Information

Related Research Units

Dana Farber Boston Childrens Cancer and Blood Disorders Center Research
Hematology and Oncology Research

Research Overview

Samuel Lux's research has focused on anemias, particularly spherocytosis and other membrane disorders of red blood cells. For the three decades, work in his laboratory has focused on the organization and functions of the spectrin-based membrane skeleton: Spectrin function. Spectrin is the major protein of the membrane skeleton. Spectrins are composed of two long flexible chains (α and β) that bind side to side. Spectrins self-associate at one end, and bind to actin with the help of protein 4.1 at the other end. Dr. Lux is studying the spectrin-actin interaction because it is poorly understood. He has helped characterize the actin and protein 4.1 binding sites at the end of beta spectrin, in collaboration with a colleague, Mohandas Narla, and has found that the neighboring portion of alpha spectrin, which was previously considered inert, binds protein 4.2 in a Ca2+-dependent manner, and is necessary for actin binding. He has also discovered new interactions between proteins 4.1 and 4.2, and between the actin binding regions on alpha and beta spectrin, all of which suggests a macromolecular complex containing multiple proteins involved in actin binding and in attachment of the membrane skeleton at the far end of spectrin to the overlying lipid bilayer. Three mouse mutations with defects in the domain that have different and interesting phenotypes have recently been discovered by Dr Lux’s collaborator at The Jackson Laboratory, in Bar Harbor, Maine. They imply even more undiscovered functions. Hereditary spherocytosis. Dr. Lux and other researchers have shown that hereditary spherocytosis (HS) is caused by defects in the connections that attach the membrane skeleton to the overlying lipid bilayer. He continues to investigate the causes of the disease and the consequences of treatments like splenectomy, particularly the possibility that splenectomy may predispose HS patients to thromboembolic disease or pulmonary hypertension. Resident education. Dr. Lux is collaborating with Drs Vincent Chiang, Fredrick Lovejoy and Stavroula Osganian to understand the outcomes of pediatric residents trained in different pathways at Children’s Hospital Boston in the hope of improving residency selection and training.

 

Research Background

Samuel E. Lux received his MD in 1967 from Kansas University School of Medicine. He completed an internship and residency at Children's Hospital in Boston and fellowships in protein chemistry at the National Institutes of Health and in hematology/oncology at Children's. He also spent two years with Harvey Lodish at the Whitehead Institute in 1985-1987 studying molecular biology. He is the recipient of numerous honors and awards for teaching and research, including the E. Mead Johnson Award for research from the Society for Pediatric Research and American Society of Hematology's prestigious Dameshek and E. Donnall Thomas Awards for pioneering research and the Society's Mentoring Award.

Selected Publications

  1. Eber SW, Gonzalez JM, Lux ML, Scarpa AL, Tse WT, Dornwell M, Herbers J, Kugler W, Ozcan R, Pekrun A, Gallagher PG, Schrter W, Forget BG, Lux SE. Ankyrin 1 mutations are a major cause of dominant and recessive spherocytosis. Nat Genet 1996; 13:214-18.
  2. Peters LL, Shivdasani RA, Liu S-C, Hanspal M, John KM, Gonzalez J, Brugnara C, Gwynn B, Mohandas N, Alper S, Orkin S, Lux SE. Anion exchanger 1 (Band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell 1996; 86: 917-927.
  3. Peters LL. Swearingen RA. Andersen SG. Gwynn B. Lambert AJ. Li R. Lux SE. Churchill GA. Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood 2004; 103:3233-40.
  4. An X, Debnath G, Guo X, Liu S, Lux SE, Baines A, Gratzer W, Mohandas N. Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate. Biochemistry 2005; 44:10681-8.
  5. Robledo RF, Lambert AJ, Birkenmeier CS, Cirlan MV, Cirlan AF, Campagna DR, Lux SE, Peters LL. Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha spectrin deficient red cells. Blood, 2010; 115:1804-14.
  6. Stankewich MC, Gwynn B, Ardito T, Ji L, Kim J, Robledo R, Lux SE, Peters LL and Morrow JS. Targeted deletion of beta III spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc Natl Acad Sci USA 2010; 107:6022-7.
  7. Korsgren C, Peters LL, Lux SE. Protein 4.2 binds to the carboxyterminal EF-hands of erythroid alpha-spectrin in a calcium and calmodulin dependent manner. J Biol Chem 2010; 285:4757-70.
  8. Korsgren C, Lux SE. The carboxyterminal EF-hands of erythroid alpha-spectrin are necessary for optimal spectrin-actin binding. Blood, 2010, in press [Blood First Edition Paper, prepublished online June 28, 2010].

