphylococcus aureus. Appl Environ Microbiol. 2007;73(1):347-52. doi: 10.1128/AEM.01616-06. [PubMed: 17085695].
  • 37. Abaev I, Foster-Frey J, Korobova O, Shishkova N, Kiseleva N, Kopylov P, et al. Staphylococcal phage 2638A endolysin is lytic for Staphylococcus aureus and harbors an inter-lytic-domain secondary translational start site. Appl Microbiol Biotechnol. 2013;97(8):3449-56. doi: 10.1007/s00253-012-4252-4. [PubMed: 22777279].
  • 38. Takac M, Blasi U. Phage P68 virion-associated protein 17 displays activity against clinical isolates of Staphylococcus aureus. Antimicrob Agents Chemother. 2005;49(7):2934-40. doi: 10.1128/AAC.49.7.2934-2940.2005. [PubMed: 15980371].
  • 39. Yokoi KJ, Kawahigashi N, Uchida M, Sugahara K, Shinohara M, Kawasaki K, et al. The two-component cell lysis genes holWMY and lysWMY of the Staphylococcus warneri M phage varphiWMY: cloning, sequencing, expression, and mutational analysis in Escherichia coli. Gene. 2005;351:97-108. doi: 10.1016/j.gene.2005.03.006. [PubMed: 15848115].
  • 40. O'Flaherty S, Coffey A, Meaney WJ, Fitzgerald GF, Ross RP. Inhibition of bacteriophage K proliferation on Staphylococcus aureus in raw bovine milk. Lett Appl Microbiol. 2005;41(3):274-9. doi: 10.1111/j.1472-765X.2005.01762.x. [PubMed: 16108920].
  • 41. O'Gara JP, Humphreys H. Staphylococcus epidermidis biofilms: importance and implications. J Med Microbiol. 2001;50(7):582-7. doi: 10.1099/0022-1317-50-7-582. [PubMed: 11444767].
  • 42. Jun SY, Jung GM, Son JS, Yoon SJ, Choi YJ, Kang SH. Comparison of the antibacterial properties of phage endolysins SAL-1 and LysK. Antimicrob Agents Chemother. 2011;55(4):1764-7. doi: 10.1128/AAC.01097-10. [PubMed: 21263051].
  • 43. Fischetti VA. 12 The Use of Phage Lytic Enzymes to Control Bacterial Infections. Bacteriophages Biol applicat. 2004:321.
  • 44. Son JS, Lee SJ, Jun SY, Yoon SJ, Kang SH, Paik HR, et al. Antibacterial and biofilm removal activity of a podoviridae Staphylococcus aureus bacteriophage SAP-2 and a derived recombinant cell-wall-degrading enzyme. Appl Microbiol Biotechnol. 2010;86(5):1439-49. doi: 10.1007/s00253-009-2386-9. [PubMed: 20013118].
  • 45. Nelson DC, Schmelcher M, Rodriguez-Rubio L, Klumpp J, Pritchard DG, Dong S, et al. Endolysins as antimicrobials. Adv Virus Res. 2012;83:299-365. doi: 10.1016/B978-0-12-394438-2.00007-4. [PubMed: 22748813].
  • 46. Visweswaran GR, Dijkstra BW, Kok J. Murein and pseudomurein cell wall binding domains of bacteria and archaea--a comparative view. Appl Microbiol Biotechnol. 2011;92(5):921-8. doi: 10.1007/s00253-011-3637-0. [PubMed: 22012341].
  • 47. Loeffler JM, Djurkovic S, Fischetti VA. Phage lytic enzyme Cpl-1 as a novel antimicrobial for pneumococcal bacteremia. Infect Immun. 2003;71(11):6199-204. [PubMed: 14573637].
  • 48. Daniel A, Euler C, Collin M, Chahales P, Gorelick KJ, Fischetti VA. Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2010;54(4):1603-12. doi: 10.1128/AAC.01625-09. [PubMed: 20086153].
  • 49. Paul VD, Sundarrajan S, Rajagopalan SS, Hariharan S, Kempashanaiah N, Padmanabhan S, et al. Lysis-deficient phages as novel therapeutic agents for controlling bacterial infection. BMC Microbiol. 2011;11:195. doi: 10.1186/1471-2180-11-195. [PubMed: 21880144].
