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Volumn 8, Issue 1, 2017, Pages

Combinatorial metabolic engineering using an orthogonal tri-functional CRISPR system

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXY 3 METHYLGLUTARYL COENZYME A; ACETYL COENZYME A; ADE2 PROTEIN; BETA CAROTENE; CELLULASE; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT PROTEIN; ERG9 PROTEIN; GLUCAN SYNTHASE; GUIDE RNA; HIGH MOBILITY GROUP B1 PROTEIN; NUCLEASE; PROTEIN; RECOMBINANT PROTEIN; ROX1 PROTEIN; SQUALENE; UNCLASSIFIED DRUG; SACCHAROMYCES CEREVISIAE PROTEIN;

EID: 85034816286     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/s41467-017-01695-x     Document Type: Article
Times cited : (250)

References (56)
  • 1
    • 84960460639 scopus 로고    scopus 로고
    • Engineering cellular metabolism
    • Nielsen, J., Keasling, J. D. Engineering cellular metabolism. Cell 164, 1185-1197 (2016).
    • (2016) Cell , vol.164 , pp. 1185-1197
    • Nielsen, J.1    Keasling, J.D.2
  • 2
    • 80051704380 scopus 로고    scopus 로고
    • Engineering microbial factories for synthesis of value-added products
    • Du, J., Shao, Z., Zhao, H. Engineering microbial factories for synthesis of value-added products. J. Ind. Microbiol. Biotechnol. 38, 873-890 (2011).
    • (2011) J. Ind. Microbiol. Biotechnol. , vol.38 , pp. 873-890
    • Du, J.1    Shao, Z.2    Zhao, H.3
  • 3
    • 84925464682 scopus 로고    scopus 로고
    • Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites
    • Lian, J., Zhao, H. Recent advances in biosynthesis of fatty acids derived products in Saccharomyces cerevisiae via enhanced supply of precursor metabolites. J. Ind. Microbiol. Biotechnol. 42, 437-451 (2015).
    • (2015) J. Ind. Microbiol. Biotechnol. , vol.42 , pp. 437-451
    • Lian, J.1    Zhao, H.2
  • 4
    • 84901808659 scopus 로고    scopus 로고
    • Design and construction of acetyl-CoA overproducing Saccharomyces cerevisiae strains
    • Lian, J., Si, T., Nair, N. U., Zhao, H. Design and construction of acetyl-CoA overproducing Saccharomyces cerevisiae strains. Metab. Eng. 24, 139-149 (2014).
    • (2014) Metab. Eng. , vol.24 , pp. 139-149
    • Lian, J.1    Si, T.2    Nair, N.U.3    Zhao, H.4
  • 5
    • 84896297653 scopus 로고    scopus 로고
    • Metabolic engineering of a Saccharomyces cerevisiae strain capable of simultaneously utilizing glucose and galactose to produce enantiopure (2R, 3R)-butanediol
    • Lian, J., Chao, R., Zhao, H. Metabolic engineering of a Saccharomyces cerevisiae strain capable of simultaneously utilizing glucose and galactose to produce enantiopure (2R, 3R)-butanediol. Metab. Eng. 23, 92-99 (2014).
    • (2014) Metab. Eng. , vol.23 , pp. 92-99
    • Lian, J.1    Chao, R.2    Zhao, H.3
  • 6
    • 33644797658 scopus 로고    scopus 로고
    • Gene disruption in the budding yeast Saccharomyces cerevisiae
    • Hegemann, J. H., Guldener, U., Kohler, G. J. Gene disruption in the budding yeast Saccharomyces cerevisiae. Methods Mol. Biol. 313, 129-144 (2006).
    • (2006) Methods Mol. Biol. , vol.313 , pp. 129-144
    • Hegemann, J.H.1    Guldener, U.2    Kohler, G.J.3
  • 7
    • 84928205754 scopus 로고    scopus 로고
    • High-throughput functional genomics using CRISPR-Cas9
    • Shalem, O., Sanjana, N. E., Zhang, F. High-throughput functional genomics using CRISPR-Cas9. Nat. Rev. Genet. 16, 299-311 (2015).