Education

Medical School

Kansas University Medical School
1967 Kansas City MO

Internship

Boston Children's Hospital
1968 Boton MA

Residency

Boston Children's Hospital
1969 Boston MA

Fellowship

Boston Children's Hospital
1973 Boston MA

Publications

  1. Application Factors Associated With Clinical Performance During Pediatric Internship. Acad Pediatr. 2020 Sep - Oct; 20(7):1007-1012. View Abstract
  2. Exome sequencing results in successful diagnosis and treatment of a severe congenital anemia. Cold Spring Harb Mol Case Stud. 2016 Jul; 2(4):a000885. View Abstract
  3. Anatomy of the red cell membrane skeleton: unanswered questions. Blood. 2016 Jan 14; 127(2):187-99. View Abstract
  4. Loss-of-function and gain-of-function phenotypes of stomatocytosis mutant RhAG F65S. Am J Physiol Cell Physiol. 2011 Dec; 301(6):C1325-43. View Abstract
  5. Training program in cancer and blood diseases: Pediatric Hematology/Oncology Fellowship Program, Children's Hospital Boston/Dana-Farber Cancer Institute. Am J Hematol. 2010 Oct; 85(10):793-4. View Abstract
  6. The carboxyterminal EF domain of erythroid alpha-spectrin is necessary for optimal spectrin-actin binding. Blood. 2010 Oct 07; 116(14):2600-7. View Abstract
  7. Targeted deletion of betaIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes. Proc Natl Acad Sci U S A. 2010 Mar 30; 107(13):6022-7. View Abstract
  8. Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha-spectrin-deficient red cells. Blood. 2010 Mar 04; 115(9):1804-14. View Abstract
  9. Protein 4.2 binds to the carboxyl-terminal EF-hands of erythroid alpha-spectrin in a calcium- and calmodulin-dependent manner. J Biol Chem. 2010 Feb 12; 285(7):4757-70. View Abstract
  10. A uniform third-year application and offer date for pediatric fellow applicants: pro and con. J Pediatr. 2006 Nov; 149(5):587-588. View Abstract
  11. Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate. Biochemistry. 2005 Aug 09; 44(31):10681-8. View Abstract
  12. Hereditary spherocytosis--defects in proteins that connect the membrane skeleton to the lipid bilayer. Semin Hematol. 2004 Apr; 41(2):118-41. View Abstract
  13. A functional magnetic resonance imaging study of local/global processing with stimulus presentation in the peripheral visual hemifields. Neuroscience. 2004; 124(1):113-20. View Abstract
  14. Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood. 2004 Apr 15; 103(8):3233-40. View Abstract
  15. Simultaneous (AC)n microsatellite polymorphism analysis and single-stranded conformation polymorphism screening is an efficient strategy for detecting ankyrin-1 mutations in dominant hereditary spherocytosis. Br J Haematol. 2003 Aug; 122(4):669-77. View Abstract
  16. Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency. Nat Genet. 2003 May; 34(1):59-64. View Abstract
  17. A new spectrin, beta IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix. J Biol Chem. 2001 Jun 29; 276(26):23974-85. View Abstract
  18. The human ankyrin-1 gene is selectively transcribed in erythroid cell lines despite the presence of a housekeeping-like promoter. Blood. 2000 Aug 01; 96(3):1136-43. View Abstract
  19. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000 Feb 17; 403(6771):776-81. View Abstract
  20. Immunolocalization of AE2 anion exchanger in rat and mouse epididymis. Biol Reprod. 1999 Oct; 61(4):973-80. View Abstract
