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Volumn 484, Issue C, 2010, Pages 397-412

Assessment of constitutive activity of a G protein-coupled receptor, Cpr2, in cryptococcus neoformans by heterologous and homologous methods

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE INHIBITOR; G PROTEIN COUPLED RECEPTOR; LEUCINE; LIGAND; PHEROMONE; PROTEIN FAR1; RGS2 PROTEIN; UNCLASSIFIED DRUG;

EID: 78049281859     PISSN: 00766879     EISSN: None     Source Type: Book Series    
DOI: 10.1016/B978-0-12-381298-8.00020-4     Document Type: Chapter
Times cited : (3)

References (53)
  • 1
    • 27644551949 scopus 로고    scopus 로고
    • Identification and linkage mapping of the genes for the putative homeodomain protein (hox1) and the putative pheromone receptor protein homologue (rcb1) in a bipolar basidiomycete, Pholiota nameko
    • Aimi T., et al. Identification and linkage mapping of the genes for the putative homeodomain protein (hox1) and the putative pheromone receptor protein homologue (rcb1) in a bipolar basidiomycete, Pholiota nameko. Curr. Genet. 2005, 48:184-194.
    • (2005) Curr. Genet. , vol.48 , pp. 184-194
    • Aimi, T.1
  • 2
    • 0030668723 scopus 로고    scopus 로고
    • Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP
    • Alspaugh J.A., et al. Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP. Genes Dev. 1997, 11:3206-3217.
    • (1997) Genes Dev. , vol.11 , pp. 3206-3217
    • Alspaugh, J.A.1
  • 4
    • 33845617675 scopus 로고    scopus 로고
    • Sensing the environment: Lessons from fungi
    • Bahn Y.S., et al. Sensing the environment: Lessons from fungi. Nat. Rev. Microbiol. 2007, 5:57-69.
    • (2007) Nat. Rev. Microbiol. , vol.5 , pp. 57-69
    • Bahn, Y.S.1
  • 5
    • 0027506471 scopus 로고
    • The probable arrangement of the helices in G protein-coupled receptors
    • Baldwin J.M. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 1993, 12:1693-1703.
    • (1993) EMBO J. , vol.12 , pp. 1693-1703
    • Baldwin, J.M.1
  • 6
    • 0028588656 scopus 로고
    • Cellular signaling by an agonist-activated receptor/Gs alpha fusion protein
    • Bertin B., et al. Cellular signaling by an agonist-activated receptor/Gs alpha fusion protein. Proc. Natl. Acad. Sci. USA 1994, 91:8827-8831.
    • (1994) Proc. Natl. Acad. Sci. USA , vol.91 , pp. 8827-8831
    • Bertin, B.1
  • 7
    • 0033118334 scopus 로고    scopus 로고
    • Molecular tinkering of G protein-coupled receptors: An evolutionary success
    • Bockaert J., Pin J.P. Molecular tinkering of G protein-coupled receptors: An evolutionary success. EMBO J. 1999, 18:1723-1729.
    • (1999) EMBO J. , vol.18 , pp. 1723-1729
    • Bockaert, J.1    Pin, J.P.2
  • 8
    • 0022422406 scopus 로고
    • The yeast alpha-factor receptor: Structural properties deduced from the sequence of the STE2 gene
    • Burkholder A.C., Hartwell L.H. The yeast alpha-factor receptor: Structural properties deduced from the sequence of the STE2 gene. Nucleic Acids Res. 1985, 13:8463-8475.
    • (1985) Nucleic Acids Res. , vol.13 , pp. 8463-8475
    • Burkholder, A.C.1    Hartwell, L.H.2
  • 9
    • 0021193681 scopus 로고
    • The mammalian beta 2-adrenergic receptor: Reconstitution of functional interactions between pure receptor and pure stimulatory nucleotide binding protein of the adenylate cyclase system
    • Cerione R.A., et al. The mammalian beta 2-adrenergic receptor: Reconstitution of functional interactions between pure receptor and pure stimulatory nucleotide binding protein of the adenylate cyclase system. Biochemistry 1984, 23:4519-4525.