    • (2015) Nat. Rev. Genet. , vol.16 , pp. 299-311
    • Shalem, O.1    Sanjana, N.E.2    Zhang, F.3
  • 8
    • 84873729095 scopus 로고    scopus 로고
    • Multiplex genome engineering using CRISPR/Cas systems
    • Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823 (2013).
    • (2013) Science , vol.339 , pp. 819-823
    • Cong, L.1
  • 9
    • 84873734105 scopus 로고    scopus 로고
    • RNA-guided human genome engineering via Cas9
    • Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823-826 (2013).
    • (2013) Science , vol.339 , pp. 823-826
    • Mali, P.1
  • 11
    • 84944632276 scopus 로고    scopus 로고
    • The new state of the art: Cas9 for gene activation and repression
    • La Russa, M. F., Qi, L. S. The new state of the art: Cas9 for gene activation and repression. Mol. Cell. Biol. 35, 3800-3809 (2015).
    • (2015) Mol. Cell. Biol. , vol.35 , pp. 3800-3809
    • La Russa, M.F.1    Qi, L.S.2
  • 12
    • 84884907424 scopus 로고    scopus 로고
    • CRISPR RNA-guided activation of endogenous human genes
    • Maeder, M. L. et al. CRISPR RNA-guided activation of endogenous human genes. Nat. Methods 10, 977-979 (2013).
    • (2013) Nat. Methods , vol.10 , pp. 977-979
    • Maeder, M.L.1
  • 13
    • 84874687019 scopus 로고    scopus 로고
    • Repurposing CRISPR as an RNA-guided platform for sequencespecific control of gene expression
    • Qi, L. S. et al. Repurposing CRISPR as an RNA-guided platform for sequencespecific control of gene expression. Cell 152, 1173-1183 (2013).
    • (2013) Cell , vol.152 , pp. 1173-1183
    • Qi, L.S.1
  • 14
    • 84908352138 scopus 로고    scopus 로고
    • Genome-scale CRISPR-mediated control of gene repression and activation
    • Gilbert, L. A. et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159, 647-661 (2014).
    • (2014) Cell , vol.159 , pp. 647-661
    • Gilbert, L.A.1
  • 15
    • 84920992414 scopus 로고    scopus 로고
    • Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds
    • Zalatan, J. G. et al. Engineering complex synthetic transcriptional programs with CRISPR RNA scaffolds. Cell 160, 339-350 (2015).
    • (2015) Cell , vol.160 , pp. 339-350
    • Zalatan, J.G.1
  • 16
    • 84946471431 scopus 로고    scopus 로고
    • Cas9 gRNA engineering for genome editing, activation and repression
    • Kiani, S. et al. Cas9 gRNA engineering for genome editing, activation and repression. Nat. Methods 12, 1051-1054 (2015).
    • (2015) Nat. Methods , vol.12 , pp. 1051-1054
    • Kiani, S.1
  • 17
    • 84947225411 scopus 로고    scopus 로고
    • Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease
    • Dahlman, J. E. et al. Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease. Nat. Biotechnol. 33, 1159-1161 (2015).
    • (2015) Nat. Biotechnol. , vol.33 , pp. 1159-1161
    • Dahlman, J.E.1
  • 18
    • 84952682854 scopus 로고    scopus 로고
    • CRISPR/Cas9 advances engineering of microbial cell factories
    • Jakociunas, T., Jensen, M. K., Keasling, J. D. CRISPR/Cas9 advances engineering of microbial cell factories. Metab. Eng. 34, 44-59 (2016).