  21. Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing CNS. J Neurosci. 1999 Sep 01; 19(17):7516-28. View Abstract
  22. The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons. Brain Res Mol Brain Res. 1999 Jun 08; 69(2):273-80. View Abstract
  23. Mild spherocytosis and altered red cell ion transport in protein 4. 2-null mice. J Clin Invest. 1999 Jun; 103(11):1527-37. View Abstract
  24. Red blood cell membrane disorders. Br J Haematol. 1999 Jan; 104(1):2-13. View Abstract
  25. Notch1 inhibits neurite outgrowth in postmitotic primary neurons. Neuroscience. 1999; 93(2):433-9. View Abstract
  26. Regulation of band 3 rotational mobility by ankyrin in intact human red cells. Biochemistry. 1998 Dec 22; 37(51):17828-35. View Abstract
  27. A widely expressed betaIII spectrin associated with Golgi and cytoplasmic vesicles. Proc Natl Acad Sci U S A. 1998 Nov 24; 95(24):14158-63. View Abstract
  28. Distribution of epithelial ankyrin (Ank3) spliceoforms in renal proximal and distal tubules. Am J Physiol. 1998 01; 274(1):F129-38. View Abstract
  29. Structure and organization of the human ankyrin-1 gene. Basis for complexity of pre-mRNA processing. J Biol Chem. 1997 Aug 01; 272(31):19220-8. View Abstract
  30. Isoforms of ankyrin-3 that lack the NH2-terminal repeats associate with mouse macrophage lysosomes. J Cell Biol. 1997 Mar 10; 136(5):1059-70. View Abstract
  31. Anion exchanger 1 (band 3) is required to prevent erythrocyte membrane surface loss but not to form the membrane skeleton. Cell. 1996 Sep 20; 86(6):917-27. View Abstract
  32. Isolated beta-globin chains reproduce, in normal red cell membranes, the defective binding of spectrin to alpha-thalassaemic membranes. Br J Haematol. 1996 Aug; 94(2):273-8. View Abstract
  33. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nat Genet. 1996 Jun; 13(2):214-8. View Abstract
  34. Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. Proc Natl Acad Sci U S A. 1996 May 28; 93(11):5663-7. View Abstract
  35. A nonsense mutation in the erythrocyte band 3 gene associated with decreased mRNA accumulation in a kindred with dominant hereditary spherocytosis. J Clin Invest. 1996 Jan 15; 97(2):373-80. View Abstract
  36. Differential expression of Na(+)-K(+)-ATPase, ankyrin, fodrin, and E-cadherin along the kidney nephron. Am J Physiol. 1995 Dec; 269(6 Pt 1):C1417-32. View Abstract
  37. Increased cation permeability in mutant mouse red blood cells with defective membrane skeletons. Blood. 1995 Dec 01; 86(11):4307-14. View Abstract
  38. Characterization of the binary interaction between human erythrocyte protein 4.1 and actin. Eur J Biochem. 1995 Aug 01; 231(3):644-50. View Abstract
  39. Ank3 (epithelial ankyrin), a widely distributed new member of the ankyrin gene family and the major ankyrin in kidney, is expressed in alternatively spliced forms, including forms that lack the repeat domain. J Cell Biol. 1995 Jul; 130(2):313-30. View Abstract
  40. Chromosomal location of the murine anion exchanger genes encoding AE2 and AE3. Mamm Genome. 1994 Dec; 5(12):827-9. View Abstract
  41. Combined spectrin and ankyrin deficiency is common in autosomal dominant hereditary spherocytosis. Blood. 1993 Nov 15; 82(10):2953-60. View Abstract
  42. A highly conserved region of human erythrocyte ankyrin contains the capacity to bind spectrin. J Biol Chem. 1993 Nov 15; 268(32):24421-6. View Abstract