    • (1984) Biochemistry , vol.23 , pp. 4519-4525
    • Cerione, R.A.1
  • 10
    • 0034646649 scopus 로고    scopus 로고
    • A G protein-coupled receptor for UDP-glucose
    • Chambers J.K., et al. A G protein-coupled receptor for UDP-glucose. J. Biol. Chem. 2000, 275:10767-10771.
    • (2000) J. Biol. Chem. , vol.275 , pp. 10767-10771
    • Chambers, J.K.1
  • 11
    • 0025605219 scopus 로고
    • Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2
    • Chang F., Herskowitz I. Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2. Cell 1990, 63:999-1011.
    • (1990) Cell , vol.63 , pp. 999-1011
    • Chang, F.1    Herskowitz, I.2
  • 12
    • 0030923134 scopus 로고    scopus 로고
    • Saccharomyces cerevisiae Mpt5p interacts with Sst2p and plays roles in pheromone sensitivity and recovery from pheromone arrest
    • Chen T., Kurjan J. Saccharomyces cerevisiae Mpt5p interacts with Sst2p and plays roles in pheromone sensitivity and recovery from pheromone arrest. Mol. Cell. Biol. 1997, 17:3429-3439.
    • (1997) Mol. Cell. Biol. , vol.17 , pp. 3429-3439
    • Chen, T.1    Kurjan, J.2
  • 13
    • 0036616588 scopus 로고    scopus 로고
    • Molecular analysis of CPRalpha, a MATalpha-specific pheromone receptor gene of Cryptococcus neoformans
    • Chung S., et al. Molecular analysis of CPRalpha, a MATalpha-specific pheromone receptor gene of Cryptococcus neoformans. Eukaryot. Cell 2002, 1:432-439.
    • (2002) Eukaryot. Cell , vol.1 , pp. 432-439
    • Chung, S.1
  • 14
    • 0037296932 scopus 로고    scopus 로고
    • Functional over-expression of the Stm1 protein, a G-protein-coupled receptor, in Schizosaccharomyces pombe
    • Chung K.S., et al. Functional over-expression of the Stm1 protein, a G-protein-coupled receptor, in Schizosaccharomyces pombe. Biotechnol. Lett. 2003, 25:267-272.
    • (2003) Biotechnol. Lett. , vol.25 , pp. 267-272
    • Chung, K.S.1
  • 15
    • 34147142000 scopus 로고    scopus 로고
    • Yeast-based screening to identify modulators of G-protein signaling using uncontrolled cell division cycle by overexpression of Stm1
    • Chung K.S., et al. Yeast-based screening to identify modulators of G-protein signaling using uncontrolled cell division cycle by overexpression of Stm1. J. Biotechnol. 2007, 129:547-554.
    • (2007) J. Biotechnol. , vol.129 , pp. 547-554
    • Chung, K.S.1
  • 16
    • 0023460928 scopus 로고
    • Pheromonal regulation and sequence of the Saccharomyces cerevisiae SST2 gene: A model for desensitization to pheromone
    • Dietzel C., Kurjan J. Pheromonal regulation and sequence of the Saccharomyces cerevisiae SST2 gene: A model for desensitization to pheromone. Mol. Cell. Biol. 1987, 7:4169-4177.
    • (1987) Mol. Cell. Biol. , vol.7 , pp. 4169-4177
    • Dietzel, C.1    Kurjan, J.2
  • 17
    • 0030274647 scopus 로고    scopus 로고
    • Genomic sciences and the medicine of tomorrow
    • Drews J. Genomic sciences and the medicine of tomorrow. Nat. Biotechnol. 1996, 14:1516-1518.
    • (1996) Nat. Biotechnol. , vol.14 , pp. 1516-1518
    • Drews, J.1
  • 18
    • 0032784390 scopus 로고    scopus 로고
    • Multiple sex pheromones and receptors of a mushroom-producing fungus elicit mating in yeast
    • Fowler T.J., et al. Multiple sex pheromones and receptors of a mushroom-producing fungus elicit mating in yeast. Mol. Biol. Cell. 1999, 10:2559-2572.