    • (2016) Metab. Eng. , vol.34 , pp. 44-59
    • Jakociunas, T.1    Jensen, M.K.2    Keasling, J.D.3
  • 19
    • 84876575031 scopus 로고    scopus 로고
    • Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems
    • DiCarlo, J. E. et al. Genome engineering in Saccharomyces cerevisiae using CRISPR-Cas systems. Nucleic Acids Res. 41, 4336-4343 (2013).
    • (2013) Nucleic Acids Res. , vol.41 , pp. 4336-4343
    • DiCarlo, J.E.1
  • 20
    • 84929572600 scopus 로고    scopus 로고
    • Homology-integrated CRISPR-Cas (HI-CRISPR) system for onestep multigene disruption in Saccharomyces cerevisiae
    • Bao, Z. et al. Homology-integrated CRISPR-Cas (HI-CRISPR) system for onestep multigene disruption in Saccharomyces cerevisiae. ACS Synth. Biol. 4, 585-594 (2015).
    • (2015) ACS Synth. Biol. , vol.4 , pp. 585-594
    • Bao, Z.1
  • 21
    • 84988917002 scopus 로고    scopus 로고
    • Construction of plasmids with tunable copy numbers in Saccharomyces cerevisiae and their applications in pathway optimization and multiplex genome integration
    • Lian, J., Jin, R., Zhao, H. Construction of plasmids with tunable copy numbers in Saccharomyces cerevisiae and their applications in pathway optimization and multiplex genome integration. Biotechnol. Bioeng. 113, 2462-2473 (2016).
    • (2016) Biotechnol. Bioeng. , vol.113 , pp. 2462-2473
    • Lian, J.1    Jin, R.2    Zhao, H.3
  • 22
    • 85018466549 scopus 로고    scopus 로고
    • A new era of genome integrationsimply cut and paste
    • Liu, Z., Liang, Y., Ang, E. L., Zhao, H. A new era of genome integrationsimply cut and paste. ACS Synth. Biol. 6, 601-609 (2017).
    • (2017) ACS Synth. Biol. , vol.6 , pp. 601-609
    • Liu, Z.1    Liang, Y.2    Ang, E.L.3    Zhao, H.4
  • 23
    • 84880571335 scopus 로고    scopus 로고
    • CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes
    • Gilbert, L. A. et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154, 442-451 (2013).
    • (2013) Cell , vol.154 , pp. 442-451
    • Gilbert, L.A.1
  • 24
    • 84926521955 scopus 로고    scopus 로고
    • Highly efficient Cas9-mediated transcriptional programming
    • Chavez, A. et al. Highly efficient Cas9-mediated transcriptional programming. Nat. Methods 12, 326-328 (2015).
    • (2015) Nat. Methods , vol.12 , pp. 326-328
    • Chavez, A.1
  • 25
    • 84884663630 scopus 로고    scopus 로고
    • Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis
    • Hou, Z. et al. Efficient genome engineering in human pluripotent stem cells using Cas9 from Neisseria meningitidis. Proc. Natl Acad. Sci. USA 110, 15644-15649 (2013).
    • (2013) Proc. Natl Acad. Sci. USA , vol.110 , pp. 15644-15649
    • Hou, Z.1
  • 26
    • 84887104139 scopus 로고    scopus 로고
    • Orthogonal Cas9 proteins for RNA-guided gene regulation and editing
    • Esvelt, K. M. et al. Orthogonal Cas9 proteins for RNA-guided gene regulation and editing. Nat. Methods 10, 1116-1121 (2013).
    • (2013) Nat. Methods , vol.10 , pp. 1116-1121
    • Esvelt, K.M.1
  • 27
    • 84937908208 scopus 로고    scopus 로고
    • Engineered CRISPR-Cas9 nucleases with altered PAM specificities
    • Kleinstiver, B. P. et al. Engineered CRISPR-Cas9 nucleases with altered PAM specificities. Nature 523, 481-485 (2015).
    • (2015) Nature , vol.523 , pp. 481-485
    • Kleinstiver, B.P.1
  • 28
    • 84927514894 scopus 로고    scopus 로고
    • In vivo genome editing using Staphylococcus aureus Cas9
    • Ran, F. A. et al. In vivo genome editing using Staphylococcus aureus Cas9. Nature 520, 186-191 (2015).