  • 50. Yang H, Linden SB, Wang J, Yu J, Nelson DC, Wei H. A chimeolysin with extended-spectrum streptococcal host range found by an induced lysis-based rapid screening method. Sci Rep. 2015;5:17257. doi: 10.1038/srep17257. [PubMed: 26607832].
  • 51. Horgan M, O'Flynn G, Garry J, Cooney J, Coffey A, Fitzgerald GF, et al. Phage lysin LysK can be truncated to its CHAP domain and retain lytic activity against live antibiotic-resistant staphylococci. Appl Environ Microbiol. 2009;75(3):872-4. doi: 10.1128/AEM.01831-08. [PubMed: 19047377].
  • 52. Becker SC, Foster-Frey J, Donovan DM. The phage K lytic enzyme LysK and lysostaphin act synergistically to kill MRSA. FEMS Microbiol Lett. 2008;287(2):185-91. doi: 10.1111/j.1574-6968.2008.01308.x. [PubMed: 18721148].
  • 53. O'Flaherty S, Coffey A, Meaney W, Fitzgerald GF, Ross RP. The recombinant phage lysin LysK has a broad spectrum of lytic activity against clinically relevant staphylococci, including methicillin-resistant Staphylococcus aureus. J Bacteriol. 2005;187(20):7161-4. doi: 10.1128/JB.187.20.7161-7164.2005. [PubMed: 16199588].
  • 54. Gilmer DB, Schmitz JE, Euler CW, Fischetti VA. Novel bacteriophage lysin with broad lytic activity protects against mixed infection by Streptococcus pyogenes and methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013;57(6):2743-50. doi: 10.1128/AAC.02526-12. [PubMed: 23571534].
  • 55. Schmelcher M, Shen Y, Nelson DC, Eugster MR, Eichenseher F, Hanke DC, et al. Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection. J Antimicrob Chemother. 2015;70(5):1453-65. doi: 10.1093/jac/dku552. [PubMed: 25630640].
  • 56. Gu J, Xu W, Lei L, Huang J, Feng X, Sun C, et al. LysGH15, a novel bacteriophage lysin, protects a murine bacteremia model efficiently against lethal methicillin-resistant Staphylococcus aureus infection. J Clin Microbiol. 2011;49(1):111-7. doi: 10.1128/JCM.01144-10. [PubMed: 21048011].
  • 57. Jun SY, Jung GM, Yoon SJ, Oh MD, Choi YJ, Lee WJ, et al. Antibacterial properties of a pre-formulated recombinant phage endolysin, SAL-1. Int J Antimicrob Agents. 2013;41(2):156-61. doi: 10.1016/j.ijantimicag.2012.10.011. [PubMed: 23276502].
  • 58. Chopra S, Harjai K, Chhibber S. Potential of sequential treatment with minocycline and S. aureus specific phage lysin in eradication of MRSA biofilms: an in vitro study. Appl Microbiol Biotechnol. 2015;99(7):3201-10. doi: 10.1007/s00253-015-6460-1. [PubMed: 25707865].
  • 59. Fenton M, Keary R, McAuliffe O, Ross RP, O'Mahony J, Coffey A. Bacteriophage-Derived Peptidase CHAP(K) Eliminates and Prevents Staphylococcal Biofilms. Int J Microbiol. 2013;2013:625341. doi: 10.1155/2013/625341. [PubMed: 23431312].
  • 60. Gutierrez D, Ruas-Madiedo P, Martinez B, Rodriguez A, Garcia P. Effective removal of staphylococcal biofilms by the endolysin LysH5. PLoS One. 2014;9(9). e107307. doi: 10.1371/journal.pone.0107307. [PubMed: 25203125].
  • 61. Nau R, Eiffert H. Modulation of release of proinflammatory bacterial compounds by antibacterials: potential impact on course of inflammation and outcome in sepsis and meningitis. Clin Microbiol Rev. 2002;15(1):95-110. [PubMed: 11781269].
  • 62. Entenza JM, Loeffler JM, Grandgirard D, Fischetti VA, Moreillon P. Therapeutic effects of bacteriophage Cpl-1 lysin against Streptococcus pneumoniae endocarditis in rats. Antimicrob Agents Chemother. 2005;49(11):4789-92. doi: 10.1128/AAC.49.11.4789-4792.2005. [PubMed: 16251333].
