Photo of Gerhard Wagner,  PhD

Gerhard Wagner, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-3213
Fax: (617) 432-4383


wagner@hms.harvard.edu

Gerhard Wagner, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Elkan Blout Professor of Biological Chemistry and Molecular Pharmacology, Biological Chemistry and Molecular Pharmacology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

The research in the Wagner laboratory is focused on protein structure, dynamics and stability, and on the relation of these to protein function. The primary research tool is Nuclear Magnetic Resonance (NMR) spectroscopy. The research is focused on T-cell proteins (CD2, CD58, CD3, TCR, CD2BP2, Nck) and proteins involved in eukaryotic translation initiation (eIF4E, 4EBP, eIF4G, eIF4A, eIF1, eIF1A, eIF5, eIF5B). We also work on proteins important for transcriptional activation (transcriptional activator/coactivator interactions) and on apoptosis proteins from the Bcl-2 family and proteins located in the outer mitochondrial membrane. We are generally interested in identifying small-molecule inhibitors of protein-protein interactions and their potential use as anti-cancer agents. We also are developing a clinical metabolomics platform that jointly uses NMR and mass spectroscopy metabolite-based disease profiling and biomarker identification, targeting chronic myelogenous leukemia.

Publications

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  • Sekiyama N, Arthanari H, Papadopoulos E, Rodriguez-Mias RA, Wagner G, Léger-Abraham M. Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1. Proc Natl Acad Sci U S A 2015. PubMed
  • Leigh KE, Sharma M, Mansueto MS, Boeszoermenyi A, Filman DJ, Hogle JM, Wagner G, Coen DM, Arthanari H. Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication. Proc Natl Acad Sci U S A 2015. PubMed
  • O'Day E, Le MT, Imai S, Tan SM, Kirchner R, Arthanari H, Hofmann O, Wagner G, Lieberman J. An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates. J Biol Chem 2015; 290:17909-22. PubMed
  • Mallis RJ, Bai K, Arthanari H, Hussey RE, Handley M, Li Z, Chingozha L, Duke-Cohan JS, Lu H, Wang JH, Zhu C, Wagner G, Reinherz EL. Pre-TCR ligand binding impacts thymocyte development before αβTCR expression. Proc Natl Acad Sci U S A 2015; 112:8373-8. PubMed
  • Takeuchi K, Sun ZY, Li S, Gal M, Wagner G. NMR resonance assignments of the catalytic domain of human serine/threonine phosphatase calcineurin in unligated and PVIVIT-peptide-bound states. Biomol NMR Assign 2015. PubMed
  • Hagn F, Wagner G. Structure refinement and membrane positioning of selectively labeled OmpX in phospholipid nanodiscs. J Biomol NMR 2015. PubMed
  • Das DK, Feng Y, Mallis RJ, Li X, Keskin DB, Hussey RE, Brady SK, Wang JH, Wagner G, Reinherz EL, Lang MJ. Force-dependent transition in the T-cell receptor β-subunit allosterically regulates peptide discrimination and pMHC bond lifetime. Proc Natl Acad Sci U S A 2015; 112:1517-22. PubMed
  • Akabayov SR, Akabayov B, Wagner G. Human translation initiation factor eIF4G1 possesses a low-affinity ATP binding site facing the ATP-binding cleft of eIF4A in the eIF4G/eIF4A complex. Biochemistry 2014; 53:6422-5. PubMed
  • Yi T, Kabha E, Papadopoulos E, Wagner G. 4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance, proliferation and metastasis. 2014; 5:6028-37. PubMed
  • Linser R, Gelev V, Hagn F, Arthanari H, Hyberts SG, Wagner G. Selective methyl labeling of eukaryotic membrane proteins using cell-free expression. J Am Chem Soc 2014; 136:11308-10. PubMed
  • Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA, Wagner G. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A 2014; 111:E3187-95. PubMed