    • (2015) Nature , vol.520 , pp. 186-191
    • Ran, F.A.1
  • 29
    • 84975678715 scopus 로고    scopus 로고
    • Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system
    • Zetsche, B. et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163, 759-771 (2015).
    • (2015) Cell , vol.163 , pp. 759-771
    • Zetsche, B.1
  • 30
    • 84917707014 scopus 로고    scopus 로고
    • Sequential control of biosynthetic pathways for balanced utilization of metabolic intermediates in Saccharomyces cerevisiae
    • Xie, W., Ye, L., Lv, X., Xu, H., Yu, H. Sequential control of biosynthetic pathways for balanced utilization of metabolic intermediates in Saccharomyces cerevisiae. Metab. Eng. 28, 8-18 (2015).
    • (2015) Metab. Eng. , vol.28 , pp. 8-18
    • Xie, W.1    Ye, L.2    Lv, X.3    Xu, H.4    Yu, H.5
  • 31
    • 34447543117 scopus 로고    scopus 로고
    • High-level production of beta-carotene in Saccharomyces cerevisiae by successive transformation with carotenogenic genes from Xanthophyllomyces dendrorhous
    • Verwaal, R. et al. High-level production of beta-carotene in Saccharomyces cerevisiae by successive transformation with carotenogenic genes from Xanthophyllomyces dendrorhous. Appl. Environ. Microbiol. 73, 4342-4350 (2007).
    • (2007) Appl. Environ. Microbiol. , vol.73 , pp. 4342-4350
    • Verwaal, R.1
  • 32
    • 84872377725 scopus 로고    scopus 로고
    • Carotenoid-based phenotypic screen of the yeast deletion collection reveals new genes with roles in isoprenoid production
    • Ozaydin, B., Burd, H., Lee, T. S., Keasling, J. D. Carotenoid-based phenotypic screen of the yeast deletion collection reveals new genes with roles in isoprenoid production. Metab. Eng. 15, 174-183 (2013).
    • (2013) Metab. Eng. , vol.15 , pp. 174-183
    • Ozaydin, B.1    Burd, H.2    Lee, T.S.3    Keasling, J.D.4
  • 33
    • 44449098258 scopus 로고    scopus 로고
    • Redirection of flux through the FPP branch-point in Saccharomyces cerevisiae by down-regulating squalene synthase
    • Paradise, E. M., Kirby, J., Chan, R., Keasling, J. D. Redirection of flux through the FPP branch-point in Saccharomyces cerevisiae by down-regulating squalene synthase. Biotechnol. Bioeng. 100, 371-378 (2008).
    • (2008) Biotechnol. Bioeng. , vol.100 , pp. 371-378
    • Paradise, E.M.1    Kirby, J.2    Chan, R.3    Keasling, J.D.4
  • 34
    • 84863629890 scopus 로고    scopus 로고
    • Metabolic engineering of recombinant protein secretion by Saccharomyces cerevisiae
    • Hou, J., Tyo, K. E., Liu, Z., Petranovic, D., Nielsen, J. Metabolic engineering of recombinant protein secretion by Saccharomyces cerevisiae. FEMS Yeast Res. 12, 491-510 (2012).
    • (2012) FEMS Yeast Res. , vol.12 , pp. 491-510
    • Hou, J.1    Tyo, K.E.2    Liu, Z.3    Petranovic, D.4    Nielsen, J.5
  • 35
    • 85020737000 scopus 로고    scopus 로고
    • Automated multiplex genome-scale engineering in yeast
    • Si, T. et al. Automated multiplex genome-scale engineering in yeast. Nat. Commun. 8, 15187 (2017).