  • 63. Bazan J, Calkosinski I, Gamian A. Phage display--a powerful technique for immunotherapy: 1. Introduction and potential of therapeutic applications. Hum Vaccin Immunother. 2012;8(12):1817-28. doi: 10.4161/hv.21703. [PubMed: 22906939].
  • 64. de Almeida SS, Magalhaes AA, de Castro Soares S, Zurita-Turk M, Goulart LR, Miyoshi A, et al. The phage display technique: advantages and recent patents. Recent Pat DNA Gene Seq. 2011;5(2):136-48. [PubMed: 21663585].
  • 65. Schmelcher M, Donovan DM, Loessner MJ. Bacteriophage endolysins as novel antimicrobials. Future Microbiol. 2012;7(10):1147-71. doi: 10.2217/fmb.12.97. [PubMed: 23030422].
  • 66. Cheng Q, Nelson D, Zhu S, Fischetti VA. Removal of group B streptococci colonizing the vagina and oropharynx of mice with a bacteriophage lytic enzyme. Antimicrob Agents Chemother. 2005;49(1):111-7. doi: 10.1128/AAC.49.1.111-117.2005. [PubMed: 15616283].
  • 67. Fenton M, Casey PG, Hill C, Gahan CG, Ross RP, McAuliffe O, et al. The truncated phage lysin CHAP(k) eliminates Staphylococcus aureus in the nares of mice. Bioeng Bugs. 2010;1(6):404-7. doi: 10.4161/bbug.1.6.13422. [PubMed: 21468207].
  • 68. Gu J, Zuo J, Lei L, Zhao H, Sun C, Feng X, et al. LysGH15 reduces the inflammation caused by lethal methicillin-resistant Staphylococcus aureus infection in mice. Bioeng Bugs. 2011;2(2):96-9. doi: 10.4161/bbug.2.2.14883. [PubMed: 21636996].
  • 69. Rahimzadeh G, Sadegh Rezai M. Characterization and lytic activity of methicillin-resistant Staphylococcus aureus(MRSA). Aust Med J. 2016;9(6). doi: 10.4066/amj.2016.2642.
  • 70. Rahimzadeh G, Gill P, Rezai MS. Characterization of Methicillin-Resistant Staphylococcus aureus (MRSA) Phages From Sewage at a Tertiary Pediatric Hospital. Arch Pediatr Infect Dis. 2016;5(1). doi: 10.5812/pedinfect.39615.
  • 71. Behzadnia S, Davoudi A, Rezai MS, Ahangarkani F. Nosocomial infections in pediatric population and antibiotic resistance of the causative organisms in north of iran. Iran Red Crescent Med J. 2014;16(2). e14562. doi: 10.5812/ircmj.14562. [PubMed: 24719744].
  • 72. Rezai MS, Shahmohammadi S. Nosocomial Infections in Iranian Pediatric Patients With Burn Injuries: A Review. J Pediatr Rev. 2015;3(2). doi: 10.17795/jpr-680.
  • 73. Weber-Dąbrowska B, Mulczyk M, Górski A. Inflammation. Springer; 2001. Bacteriophage therapy of bacterial infections: an update of our institute’s experience; p. 201-9.
  • 74. Islam KK. Bacteriophage: A Potential Therapeutic Agent (A Review)" Mahmud Morshed Sagor," Khandker Khaldun Islam," Md. Raihan Ali," SM Abdul-Awal," Partho Protim Adhikary,“Palash Kumar Sarker and" Abu Syed Md. Rakib. J Med Sci. 2005;5(1):1-9.
  • 75. Skurnik M, Strauch E. Phage therapy: facts and fiction. Int J Med Microbiol. 2006;296(1):5-14. doi: 10.1016/j.ijmm.2005.09.002. [PubMed: 16423684].
  • 76. Loeffler JM, Nelson D, Fischetti VA. Rapid killing of Streptococcus pneumoniae with a bacteriophage cell wall hydrolase. Science. 2001;294(5549):2170-2. doi: 10.1126/science.1066869. [PubMed: 11739958].
  • 77. Walsh S, Shah A, Mond J. Improved pharmacokinetics and reduced antibody reactivity of lysostaphin conjugated to polyethylene glycol. Antimicrob Agents Chemother. 2003;47(2):554-8. [PubMed: 12543658].
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