    • (1999) Mol. Biol. Cell. , vol.10 , pp. 2559-2572
    • Fowler, T.J.1
  • 19
    • 0009447741 scopus 로고
    • Evidence the yeast STE3 gene encodes a receptor for the peptide pheromone a factor: Gene sequence and implications for the structure of the presumed receptor
    • Hagen D.C., et al. Evidence the yeast STE3 gene encodes a receptor for the peptide pheromone a factor: Gene sequence and implications for the structure of the presumed receptor. Proc. Natl. Acad. Sci. USA 1986, 83:1418-1422.
    • (1986) Proc. Natl. Acad. Sci. USA , vol.83 , pp. 1418-1422
    • Hagen, D.C.1
  • 20
    • 0025865002 scopus 로고
    • Pheromone response elements are necessary and sufficient for basal and pheromone-induced transcription of the FUS1 gene of Saccharomyces cerevisiae
    • Hagen D.C., et al. Pheromone response elements are necessary and sufficient for basal and pheromone-induced transcription of the FUS1 gene of Saccharomyces cerevisiae. Mol. Cell. Biol. 1991, 11:2952-2961.
    • (1991) Mol. Cell. Biol. , vol.11 , pp. 2952-2961
    • Hagen, D.C.1
  • 21
    • 13744253964 scopus 로고    scopus 로고
    • Nutrient control of dimorphic growth in Saccharomyces cerevisiae
    • Springer-Verlag, Berlin, Germany
    • Harashima T., Heitman J. Nutrient control of dimorphic growth in Saccharomyces cerevisiae. Nutrient Induced Responses in Eukaryotic Cells 2004, Vol. 7:131-169. Springer-Verlag, Berlin, Germany.
    • (2004) Nutrient Induced Responses in Eukaryotic Cells , vol.7 , pp. 131-169
    • Harashima, T.1    Heitman, J.2
  • 22
    • 34548478560 scopus 로고    scopus 로고
    • G protein signaling governing cell fate decisions involves opposing Galpha subunits in Cryptococcus neoformans
    • Hsueh Y.P., et al. G protein signaling governing cell fate decisions involves opposing Galpha subunits in Cryptococcus neoformans. Mol. Biol. Cell. 2007, 18:3237-3249.
    • (2007) Mol. Biol. Cell. , vol.18 , pp. 3237-3249
    • Hsueh, Y.P.1
  • 23
    • 65649135441 scopus 로고    scopus 로고
    • A constitutively active GPCR governs morphogenic transitions in Cryptococcus neoformans
    • Hsueh Y.P., et al. A constitutively active GPCR governs morphogenic transitions in Cryptococcus neoformans. EMBO J. 2009, 28:1220-1233.
    • (2009) EMBO J. , vol.28 , pp. 1220-1233
    • Hsueh, Y.P.1
  • 24
    • 0036894726 scopus 로고    scopus 로고
    • Cell identity and sexual development in Cryptococcus neoformans are controlled by the mating-type-specific homeodomain protein Sxi1alpha
    • Hull C.M., et al. Cell identity and sexual development in Cryptococcus neoformans are controlled by the mating-type-specific homeodomain protein Sxi1alpha. Genes Dev. 2002, 16:3046-3060.
    • (2002) Genes Dev. , vol.16 , pp. 3046-3060
    • Hull, C.M.1
  • 25
    • 15244354604 scopus 로고    scopus 로고
    • Sex-specific homeodomain proteins Sxi1alpha and Sxi2a coordinately regulate sexual development in Cryptococcus neoformans
    • Hull C.M., et al. Sex-specific homeodomain proteins Sxi1alpha and Sxi2a coordinately regulate sexual development in Cryptococcus neoformans. Eukaryot. Cell 2005, 4:526-535.