    • (2017) Nat. Commun. , vol.8 , pp. 15187
    • Si, T.1
  • 36
    • 84971219370 scopus 로고    scopus 로고
    • N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae
    • Tang, H. et al. N-hypermannose glycosylation disruption enhances recombinant protein production by regulating secretory pathway and cell wall integrity in Saccharomyces cerevisiae. Sci. Rep. 6, 25654 (2016).
    • (2016) Sci. Rep. , vol.6 , pp. 25654
    • Tang, H.1
  • 37
    • 84865278051 scopus 로고    scopus 로고
    • Customized optimization of metabolic pathways by combinatorial transcriptional engineering
    • Du, J., Yuan, Y., Si, T., Lian, J., Zhao, H. Customized optimization of metabolic pathways by combinatorial transcriptional engineering. Nucleic Acids Res. 40, e142 (2012).
    • (2012) Nucleic Acids Res. , vol.40 , pp. e142
    • Du, J.1    Yuan, Y.2    Si, T.3    Lian, J.4    Zhao, H.5
  • 38
    • 77957329119 scopus 로고    scopus 로고
    • Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli
    • Ajikumar, P. K. et al. Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 330, 70-74 (2010).
    • (2010) Science , vol.330 , pp. 70-74
    • Ajikumar, P.K.1
  • 39
    • 84877804801 scopus 로고    scopus 로고
    • Modular optimization of multi-gene pathways for fatty acids production in E. Coli
    • Xu, P. et al. Modular optimization of multi-gene pathways for fatty acids production in E. coli. Nat. Commun. 4, 1409 (2013).
    • (2013) Nat. Commun. , vol.4 , pp. 1409
    • Xu, P.1
  • 41
    • 33747078696 scopus 로고    scopus 로고
    • Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes
    • Pfleger, B. F., Pitera, D. J., Smolke, C. D., Keasling, J. D. Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes. Nat. Biotechnol. 24, 1027-1032 (2006).
    • (2006) Nat. Biotechnol. , vol.24 , pp. 1027-1032
    • Pfleger, B.F.1    Pitera, D.J.2    Smolke, C.D.3    Keasling, J.D.4
  • 42
    • 84881004490 scopus 로고    scopus 로고
    • Use of expressionenhancing terminators in Saccharomyces cerevisiae to increase mRNA half-life and improve gene expression control for metabolic engineering applications
    • Curran, K. A., Karim, A. S., Gupta, A., Alper, H. S. Use of expressionenhancing terminators in Saccharomyces cerevisiae to increase mRNA half-life and improve gene expression control for metabolic engineering applications. Metab. Eng. 19, 88-97 (2013).
    • (2013) Metab. Eng. , vol.19 , pp. 88-97
    • Curran, K.A.1    Karim, A.S.2    Gupta, A.3    Alper, H.S.4
  • 43
    • 84859633048 scopus 로고    scopus 로고
    • Design of a dynamic sensorregulator system for production of chemicals and fuels derived from fatty acids
    • Zhang, F., Carothers, J. M., Keasling, J. D. Design of a dynamic sensorregulator system for production of chemicals and fuels derived from fatty acids. Nat. Biotechnol. 30, 354-359 (2012).
    • (2012) Nat. Biotechnol. , vol.30 , pp. 354-359
    • Zhang, F.1    Carothers, J.M.2    Keasling, J.D.3
  • 44
    • 68949161807 scopus 로고    scopus 로고
    • Programming cells by multiplex genome engineering and accelerated evolution
    • Wang, H. H. et al. Programming cells by multiplex genome engineering and accelerated evolution. Nature 460, 894-898 (2009).
    • (2009) Nature , vol.460 , pp. 894-898
    • Wang, H.H.1
  • 45
  • 46
    • 84862984706 scopus 로고    scopus 로고
    • Strategy for directing combinatorial genome engineering in Escherichia coli
    • Sandoval, N. R. et al. Strategy for directing combinatorial genome engineering in Escherichia coli. Proc. Natl Acad. Sci. USA 109, 10540-10545 (2012).