  43. Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1. J Clin Invest. 1993 Aug; 92(2):612-6. View Abstract
  44. Complex patterns of sequence variation and multiple 5' and 3' ends are found among transcripts of the erythroid ankyrin gene. J Biol Chem. 1993 May 05; 268(13):9533-40. View Abstract
  45. Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2. Nature. 1993 Apr 22; 362(6422):768-70. View Abstract
  46. Ankyrins: structure and function in normal cells and hereditary spherocytes. Semin Hematol. 1993 Apr; 30(2):85-118. View Abstract
  47. The murine pallid mutation is a platelet storage pool disease associated with the protein 4.2 (pallidin) gene. Nat Genet. 1992 Sep; 2(1):80-3. View Abstract
  48. Expression, purification, and characterization of the functional dimeric cytoplasmic domain of human erythrocyte band 3 in Escherichia coli. Protein Sci. 1992 Sep; 1(9):1206-14. View Abstract
  49. Changing patterns in cytoskeletal mRNA expression and protein synthesis during murine erythropoiesis in vivo. Proc Natl Acad Sci U S A. 1992 Jul 01; 89(13):5749-53. View Abstract
  50. Murine erythrocyte ankyrin cDNA: highly conserved regions of the regulatory domain. Mamm Genome. 1992; 3(5):281-5. View Abstract
  51. Large numbers of alternatively spliced isoforms of the regulatory region of human erythrocyte ankyrin. Trans Assoc Am Physicians. 1992; 105:268-77. View Abstract
  52. Purkinje cell degeneration associated with erythroid ankyrin deficiency in nb/nb mice. J Cell Biol. 1991 Sep; 114(6):1233-41. View Abstract
  53. Isolation and chromosomal localization of a novel nonerythroid ankyrin gene. Genomics. 1991 Aug; 10(4):858-66. View Abstract
  54. Radiolabel-transfer cross-linking demonstrates that protein 4.1 binds to the N-terminal region of beta spectrin and to actin in binary interactions. Eur J Biochem. 1990 Nov 13; 193(3):827-36. View Abstract
  55. Linkage of dominant hereditary spherocytosis to the gene for the erythrocyte membrane-skeleton protein ankyrin. N Engl J Med. 1990 Oct 11; 323(15):1046-50. View Abstract
  56. Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8. Nature. 1990 Jun 21; 345(6277):736-9. View Abstract
  57. Ankyrin and the hemolytic anemia mutation, nb, map to mouse chromosome 8: presence of the nb allele is associated with a truncated erythrocyte ankyrin. Proc Natl Acad Sci U S A. 1990 Apr; 87(8):3117-21. View Abstract
  58. Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins. Nature. 1990 Mar 01; 344(6261):36-42. View Abstract
  59. Demonstration of the deletion of a copy of the ankyrin gene in a patient with hereditary spherocytosis by in situ hybridization. Trans Assoc Am Physicians. 1990; 103:242-8. View Abstract
  60. Cloning and characterization of band 3, the human erythrocyte anion-exchange protein (AE1). Proc Natl Acad Sci U S A. 1989 Dec; 86(23):9089-93. View Abstract
  61. Hereditary disorders of the red cell membrane skeleton. Trends Genet. 1989 Jul; 5(7):222-7. View Abstract
  62. Mapping the ankyrin-binding site of the human erythrocyte anion exchanger. J Biol Chem. 1989 Jun 05; 264(16):9665-72. View Abstract
  63. Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia. J Clin Invest. 1989 Feb; 83(2):404-10. View Abstract
  64. Hemoglobin Brockton [beta 138 (H16) Ala----Pro]: an unstable variant near the C-terminus of the beta-subunits with normal oxygen-binding properties. Biochemistry. 1988 Oct 04; 27(20):7614-9. View Abstract
