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Study on file RAGE signaling in vascular cells - a novel mechanism of the development of diabetic vascular complications

Research Project

Project/Area Number 13670113
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General medical chemistry
Research InstitutionKanazawa University

Principal Investigator

YONEKURA Hideto  Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (80240373)

Co-Investigator(Kenkyū-buntansha) SAKURAI Shigeru  Kanazawa University, Graduate School of Medical Science, Instructor, 医学系研究科, 助手 (60332665)
YAMAMOTO Yasuhiko  Kanazawa University, Graduate School of Medical Science, Instructor, 医学系研究科, 助手 (20313637)
WATANABE Takuo  Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (40303268)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
Keywordsdiabetic complications / transgenic mouse / advanced glycation endproducts (AGE) / alternative splicing / endogenous soluble receptor / receptor for AGE (RAGE) / esRAGE / gene knockout mouse / receptor for AGE (RAGE) / gene knockout mous / advanced glycation endproducts / RAGE / splice variants / gene targeting
Research Abstract

In this research, we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGE) and their receptor, RAGE, lead to diabetic vascular derangements. We also found the presence of a cytoprotective secretory form of RAGE (endogenous secretory RAGE, esRAGE) in human and identified new RAGE ligands, which are abundantly present in human circulation.
(1) We created transgenic mice that overexpress human RAGE in vascular cells. The diabetic RAGE transgenic mice exhibited an accelerated development of diabetic nephropathy. This transgenic mouse will be a useful animal model that shows the renal changes seen in humans.
(2) We also created transgenic mice that overexpress human RAGE in the heart and obtained evidence suggesting that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.
(3) We created RAGE gene-knockout mice and showed that the advanced diabetic nephropathy was significantly suppressed in the diabetic knockout mice.
(4) We demonstrated that human vascular endothelial cells (EC) and pericytes express a novel splice variant encoding a novel secretory form of RAGE (esRAGE). The AGE induction of ERK phosphorylation and vascular endothelial growth factor in EC and of the growth and cord-like structure formation of EC was perfectly abolished by this RAGE variant, indicating that esRAGE is cytoprotective against AGE. The findings may contribute to our understanding of the molecular basis for the diversity of cellular responses to AGE and for individual variations in susceptibility or resistance to diabetic vascular complications.
(5) We identified glyceraldehyde- and glycolaldehydee-derived AGE as new RAGE ligands. The AGE fractions increased VEGF mRNA levels in human EC as well as cell growth. These results suggested that glyceraldehyde- and glycolaldehyde-derived AGE participate in vascular injury in diabetes.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (61 results)

All Other

All Publications (61 results)