  • Gal M, Li S, Luna RE, Takeuchi K, Wagner G. The LxVP and PxIxIT NFAT motifs bind jointly to overlapping epitopes on calcineurin's catalytic domain distant to the regulatory domain. Structure 2014; 22:1016-27. PubMed
  • Brazin KN, Mallis RJ, Li C, Keskin DB, Arthanari H, Gao Y, Wu SL, Karger BL, Wagner G, Reinherz EL. Constitutively oxidized CXXC motifs within the CD3 heterodimeric ectodomains of the T cell receptor complex enforce the conformation of juxtaposed segments. J Biol Chem 2014. PubMed
  • Mahalingam P, Takrouri K, Chen T, Sahoo R, Papadopoulos E, Chen L, Wagner G, Aktas BH, Halperin JA, Chorev M. Synthesis of rigidified eIF4E/eIF4G inhibitor-1 (4EGI-1) mimetic and their in vitro characterization as inhibitors of protein-protein interaction. J Med Chem 2014. PubMed
  • Yi T, Zhai B, Yu Y, Kiyotsugu Y, Raschle T, Etzkorn M, Seo HC, Nagiec M, Luna RE, Reinherz EL, Blenis J, Gygi SP, Wagner G. Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. Proc Natl Acad Sci U S A 2014; 111:E2182-90. PubMed
  • Avnir Y, Tallarico AS, Zhu Q, Bennett AS, Connelly G, Sheehan J, Sui J, Fahmy A, Huang CY, Cadwell G, Bankston LA, McGuire AT, Stamatatos L, Wagner G, Liddington RC, Marasco WA. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog. 2014; 10:e1004103. PubMed
  • Takrouri K, Chen T, Papadopoulos E, Sahoo R, Kabha E, Chen H, Cantel S, Wagner G, Halperin JA, Aktas BH, Chorev M. Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors. Eur J Med Chem 2014; 77:361-77. PubMed
  • Luna RE, Akabayov SR, Ziarek JJ, Wagner G. Examining weak protein-protein interactions in start codon recognition via NMR spectroscopy. FEBS J 2014; 281:1965-73. PubMed
  • Yefidoff-Freedman R, Chen T, Sahoo R, Chen L, Wagner G, Halperin JA, Aktas BH, Chorev M. 3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction. Chembiochem 2014; 15:595-611. PubMed
  • Hiraishi H, Oatman J, Haller SL, Blunk L, McGivern B, Morris J, Papadopoulos E, Gutierrez W, Gordon M, Bokhari W, Ikeda Y, Miles D, Fellers J, Asano M, Wagner G, Tazi L, Rothenburg S, Brown SJ, Asano K. Essential role of eIF5-mimic protein in animal development is linked to control of ATF4 expression. Nucleic Acids Res 2014; 42:10321-30. PubMed
  • Schmidt JC, Arthanari H, Boeszoermenyi A, Dashkevich NM, Wilson-Kubalek EM, Monnier N, Markus M, Oberer M, Milligan RA, Bathe M, Wagner G, Grishchuk EL, Cheeseman IM. The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments. Dev Cell 2012; 23:968-80. PubMed
  • Chen L, Aktas BH, Wang Y, He X, Sahoo R, Zhang N, Denoyelle S, Kabha E, Yang H, Freedman RY, Supko JG, Chorev M, Wagner G, Halperin JA. Tumor suppression by small molecule inhibitors of translation initiation. 2012; 3:869-81. PubMed
  • Luna RE, Arthanari H, Hiraishi H, Nanda J, Martin-Marcos P, Markus MA, Akabayov B, Milbradt AG, Luna LE, Seo HC, Hyberts SG, Fahmy A, Reibarkh M, Miles D, Hagner PR, O'Day EM, Yi T, Marintchev A, Hinnebusch AG, Lorsch JR, Asano K, Wagner G. The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2β. Cell Rep 2012; 1:689-702. PubMed
  • Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Näär AM, Wagner G. Structure of the VP16 transactivator target in the Mediator. Nat Struct Mol Biol 2011; 18:410-5. PubMed
  • Kang S, Kwon H, Wen H, Song Y, Frueh D, Ahn HC, Yoo SH, Wagner G, Park S. Global dynamic conformational changes in the suppressor domain of IP3 receptor by stepwise binding of the two lobes of calmodulin. FASEB J 2011; 25:840-50. PubMed