  65. Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding. J Clin Invest. 1987 Aug; 80(2):557-65. View Abstract
  66. Molecular defect in the membrane skeleton of blood bank-stored red cells. Abnormal spectrin-protein 4.1-actin complex formation. J Clin Invest. 1986 Dec; 78(6):1681-6. View Abstract
  67. Cation depletion by the sodium pump in red cells with pathologic cation leaks. Sickle cells and xerocytes. J Clin Invest. 1986 Dec; 78(6):1487-96. View Abstract
  68. The effect of mild diamide oxidation on the structure and function of human erythrocyte spectrin. J Biol Chem. 1986 Apr 05; 261(10):4620-8. View Abstract
  69. An examination of the soluble oligomeric complexes extracted from the red cell membrane and their relation to the membrane cytoskeleton. Eur J Cell Biol. 1985 Mar; 36(2):299-306. View Abstract
  70. Hereditary spherocytosis and related disorders. Clin Haematol. 1985 Feb; 14(1):15-43. View Abstract
  71. The effect of oxidation on the structure and function of human erythrocyte spectrin. Prog Clin Biol Res. 1985; 195:185-93. View Abstract
  72. Molecular defect in the sickle erythrocyte skeleton. Abnormal spectrin binding to sickle inside-our vesicles. J Clin Invest. 1985 Jan; 75(1):266-71. View Abstract
  73. Platelet membrane glycoprotein IIIa contains target antigens that bind anti-platelet antibodies in immune thrombocytopenias. J Clin Invest. 1984 Nov; 74(5):1701-7. View Abstract
  74. The erythrocyte membrane skeleton: pathophysiology. Hosp Pract (Off Ed). 1984 Nov; 19(11):89-95, 99, 103 passim. View Abstract
  75. The erythrocyte membrane skeleton: biochemistry. Hosp Pract (Off Ed). 1984 Oct; 19(10):77-83. View Abstract
  76. Analysis of the ternary interaction of the red cell membrane skeletal proteins spectrin, actin, and 4.1. Biochemistry. 1984 Sep 11; 23(19):4416-20. View Abstract
  77. An analogue of the erythroid membrane skeletal protein 4.1 in nonerythroid cells. J Cell Biol. 1984 Sep; 99(3):886-93. View Abstract
  78. A phenomenological difference between membrane skeletal protein complexes isolated from normal and hereditary spherocytosis erythrocytes. Br J Haematol. 1983 Nov; 55(3):455-63. View Abstract
  79. High yield purification of protein 4.1 from human erythrocyte membranes. Anal Biochem. 1983 Jul 01; 132(1):195-201. View Abstract
  80. Red cell membrane skeletal defects in hereditary and acquired hemolytic anemias. Semin Hematol. 1983 Jul; 20(3):189-224. View Abstract
  81. Hemolytic anemia in the mouse. Report of a new mutation and clarification of its genetics. J Hered. 1983 Mar-Apr; 74(2):88-92. View Abstract
  82. A genetic defect in the binding of protein 4.1 to spectrin in a kindred with hereditary spherocytosis. N Engl J Med. 1982 Nov 25; 307(22):1367-74. View Abstract
  83. A technique to detect reduced mechanical stability of red cell membranes: relevance to elliptocytic disorders. Blood. 1982 Apr; 59(4):768-74. View Abstract
  84. Exercise-induced hemolysis in xerocytosis. Erythrocyte dehydration and shear sensitivity. J Clin Invest. 1981 Sep; 68(3):631-8. View Abstract
  85. Elliptical erythrocyte membrane skeletons and heat-sensitive spectrin in hereditary elliptocytosis. Proc Natl Acad Sci U S A. 1981 Mar; 78(3):1911-5. View Abstract
  86. Hemolytic anemias due to abnormalities in red cell spectrin: a brief review. Prog Clin Biol Res. 1981; 45:159-68. View Abstract