  • [Publications] Yamamoto, Y., et al.: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"J.Clin.Invest.. 108. 261-268 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, P., et al.: "Hypoxia down-regulates endostatin production by human microvascular endothelial cells and pericytes"Biochem.Biophys.Res.Commun.. 288. 1149-1154 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H.: "Antisense display -A new method for functional gene screen and its application to angiogenesis-related gene isolation"Ann.N.Y.Acad.Sci.. 947. 382-386 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, S., et al.: "Effects of ELF high magnetic fields on enzyme-catalyzed DNA and RNA synthesis in vitro and on a cell-free DNA mismatch repair"Bioelectromagnetics. 22. 260-266 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Petrova, G.et al.: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J.Mol.Cell.Cardiol.. 34. 1425-1431 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto, Y.et al.: "The role of AGE-RAGE system in the development of diabetic nephropathy in vivo"Excerpta Medica International Congress Series. 1245. 45-50 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H.et al.: "RAGE engagement and vascular cell derangement by short chain sugar-derived advanced glycation endproducts"Excerpta Medica International Congress Series. 1245. 129-135 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakurai, S.et al.: "Identincation of a novel AGE-capturable soluble variant of the RAGE in human sera"Excerpta Medica International Congress Series. 1245. 163-167 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H.et al.: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular in injury"Biochem.J.. 370(3). 1097-1109 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakurai, S.et al.: "The AGE-RAGE system and diabetic nephropathy"J.Am.Soc.Nephrol.. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miura, J.et al.: "AGE downregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J.Diabetes Complications. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kim Y.M.et al.: "PNUTS, a protein phosphatase 1(PP1) nuclear targeting subunit : Characterization of its PP1-and RNA-binding domains and regulation by phosphorylation"J Biol Chem.. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Unoki H.et al.: "Cyr61 Upregulation in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats"Lab.Invest.. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 山本靖彦 他: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"ゲノムニュース(文部科学省科学研究費特定領域研究C「ゲノム」4領域広報委員会編). 1. 32-33 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 米倉秀人: "新しい機能性遺伝子スクリーニング法-アンチセンスディスプレイ法-の開発と新規遺伝子探索への適用"バイオサイエンスとインダストリー((財)バイオインダストリー協会). 60. 36-37 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 渡辺琢夫 他: "高血糖による細胞内酸化ストレス増強機序 1.終末糖化産物"Diabetes Frontier. 13. 164-168 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 山本靖彦 他: "AGE-RAGE系を標的とした糖尿病血管障害抑制の可能性"日本薬理学会誌. 121. 49-56 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 李 慧 他: "生体諸システムの制御臓器としての血管内皮細胞;5.血管新生系制御"血管医学(メディカルビュー社). 4. 41-46 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 山本 博 他: "細小血管合併症の成因"116回日本医学会シンポジウム記録集(日本医学会). 62-66 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 山本靖彦 他: "RAGEトランスジェニック糖尿病マウスにおける糖尿病腎症"糖尿病学2002(診断と治療社(岡 芳知 編)). 1-4 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 米倉秀人: "3章,個体と発生,pp6-7:41章,フリーラジカルとNO"医学のための基礎分子細胞生物学 改訂3版(南山堂(平賀 紘一, 伊達 孝保, 山本 博, 宮本 薫 編). 82-83 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 米倉秀人: "トレーサー,ドミナントネガティブ変異,ポジショナルクローニング,位置的候補遺伝子"医学大辞典(医学書院(伊藤正男, 井村裕夫, 高久史麿 編)). 1799,1786,2285,118 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto, Y., Kato, I, Doi, T., Yonekuia, H., Ohashi, S., Takeuchi, M., Watanabe, T., Yamagishi, S., Sakurai, S., Takasawa, S., Okamoto, H., and Yamamoto, H.: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"J. Clin. Invest.. 108(2). 261-268 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Wu, P., Yonekura, H., Li, H., Nozaki, I, Tomono, Y., Naito, I., Ninomrya, Y and Yamamoto, H.: "Hypoxia down-regulates endostatin production by human microvascular endothelial cells and pericytes"Biochem. Biophys. Res. Commun.. 288 (5). 1149-1154 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H., Yasui, K., Sakurai, S., Li, H., Yamamoto, Y., and Yamamoto, H.: ""Antisense display" - A new method for functional gene screen and its application to angiogenesis-related gene isolation"Ann. N. Y. Acad. Sci.. 947. 