  • Shaw BF, Arthanari H, Narovlyansky M, Durazo A, Frueh DP, Pollastri MP, Lee A, Bilgicer B, Gygi SP, Wagner G, Whitesides GM. Neutralizing Positive Charges at the Surface of a Protein Lowers Its Rate of Amide Hydrogen Exchange without Altering Its Structure or Increasing Its Thermostability. J Am Chem Soc 2010. PubMed
  • Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV, Schaffhausen B, Wagner G, Torchilin V, Yuan J, Degterev A. Small molecule inhibition of phosphatidylinositol-3,4,5-triphosphate (PIP3) binding to pleckstrin homology domains. Proc Natl Acad Sci U S A 2010; 107:20126-31. PubMed
  • Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010; 329:1492-9. PubMed
  • Kim ST, Touma M, Takeuchi K, Sun ZY, Dave VP, Kappes DJ, Wagner G, Reinherz EL. Distinctive CD3 heterodimeric ectodomain topologies maximize antigen-triggered activation of alpha beta T cell receptors. J Immunol 2010; 185:2951-9. PubMed
  • Hiller S, Abramson J, Mannella C, Wagner G, Zeth K. The 3D structures of VDAC represent a native conformation. Trends Biochem Sci 2010; 35:514-21. PubMed
  • Raschle T, Hiller S, Etzkorn M, Wagner G. Nonmicellar systems for solution NMR spectroscopy of membrane proteins. Curr Opin Struct Biol 2010; 20:471-9. PubMed
  • Takeuchi K, Heffron G, Sun ZY, Frueh DP, Wagner G. Nitrogen-detected CAN and CON experiments as alternative experiments for main chain NMR resonance assignments. J Biomol NMR 2010; 47:271-82. PubMed
  • Takeuchi K, Sun ZY, Park S, Wagner G. Autoinhibitory interaction in the multidomain adaptor protein Nck: possible roles in improving specificity and functional diversity. Biochemistry 2010; 49:5634-41. PubMed
  • Takeuchi K, Frueh DP, Sun ZY, Hiller S, Wagner G. CACA-TOCSY with alternate 13C-12C labeling: a 13Calpha direct detection experiment for mainchain resonance assignment, dihedral angle information, and amino acid type identification. J Biomol NMR 2010; 47:55-63. PubMed
  • Hiller S, Malia TJ, Garces RG, Orekhov VY, Wagner G. Backbone and ILV side chain methyl group assignments of the integral human membrane protein VDAC-1. Biomol NMR Assign 2010; 4:29-32. PubMed
  • Takeuchi K, Frueh DP, Hyberts SG, Sun ZY, Wagner G. High-resolution 3D CANCA NMR experiments for complete mainchain assignments using C(alpha) direct detection. J Am Chem Soc 2010; 132:2945-51. PubMed
  • Hyberts SG, Takeuchi K, Wagner G. Poisson-gap sampling and forward maximum entropy reconstruction for enhancing the resolution and sensitivity of protein NMR data. J Am Chem Soc 2010; 132:2145-7. PubMed
  • Zhou P, Wagner G. Overcoming the solubility limit with solubility-enhancement tags: successful applications in biomolecular NMR studies. J Biomol NMR 2010; 46:23-31. PubMed
  • Wagner G. A topical issue: production and labeling of biological macromolecules for NMR investigations. J Biomol NMR 2010; 46:1-2. PubMed
  • Raschle T, Hiller S, Yu TY, Rice AJ, Walz T, Wagner G. Structural and functional characterization of the integral membrane protein VDAC-1 in lipid bilayer nanodiscs. J Am Chem Soc 2009; 131:17777-9. PubMed
  • Kim ST, Takeuchi K, Sun ZY, Touma M, Castro CE, Fahmy A, Lang MJ, Wagner G, Reinherz EL. The alphabeta T cell receptor is an anisotropic mechanosensor. J Biol Chem 2009; 284:31028-37. PubMed
  • Hyberts SG, Frueh DP, Arthanari H, Wagner G. FM reconstruction of non-uniformly sampled protein NMR data at higher dimensions and optimization by distillation. J Biomol NMR 2009; 45:283-94. PubMed
  • Frueh DP, Leed A, Arthanari H, Koglin A, Walsh CT, Wagner G. Time-shared HSQC-NOESY for accurate distance constraints measured at high-field in (15)N-(13)C-ILV methyl labeled proteins. J Biomol NMR 2009; 45:311-8. PubMed