    • (2012) Proc. Natl Acad. Sci. USA , vol.109 , pp. 10540-10545
    • Sandoval, N.R.1
  • 47
    • 84890920555 scopus 로고    scopus 로고
    • Yeast oligo-mediated genome engineering (YOGE)
    • DiCarlo, J. E. et al. Yeast oligo-mediated genome engineering (YOGE). ACS Synth. Biol. 2, 741-749 (2013).
    • (2013) ACS Synth. Biol. , vol.2 , pp. 741-749
    • DiCarlo, J.E.1
  • 48
    • 85015147103 scopus 로고    scopus 로고
    • Transcriptional reprogramming in yeast using dCas9 and combinatorial gRNA strategies
    • Jensen, E. D. et al. Transcriptional reprogramming in yeast using dCas9 and combinatorial gRNA strategies. Microb. Cell Fact. 16, 46 (2017).
    • (2017) Microb. Cell Fact. , vol.16 , pp. 46
    • Jensen, E.D.1
  • 49
    • 84907483760 scopus 로고    scopus 로고
    • Altered sterol composition renders yeast thermotolerant
    • Caspeta, L. et al. Altered sterol composition renders yeast thermotolerant. Science 346, 75-78 (2014).
    • (2014) Science , vol.346 , pp. 75-78
    • Caspeta, L.1
  • 50
    • 84874499132 scopus 로고    scopus 로고
    • Rational and evolutionary engineering approaches uncover a small set of genetic changes efficient for rapid xylose fermentation in Saccharomyces cerevisiae
    • Kim, S. R. et al. Rational and evolutionary engineering approaches uncover a small set of genetic changes efficient for rapid xylose fermentation in Saccharomyces cerevisiae. PLoS ONE 8, e57048 (2013).
    • (2013) PLoS ONE , vol.8 , pp. e57048
    • Kim, S.R.1
  • 51
    • 59649108349 scopus 로고    scopus 로고
    • DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways
    • Shao, Z., Zhao, H., Zhao, H. DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways. Nucleic Acids Res. 37, e16 (2009).
    • (2009) Nucleic Acids Res. , vol.37 , pp. e16
    • Shao, Z.1    Zhao, H.2    Zhao, H.3
  • 52
    • 84925666935 scopus 로고    scopus 로고
    • Reversal of the-oxidation cycle in Saccharomyces cerevisiae for production of fuels and chemicals
    • Lian, J., Zhao, H. Reversal of the-oxidation cycle in Saccharomyces cerevisiae for production of fuels and chemicals. ACS Synth. Biol. 4, 332-341 (2015).
    • (2015) ACS Synth. Biol. , vol.4 , pp. 332-341
    • Lian, J.1    Zhao, H.2
  • 53
    • 84978708772 scopus 로고    scopus 로고
    • Functional reconstitution of a pyruvate dehydrogenase in the cytosol of Saccharomyces cerevisiae through lipoylation machinery engineering
    • Lian, J., Zhao, H. Functional reconstitution of a pyruvate dehydrogenase in the cytosol of Saccharomyces cerevisiae through lipoylation machinery engineering. ACS Synth. Biol. 5, 689-697 (2016).
    • (2016) ACS Synth. Biol. , vol.5 , pp. 689-697
    • Lian, J.1    Zhao, H.2
  • 55
    • 84923096541 scopus 로고    scopus 로고
    • Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex
    • Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517, 583-588 (2015).
    • (2015) Nature , vol.517 , pp. 583-588
    • Konermann, S.1
  • 56
    • 84960094162 scopus 로고    scopus 로고
    • Quantitative CRISPR interference screens in yeast identify chemical-genetic interactions and new rules for guide RNA design
    • Smith, J. D. et al. Quantitative CRISPR interference screens in yeast identify chemical-genetic interactions and new rules for guide RNA design. Genome Biol. 17, 45 (2016).
    • (2016) Genome Biol. , vol.17 , pp. 45
    • Smith, J.D.1


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