382-386 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada, S., Yamada, S., Kuramata, O., Gunji, Y., Kawasaki, M, Miyakawa, T., Yonekura, H., Sakurai, S., Bessho, K., Hosono, R. and Yamamoto, H.: "Effects of ELF high magnetic fields on enzyme-catalyzed DNA and RNA synthesis in vitro and on a cell-free DNA mismatch repair"Bioelectromagnetics. 22 (4). 260-266 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Petrova, G., Yamamoto, Y., Muraki, K., Yonekura, H., Sakurai, S., Watanabe, T., Li, H., Takeuchi, M., Makita, Z., Kato, I, Takasawa, S., Okamoto, H., Imaizumi, Y., and Yamamoto, H.: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J. Mol. Cell. Cardiol.. 34 (10). 1425-1431 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto, Y., Kato, I., Doi, T., Yonekura, H., Ohashi, S., Takeuchi, M., Watanabe, T., Sakurai, S., Yasui, K., Petrova R. G., Abedin, Md. J., Li, H., Rahman, A. K. M. A., Takasawa, S., Okamoto, H., and Yamamoto, H.: "The role of AGE-RAGE system in the development of diabetic nephropathy in vivo"Excerpta Medica International Congress Series 1245, The Maillard Reaction in Food Chemistry and Medical Science : Update for Post-genomic Era, Edited by S. Horiuchi, N. Taniguchi, F. Hayase, T. Kurata, T. Osawa, Elsevier Science B. V., Amsterdam, The Netherland. 45-50 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H., Yamamoto, Y., Sakurai. S., Yasui, K., Petrova, G, P., Abedin. Md. J., Li, H., Watanabe, T., Makita, Z., Takeuchi, M., and Yamamoto, H.: "RAGE engagement and vascular cell derangement by short chain sugar-derived advanced glycation endproducts"Excerpta Medica International Congress Series 1245, The Maillard Reaction in Food Chemistry and Medical Science : Update for Post-genomic Era, Edited by S. Horiuchi, N. Taniguchi, F. Hayase, T. Kurata, T. Osawa, Elsevier Science B. V., Amsterdam, The Netherland. 129-135 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakurai, S., Yonekura, H., Yamamoto, Y., Watanabe, T., Petrova, R. G., Abedin, Md. J., Yasui, K., Li, H., Rahman, A. K. M. A., Obata, K., and Yamamoto, H.: "Identification of a novel AGE-capturable soluble variant of the RAGE in human sera"Excerpta Medica International Congress Series 1245, The Maillard Reaction in Food Chemistry and Medical Science : Update for Post-genomic Era, Edited by S. Horiuchi, N. Taniguchi, F. Hayase, T. Kurata, T. Osawa, Elsevier Science B. V., Amsterdam. The Netherland. 163-167 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yonekura, H., Yamamoto, Y., Sakurai, S., Petrova, R. G., Abedin, Md. J., Li, H., Yasui, K., Takeuchi, M., Makita, Z., Takasawa, S., Okamota, H., Watanabe, T., and Yamamoto, H.: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury"Biochem. J.. 370 (3). 1097-1109 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kim YM, Watanabe T, Allen PB, Kim YM, Lee SJ, Greengard P, Nairn AC, Kwon YG.: "PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit : Characterization of its PP1-and RNA-binding domains and regulation by phosphorylation"J Biol Chem.. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Unoki H., Furukawa K., Yonekura H., Ueda Y., Katsuda S., Amano H., Nakagawara K., Mabuchi H., and Yamamoto, H.: "Cyr61 Upregulation in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats"Lab. Invest.. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Miura, J., Uchigata, Y., Yamamoto, Y., Takeuchi M, Sakurai, S., Watanabe, T., Yonekura, H., Yamagishi, S., Makita Z, Sato, A., Omori, Y., Yamamoto H, and Iwamoto Y.: "AGE downregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J. Diabetes Complications. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakurai, S., Yonekura, H., Yamamoto, Y., Watanabe, T., Tanaka, N., Li, H., Rahman, A. K. M. A., Myint, K.-M., Kim, C.-H., and Yamamoto, H.: "The AGE-RAGE system and diabetic nephropathy"J. Am. Soc. Nephrol.. in press. (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto Y, Sakurai S, Watanabe T, Yonekura H, Yamamoto H.: "Possible participation of advanced glycation endproducts and their receptor system in the development of diabetic vascular complications"Nippon Yakurigaku Zasshi. 121 (1). 49-55 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Petrova, G. et al.: "Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes"J. Mol. Cell. Cardiol.. 34(10). 