  • Hiller S, Ibraghimov I, Wagner G, Orekhov VY. Coupled decomposition of four-dimensional NOESY spectra. J Am Chem Soc 2009; 131:12970-8. PubMed
  • Frueh DP, Arthanari H, Koglin A, Walsh CT, Wagner G. A double TROSY hNCAnH experiment for efficient assignment of large and challenging proteins. J Am Chem Soc 2009; 131:12880-1. PubMed
  • Yu Y, Marintchev A, Kolupaeva VG, Unbehaun A, Veryasova T, Lai SC, Hong P, Wagner G, Hellen CU, Pestova TV. Position of eukaryotic translation initiation factor eIF1A on the 40S ribosomal subunit mapped by directed hydroxyl radical probing. Nucleic Acids Res 2009; 37:5167-82. PubMed
  • Hiller S, Wagner G. The role of solution NMR in the structure determinations of VDAC-1 and other membrane proteins. Curr Opin Struct Biol 2009; 19:396-401. PubMed
  • Song L,Sun ZY,Coleman KE,Zwick MB,Gach JS,Wang JH,Reinherz EL,Wagner G,Kim M. Broadly neutralizing anti-HIV-1 antibodies disrupt a hinge-related function of gp41 at the membrane interface. Proc Natl Acad Sci U S A 2009; 106:9057-62. PubMed
  • Yoffe Y,Leger M,Zinoviev A,Zuberek J,Darzynkiewicz E,Wagner G,Shapira M. Evolutionary changes in the Leishmania eIF4F complex involve variations in the eIF4E-eIF4G interactions. Nucleic Acids Res 2009; 37:3243-53. PubMed
  • Hemond M,Rothstein TL,Wagner G. Fas apoptosis inhibitory molecule contains a novel beta-sandwich in contact with a partially ordered domain. J Mol Biol 2009; 386:1024-37. PubMed
  • Thakur JK,Arthanari H,Yang F,Chau KH,Wagner G,Naar AM. Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p. J Biol Chem 2008; 284:4422-8. PubMed
  • Marintchev A,Edmonds KA,Marintcheva B,Hendrickson E,Oberer M,Suzuki C,Herdy B,Sonenberg N,Wagner G. Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation. Cell 2009; 136:447-60. PubMed
  • Bodner-Adler B,Bartl M,Wagner G. Intravenous leiomyomatosis of the uterus with pulmonary metastases or a case with benign metastasizing leiomyoma? Anticancer Res 2009; 29:495-6. PubMed
  • Takeuchi K,Sun ZY,Wagner G. Alternate 13C-12C labeling for complete mainchain resonance assignments using C alpha direct-detection with applicability toward fast relaxing protein systems. J Am Chem Soc 2008; 130:17210-1. PubMed
  • Billeter M,Wagner G,Wuthrich K. Solution NMR structure determination of proteins revisited. J Biomol NMR 2008; 42:155-8. PubMed
  • Kang S,Kang J,Kwon H,Frueh D,Yoo SH,Wagner G,Park S. Effects of redox potential and Ca2+ on the inositol 1,4,5-trisphosphate receptor L3-1 loop region: implications for receptor regulation. J Biol Chem 2008; 283:25567-75. PubMed
  • Hiller S,Garces RG,Malia TJ,Orekhov VY,Colombini M,Wagner G. Solution structure of the integral human membrane protein VDAC-1 in detergent micelles. Science 2008; 321:1206-10. PubMed
  • Frueh DP,Arthanari H,Koglin A,Vosburg DA,Bennett AE,Walsh CT,Wagner G. Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature 2008; 454:903-6. PubMed
  • Koglin A,Lohr F,Bernhard F,Rogov VV,Frueh DP,Strieter ER,Mofid MR,Guntert P,Wagner G,Walsh CT,Marahiel MA,Dotsch V. Structural basis for the selectivity of the external thioesterase of the surfactin synthetase. Nature 2008; 454:907-11. PubMed
  • Takeuchi K,Yang H,Ng E,Park SY,Sun ZY,Reinherz EL,Wagner G. Structural and functional evidence that Nck interaction with CD3epsilon regulates T-cell receptor activity. J Mol Biol 2008; 380:704-16. PubMed
  • Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 2008; 4:313-21. PubMed
  • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 2008; 452:604-9. PubMed
  • Suzuki C, Garces RG, Edmonds KA, Hiller S, Hyberts SG, Marintchev A, Wagner G. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc Natl Acad Sci U S A 2008; 105:3274-9. PubMed