    • (2005) Eukaryot. Cell , vol.4 , pp. 526-535
    • Hull, C.M.1
  • 26
    • 33645217329 scopus 로고    scopus 로고
    • Evolution of the bipolar mating system of the mushroom Coprinellus disseminatus from its tetrapolar ancestors involves loss of mating-type-specific pheromone receptor function
    • James T.Y., et al. Evolution of the bipolar mating system of the mushroom Coprinellus disseminatus from its tetrapolar ancestors involves loss of mating-type-specific pheromone receptor function. Genetics 2006, 172:1877-1891.
    • (2006) Genetics , vol.172 , pp. 1877-1891
    • James, T.Y.1
  • 27
    • 0025353702 scopus 로고
    • Effects of expression of mammalian G alpha and hybrid mammalian-yeast G alpha proteins on the yeast pheromone response signal transduction pathway
    • Kang Y.S., et al. Effects of expression of mammalian G alpha and hybrid mammalian-yeast G alpha proteins on the yeast pheromone response signal transduction pathway. Mol. Cell. Biol. 1990, 10:2582-2590.
    • (1990) Mol. Cell. Biol. , vol.10 , pp. 2582-2590
    • Kang, Y.S.1
  • 28
    • 0025153120 scopus 로고
    • Control of yeast mating signal transduction by a mammalian beta 2-adrenergic receptor and Gs alpha subunit
    • King K., et al. Control of yeast mating signal transduction by a mammalian beta 2-adrenergic receptor and Gs alpha subunit. Science 1990, 250:121-123.
    • (1990) Science , vol.250 , pp. 121-123
    • King, K.1
  • 29
    • 0032547154 scopus 로고    scopus 로고
    • Mutagenesis of human Mel1a melatonin receptor expressed in yeast reveals domains important for receptor function
    • Kokkola T., et al. Mutagenesis of human Mel1a melatonin receptor expressed in yeast reveals domains important for receptor function. Biochem. Biophys. Res. Commun. 1998, 249:531-536.
    • (1998) Biochem. Biophys. Res. Commun. , vol.249 , pp. 531-536
    • Kokkola, T.1
  • 30
    • 0030990397 scopus 로고    scopus 로고
    • A novel system that reports the G-proteins linked to a given receptor: A study of type 3 somatostatin receptor
    • Komatsuzaki K., et al. A novel system that reports the G-proteins linked to a given receptor: A study of type 3 somatostatin receptor. FEBS Lett. 1997, 406:165-170.
    • (1997) FEBS Lett. , vol.406 , pp. 165-170
    • Komatsuzaki, K.1
  • 31
    • 0029900790 scopus 로고    scopus 로고
    • Mutation of Pro-258 in transmembrane domain 6 constitutively activates the G protein-coupled alpha-factor receptor
    • Konopka J.B., et al. Mutation of Pro-258 in transmembrane domain 6 constitutively activates the G protein-coupled alpha-factor receptor. Proc. Natl. Acad. Sci. USA 1996, 93:6764-6769.
    • (1996) Proc. Natl. Acad. Sci. USA , vol.93 , pp. 6764-6769
    • Konopka, J.B.1
  • 32
    • 0020353195 scopus 로고
    • + and GTP in inhibitory regulation of adenylate cyclase
    • + and GTP in inhibitory regulation of adenylate cyclase. J. Biol. Chem. 1982, 257:14035-14040.
    • (1982) J. Biol. Chem. , vol.257 , pp. 14035-14040
    • Koski, G.1
  • 33
    • 0030879688 scopus 로고    scopus 로고
    • Genetic analysis of receptor-Galphaq coupling selectivity
    • Kostenis E., et al. Genetic analysis of receptor-Galphaq coupling selectivity. J. Biol. Chem. 1997, 272:23675-23681.
    • (1997) J. Biol. Chem. , vol.272 , pp. 23675-23681
    • Kostenis, E.1
  • 34
    • 0032986914 scopus 로고    scopus 로고
    • A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose
    • Kraakman L., et al. A Saccharomyces cerevisiae G-protein coupled receptor, Gpr1, is specifically required for glucose activation of the cAMP pathway during the transition to growth on glucose. Mol. Microbiol. 1999, 32:1002-1012.