1425-1431 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yonekura, H. et al.: "RAGE engagement and vascular cell derangement by short chain sugarderived advanced glycation endproducts"Excerpta Medica International Congress Series. 1245. 129-135 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto, Y. et al.: "The role of AGE-RAGE system in the development of diabetic nephropathy in vivo"Excerpta Medica International Congress Series. 1245. 45-50 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakural, S. et al.: "Identification of a novel AGE-capturable soluble variant of the RAGE in human sera"Excerpta Medica International Congress Series. 1245. 163-167 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yonekura, H. et al.: "Novel splice variants of the receptor for advanced glycation endproducts (RAGE) expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury"Biochem. J.. 370(3). 1097-1109 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakurai, S. et al.: "The AGE-RAGE system and diabetic nephropathy"J. Am. Soc. Nephrol.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Unoki H. et al.: "Cyr61 Upregulation in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats."Lab. Invest.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kim, Y.M.et al.: "PNUTS, a protein phosphatase 1 (PP1) nuclear targeting subunit : Characterization of itsPP1-and RNA-binding domains and regulation by phosphorylation"J Biol Chem.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miura J. et al.: "AGE dowuregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J Diabetes Complications. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 山本靖彦 他: "RAGEトランスジェニック糖尿病マウスにおける糖尿病腎症"糖尿病学2002(岡 芳知 編,診断と治療社). 1-3 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 米倉秀人: "新しい機能性遺伝子スクリーニング法-アンチセンスディスブレイ法-の開発と新規遺伝子探索への適用"バイオサイエンスとインダストリー((財)バイオインダストリー協会). 60(7). 36-37 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 山本靖彦 他: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"ゲノムニュース(文部科学省 科学研究費特定領域研究C「ゲノム」4領域広報委員会編). 1(1). 32-33 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 山本靖彦 他: "AGE-RAGE系を標的とした糖尿病血管障害抑制の可能性"日本薬理学会誌. 121(1). 49-56 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 李 慧 他: "生体諸システムの制御臓器としての血管内皮細胞:血管新生系制御"血管医学(メディカルレビュー社). (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 米倉秀人(分担執筆): "医学のための基礎分子細胞生物学(第3版)"平賀紘一, 山本 博, 伊達孝保, 編(南山堂、東京)(印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto, Y.: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"J. Clin. Invest. 108(2). 261-268 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yonekura, H.: ""Antisense display" - A new method for functional gene screen and its application to angiogenesis-related gene isolation"Ann. N. Y. Acad. Sci.. 947. 382-386 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wu, P.: "Hypoxia down-regulates endostatin production by human microvascular endothelial cells an pericytes"Biochem. Biophys. Res. Commun. 288(5). 1149-1154 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Harada, S.: "Effects of ELF high magnetic fields on enzyme-catalyzed DNA and RNA synthesis in vitro and on a cell-free DNA mismatch repair."Bioelectromagnetics. 22(4). 260-266 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyakawa, T.: "Exposure of C.elegans to extremely low frequency high magnetic fields induces stress responses"Bioelectromagnetics. 22(5). 333-339 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yonekura, H.: "RAGE engagement and vascular cell derangement by short chain sugar-derived advanced glycation endproducts"Excerpta Medica International Congress Series. 1245(in press.). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yonemura, Y.: "Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 ingastric cancer"Eur. J. Cancer. 37(7). 918-923 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kaneko T.: "Calpain-dependent proteolysis of merlin occurs by oxidative stress in meningiomas : a novel hypothesis of tumorigenesis"Cancer. 92(10). 2662-2672 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamamoto, Y.: "Advanced diabetic nephropathy in RAGE-overexpressing mice"Excerpta Medica International Congress Series. 1245(in press.). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakurai, S.: "Identification of a novel AGE-capturable variant of the receptor for AGE in the human sera"Excerpta Medica International Congress Series. 1245(in press.). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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