  • Selenko P, Frueh DP, Elsaesser SJ, Haas W, Gygi SP, Wagner G. In situ observation of protein phosphorylation by high-resolution NMR spectroscopy. Nat Struct Mol Biol 2008; 15:321-9. PubMed
  • Marintcheva B, Marintchev A, Wagner G, Richardson CC. Acidic C-terminal tail of the ssDNA-binding protein of bacteriophage T7 and ssDNA compete for the same binding surface. Proc Natl Acad Sci U S A 2008; 105:1855-60. PubMed
  • Reibarkh M, Yamamoto Y, Singh CR, del Rio F, Fahmy A, Lee B, Luna RE, Ii M, Wagner G, Asano K. Eukaryotic initiation factor (eIF) 1 carries two distinct eIF5-binding faces important for multifactor assembly and AUG selection. J Biol Chem 2007; 283:1094-103. PubMed
  • Lindqvist L, Oberer M, Reibarkh M, Cencic R, Bordeleau ME, Vogt E, Marintchev A, Tanaka J, Fagotto F, Altmann M, Wagner G, Pelletier J. Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE 2008; 3:e1583. PubMed
  • Sun ZY, Oh KJ, Kim M, Yu J, Brusic V, Song L, Qiao Z, Wang JH, Wagner G, Reinherz EL. HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane. Immunity 2008; 28:52-63. PubMed
  • Tsodikov OV, Ivanov D, Orelli B, Staresincic L, Shoshani I, Oberman R, Scharer OD, Wagner G, Ellenberger T. Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA. EMBO J 2007; 26:4768-76. PubMed
  • Zhong W, Dixit SB, Mallis RJ, Arthanari H, Lugovskoy AA, Beveridge DL, Wagner G, Reinherz EL. CTL recognition of a protective immunodominant influenza A virus nucleoprotein epitope utilizes a highly restricted Vbeta but diverse Valpha repertoire: functional and structural implications. J Mol Biol 2007; 372:535-48. PubMed
  • Catic A, Sun ZY, Ratner DM, Misaghi S, Spooner E, Samuelson J, Wagner G, Ploegh HL. Sequence and structure evolved separately in a ribosomal ubiquitin variant. EMBO J 2007; 26:3474-83. PubMed
  • Unbehaun A, Marintchev A, Lomakin IB, Didenko T, Wagner G, Hellen CU, Pestova TV. Position of eukaryotic initiation factor eIF5B on the 80S ribosome mapped by directed hydroxyl radical probing. EMBO J 2007; 26:3109-23. PubMed
  • Lejard V, Brideau G, Blais F, Salingcarnboriboon R, Wagner G, Roehrl MH, Noda M, Duprez D, Houillier P, Rossert J. Scleraxis and NFATc regulate the expression of the pro-alpha1(I) collagen gene in tendon fibroblasts. J Biol Chem 2007; 282:17665-75. PubMed
  • Ito T, Wagner G. Resonance assignments of the alpha subunit of human eukaryotic initiation factor 2 (heIF2alpha). J Biomol NMR 2006; 38:173. PubMed
  • Lai KP, Law AY, Yeung HY, Lee LS, Wagner GF, Wong CK. Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53. Biochem Biophys Res Commun 2007; 356:968-75. PubMed
  • Takeuchi K, Roehrl MH, Sun ZY, Wagner G. Structure of the Calcineurin-NFAT Complex: Defining a T Cell Activation Switch Using Solution NMR and Crystal Coordinates. Structure 2007; 15:587-597. PubMed
  • Selenko P, Wagner G. Looking into live cells with in-cell NMR spectroscopy. J Struct Biol 2007; 158:244-53. PubMed
  • Ellard JP, McCudden CR, Tanega C, James KA, Ratkovic S, Staples JF, Wagner GF. The respiratory effects of stanniocalcin-1 (STC-1) on intact mitochondria and cells: STC-1 uncouples oxidative phosphorylation and its actions are modulated by nucleotide triphosphates. Mol Cell Endocrinol 2006; 264:90-101. PubMed
  • Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128:257-67. PubMed
  • Selenko P, Serber Z, Gadea B, Ruderman J, Wagner G. Quantitative NMR analysis of the protein G B1 domain in Xenopus laevis egg extracts and intact oocytes. Proc Natl Acad Sci U S A 2006; 103:11904-9. PubMed
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