    • (1999) Mol. Microbiol. , vol.32 , pp. 1002-1012
    • Kraakman, L.1
  • 35
    • 13144265744 scopus 로고    scopus 로고
    • A constitutively active GPCR retains its G protein specificity and the ability to form dimers
    • Ladds G., et al. A constitutively active GPCR retains its G protein specificity and the ability to form dimers. Mol. Microbiol. 2005, 55:482-497.
    • (2005) Mol. Microbiol. , vol.55 , pp. 482-497
    • Ladds, G.1
  • 36
    • 33644850470 scopus 로고    scopus 로고
    • Interacting residues in an activated state of a G protein-coupled receptor
    • Lee Y.H., et al. Interacting residues in an activated state of a G protein-coupled receptor. J. Biol. Chem. 2006, 281:2263-2272.
    • (2006) J. Biol. Chem. , vol.281 , pp. 2263-2272
    • Lee, Y.H.1
  • 37
    • 0034444677 scopus 로고    scopus 로고
    • Signal transduction cascades regulating fungal development and virulence
    • Lengeler K.B., et al. Signal transduction cascades regulating fungal development and virulence. Microbiol. Mol. Biol. Rev. 2000, 64:746-785.
    • (2000) Microbiol. Mol. Biol. Rev. , vol.64 , pp. 746-785
    • Lengeler, K.B.1
  • 38
    • 35948947869 scopus 로고    scopus 로고
    • Canonical heterotrimeric G proteins regulating mating and virulence of Cryptococcus neoformans
    • Li L., et al. Canonical heterotrimeric G proteins regulating mating and virulence of Cryptococcus neoformans. Mol. Biol. Cell. 2007, 18:4201-4209.
    • (2007) Mol. Biol. Cell. , vol.18 , pp. 4201-4209
    • Li, L.1
  • 39
    • 0035719181 scopus 로고    scopus 로고
    • Functional assays for mammalian G-protein-coupled receptors in yeast
    • Mentesana P.E., et al. Functional assays for mammalian G-protein-coupled receptors in yeast. Methods Enzymol. 2002, 344:92-111.
    • (2002) Methods Enzymol. , vol.344 , pp. 92-111
    • Mentesana, P.E.1
  • 40
    • 0028263498 scopus 로고
    • Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor
    • Milano C.A., et al. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science 1994, 264:582-586.
    • (1994) Science , vol.264 , pp. 582-586
    • Milano, C.A.1
  • 41
    • 0033577779 scopus 로고    scopus 로고
    • A constitutively active G-protein-coupled receptor causes mating self-compatibility in the mushroom Coprinus
    • Olesnicky N.S., et al. A constitutively active G-protein-coupled receptor causes mating self-compatibility in the mushroom Coprinus. EMBO J. 1999, 18:2756-2763.
    • (1999) EMBO J. , vol.18 , pp. 2756-2763
    • Olesnicky, N.S.1
  • 42
    • 0028840683 scopus 로고
    • Functional coupling of a mammalian somatostatin receptor to the yeast pheromone response pathway
    • Price L.A., et al. Functional coupling of a mammalian somatostatin receptor to the yeast pheromone response pathway. Mol. Cell. Biol. 1995, 15:6188-6195.
    • (1995) Mol. Cell. Biol. , vol.15 , pp. 6188-6195
    • Price, L.A.1
  • 43
    • 0029862555 scopus 로고    scopus 로고
    • Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway
    • Price L.A., et al. Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway. Mol. Pharmacol. 1996, 50:829-837.
    • (1996) Mol. Pharmacol. , vol.50 , pp. 829-837
    • Price, L.A.1
  • 44
    • 33744948051 scopus 로고    scopus 로고
    • Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity
    • Rosenkilde M.M., et al. Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity. J. Biol. Chem. 2006, 281:13199-13208.