  87. Structural characterization of the phosphorylation sites of human erythrocyte spectrin. J Biol Chem. 1980 Dec 10; 255(23):11512-20. View Abstract
  88. Comparison of the phosphorylation of human erythrocyte spectrin in the intact red cell and in various cell-free systems. J Biol Chem. 1980 Dec 10; 255(23):11521-5. View Abstract
  89. Inherited disorders of the red cell membrane skeleton. Pediatr Clin North Am. 1980 May; 27(2):463-86. View Abstract
  90. Dissecting the red cell membrane skeleton. Nature. 1979 Oct 11; 281(5731):426-9. View Abstract
  91. Spectrin-actin membrane skeleton of normal and abnormal red blood cells. Semin Hematol. 1979 Jan; 16(1):21-51. View Abstract
  92. Hemolytic anemias associated with deficient or dysfunctional spectrin. Prog Clin Biol Res. 1979; 30:463-9. View Abstract
  93. Energy reserve and cation composition of irreversibly sickled cells in vivo. Br J Haematol. 1978 Dec; 40(4):527-32. View Abstract
  94. Membrane protein phosphorylation of intact normal and hereditary spherocytic erythrocytes. J Biol Chem. 1978 May 10; 253(9):3336-42. View Abstract
  95. Diminished spectrin extraction from ATP-depleted human erythrocytes. Evidence relating spectrin to changes in erythrocyte shape and deformability. J Clin Invest. 1978 Mar; 61(3):815-27. View Abstract
  96. Isolation and partial characterization of a high molecular weight red cell membrane protein complex normally removed by the spleen. Blood. 1977 Oct; 50(4):625-41. View Abstract
  97. Evidence that spectrin is a determinant of shape and deformability in the human erythrocyte. Prog Clin Biol Res. 1977; 17:481-91. View Abstract
  98. Irreversible deformation of the spectrin-actin lattice in irreversibly sickled cells. J Clin Invest. 1976 Oct; 58(4):955-63. View Abstract
  99. Human plasma high density lipoprotein. Interaction of the cyanogen bromide fragments from apolipoprotein glutamine II (A-II) with phosphatidylcholine. J Biol Chem. 1973 Dec 25; 248(24):8449-56. View Abstract
  100. Isolation and characterization of apoLp-Gln-II (apoA-II), a plasma high density apolipoprotein containing two identical polypeptide chains. J Biol Chem. 1972 Dec 10; 247(23):7510-8. View Abstract
  101. Isolation and characterization of the tryptic and cyanogen bromide peptides of apoLp-Gln-II (apoA-II), plasma high density apolipoprotein. J Biol Chem. 1972 Dec 10; 247(23):7519-27. View Abstract
  102. Identification of the lipid-binding cyanogen bromide fragment from the cystine-containing high density apolipoprotein, APOLP-GLN-II. Biochem Biophys Res Commun. 1972 Oct 06; 49(1):23-9. View Abstract
  103. Studies on the protein defect in Tangier disease. Isolation and characterization of an abnormal high density lipoprotein. J Clin Invest. 1972 Oct; 51(10):2505-19. View Abstract
  104. Further characterization of the polymorphic forms of a human high density apolipoprotein, apoLP-Gln-I (apoA-I). Biochim Biophys Acta. 1972 Sep 29; 278(2):266-70. View Abstract
  105. Amino acid sequence of human apoLp-Gln-II (apoA-II), an apolipoprotein isolated from the high-density lipoprotein complex. Proc Natl Acad Sci U S A. 1972 May; 69(5):1304-8. View Abstract
  106. Degradation of membrane phospholipids and thiols in peroxide hemolysis: studies in vitamin E deficiency. Blood. 1968 Oct; 32(4):549-68. View Abstract

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