    • (2006) J. Biol. Chem. , vol.281 , pp. 13199-13208
    • Rosenkilde, M.M.1
  • 45
    • 0036033424 scopus 로고    scopus 로고
    • Constitutive activity of G-protein-coupled receptors: Cause of disease and common property of wild-type receptors
    • Seifert R., Wenzel-Seifert K. Constitutive activity of G-protein-coupled receptors: Cause of disease and common property of wild-type receptors. Naunyn Schmiedebergs Arch. Pharmacol. 2002, 366:381-416.
    • (2002) Naunyn Schmiedebergs Arch. Pharmacol. , vol.366 , pp. 381-416
    • Seifert, R.1    Wenzel-Seifert, K.2
  • 46
    • 0034643882 scopus 로고    scopus 로고
    • A limited spectrum of mutations causes constitutive activation of the yeast alpha-factor receptor
    • Sommers C.M., et al. A limited spectrum of mutations causes constitutive activation of the yeast alpha-factor receptor. Biochemistry 2000, 39:6898-6909.
    • (2000) Biochemistry , vol.39 , pp. 6898-6909
    • Sommers, C.M.1
  • 47
    • 0031941108 scopus 로고    scopus 로고
    • Mechanisms governing the activation and trafficking of yeast G protein-coupled receptors
    • Stefan C.J., et al. Mechanisms governing the activation and trafficking of yeast G protein-coupled receptors. Mol. Biol. Cell. 1998, 9:885-899.
    • (1998) Mol. Biol. Cell. , vol.9 , pp. 885-899
    • Stefan, C.J.1
  • 48
    • 0029360448 scopus 로고
    • Somatic and germline mutations of the TSH receptor gene in thyroid diseases
    • Van Sande J., et al. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J. Clin. Endocrinol. Metab. 1995, 80:2577-2585.
    • (1995) J. Clin. Endocrinol. Metab. , vol.80 , pp. 2577-2585
    • Van Sande, J.1
  • 49
    • 0031437841 scopus 로고    scopus 로고
    • Measurement of agonist efficacy using an alpha2A-adrenoceptor-Gi1alpha fusion protein
    • Wise A., et al. Measurement of agonist efficacy using an alpha2A-adrenoceptor-Gi1alpha fusion protein. FEBS Lett. 1997, 419:141-146.
    • (1997) FEBS Lett. , vol.419 , pp. 141-146
    • Wise, A.1
  • 50
    • 31944437746 scopus 로고    scopus 로고
    • G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans
    • Xue C., et al. G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans. Mol. Biol. Cell. 2006, 17:667-679.
    • (2006) Mol. Biol. Cell. , vol.17 , pp. 667-679
    • Xue, C.1
  • 51
    • 52649135641 scopus 로고    scopus 로고
    • The RGS protein Crg2 regulates both pheromone and cAMP signalling in Cryptococcus neoformans
    • Xue C., et al. The RGS protein Crg2 regulates both pheromone and cAMP signalling in Cryptococcus neoformans. Mol. Microbiol. 2008, 70:379-395.
    • (2008) Mol. Microbiol. , vol.70 , pp. 379-395
    • Xue, C.1
  • 52
    • 53749087941 scopus 로고    scopus 로고
    • Magnificent seven: Roles of G protein-coupled receptors in extracellular sensing in fungi
    • Xue C., et al. Magnificent seven: Roles of G protein-coupled receptors in extracellular sensing in fungi. FEMS Microbiol. Rev. 2008, 32:1010-1032.
    • (2008) FEMS Microbiol. Rev. , vol.32 , pp. 1010-1032
    • Xue, C.1
  • 53
    • 2442716363 scopus 로고    scopus 로고
    • Probing receptor structure/function with chimeric G-protein-coupled receptors
    • Yin D., et al. Probing receptor structure/function with chimeric G-protein-coupled receptors. Mol. Pharmacol. 2004, 65:1323-1332.
    • (2004) Mol. Pharmacol. , vol.65 , pp. 1323-1332
    • Yin, D.1


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