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Biological molecules enhancing/inhibiting amyloid fibril formation: Integration of in vitro experiment and proteomic analysis

Research Project

Project/Area Number 21K06967
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionUniversity of Fukui

Principal Investigator

Naiki Hironobu  福井大学, 学術研究院医学系部門, 教授 (10227704)

Co-Investigator(Kenkyū-buntansha) 植田 光晴  熊本大学, 大学院生命科学研究部(医), 教授 (60452885)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywordsアミロイドーシス / β2-ミクログロブリン / プロテオーム解析 / 免疫染色 / プロテオグリカン
Outline of Research at the Start

本研究は、ヒト疾患モデルとしてβ2-ミクログロブリン(β2-m)アミロイドーシスを選び、発症の分子機構を、プロテオーム解析、独自開発した試験管内実験系、病理組織学的解析を有機的に組み合わせ解明する。具体的に、① β2-mアミロイド沈着組織のプロテオーム解析により未知のアミロイド共存蛋白質を同定すること、② それらがアミロイド線維形成に及ぼす影響を、われわれが独自に開発した試験管内実験系を駆使して明らかにすること、③ 各分子に対する抗体を用いた免疫染色により、アミロイド沈着組織における各分子の局在を明らかにすること、の3点を目的とする。

Outline of Final Research Achievements

We first showed that in addition to high serum β2-microglobulin (β2-m) levels and a long dialysis vintage as the primary and secondary risk factors for the onset of dialysis-related amyloidosis (DRA), respectively, decreased serum albumin concentration in dialysis patients is the tertiary risk factor. Next, we showed that class I small leucine-rich proteoglycans (SLRPs) (decorin, biglycan and asporin) colocalize with β2-m amyloid deposits. We suggested that the core protein of SLRPs could enhance the deposition of β2-m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of β2-m in the fibrils, as well as by acting as a scaffold for the polymerization of β2-m into the fibrils. Finally, we reported the first case with transthyretin amyloid cardiomyopathy complicated with rapidly progressive aortic stenosis possibly caused by transthyretin amyloid deposition in the aortic valve.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた上記成果は、単にβ2-mアミロイドーシスのみならず、ヒトアミロイドーシスに共通する発症機構の解明や治療戦略の構築に向け、有益な示唆をもたらした。また、本研究で得られた新たな実験ツールは、他のヒトアミロイドーシス発症機構解明に向けた研究にも普遍的に活用することが出来、本研究の学術的波及効果は大きいと考える。さらに、厚労省指定難病である全身性アミロイドーシスの治療法開発にも貢献し、社会的意義も大きいと考える。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (44 results)

All 2024 2023 2022 2021 Other

All Journal Article (24 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 20 results,  Open Access: 14 results) Presentation (19 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results) Remarks (1 results)

  • [Journal Article] Silencing of ocular transthyretin, a gene responsible for hereditary transthyretin amyloidosis, by intravitreal injection of an siRNA conjugate into rabbit eyes2024

    • Author(s)
      Watanabe T, Takihara Y, Jono H, Fujimoto T, Tasaki M, Isoguchi A, Urahashi Y, Shimoda T, Takahashi E, Ando Y, Ueno S, Ueda M, Inoue T.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 694 Issue: 2 Pages: 149397-149397

    • DOI

      10.1111/pin.13395

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 10.3389/fped.2023.11952222023

    • Author(s)
      Kawamura H, Ikawa M, Hirono K, Kimura J, Okuno T, Kawatani M, Inai K, Hata Y, Nishida N, Yoshida Y.
    • Journal Title

      Front Pediatr.

      Volume: 11 Pages: 1195222-1195222

    • DOI

      10.3389/fped.2023.1195222

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exploration of sepsis assisting parameters in hospital autopsied-patients: a prospective study.2023

    • Author(s)
      Inai K, Higuchi S, Shimada A, Hisada K, Hida Y, Hatta S, Kitano F, Uno M, Matsukawa H, Noriki S, Iwasaki H, Naiki H.
    • Journal Title

      Sci Rep

      Volume: 13 Issue: 1 Pages: 10681-10681

    • DOI

      10.1038/s41598-023-37752-3

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Light and heavy chain deposition disease with focal amyloid deposition diagnosed with mass spectrometry: a case report2023

    • Author(s)
      Shimamoto Yuki、Takahashi Naoki、Katoh Nagaaki、Matsui Yuki、Mochizuki Yusuke、Ito Masanori、Yazaki Masahide、Kametani Fuyuki、Kasuno Kenji、Sekijima Yoshiki、Naiki Hironobu、Iwano Masayuki
    • Journal Title

      BMC Nephrology

      Volume: 24 Issue: 1 Pages: 187-187

    • DOI

      10.1186/s12882-023-03207-0

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Improved artificial intelligence discrimination of minor histological populations by supplementing with color-adjusted images2023

    • Author(s)
      Hatta Satomi、Ichiuji Yoshihito、Mabu Shingo、Kugler Mauricio、Hontani Hidekata、Okoshi Tadakazu、Fuse Haruki、Kawada Takako、Kido Shoji、Imamura Yoshiaki、Naiki Hironobu、Inai Kunihiro
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 19068-19068

    • DOI

      10.1038/s41598-023-46472-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Solitary follicular lymphoma with plasmacytic differentiation associated with localized AL amyloidosis in the jejunum2023

    • Author(s)
      Tajima Katsushi、Nomura Takashi、Terada Taichi、Okuyama Shuhei、Kumagai Hiroaki、Maeda Kunihiko、Ogata Shinya、Naiki Hironobu
    • Journal Title

      Annals of Hematology

      Volume: 102 Issue: 6 Pages: 1625-1627

    • DOI

      10.1007/s00277-023-05207-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A retrospective analysis of clinical features and treatment outcome in 21 patients with immunoglobulin M-related light-chain amyloidosis in Japan: a study from the Amyloidosis Research Committee.2023

    • Author(s)
      Fuchida SI, Ogura M, Ishida T, Hata H, Handa H, Katoh N, Nakaseko C, Sunami K, Katayama Y, Nobata H, Oshiro K, Iida S, Sekijima Y, Naiki H, Shimazaki C.
    • Journal Title

      Int J Hematol

      Volume: 118 Issue: 4 Pages: 443-449

    • DOI

      10.1007/s12185-023-03647-2

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A case of?immunoglobulin G4?related retroperitoneal fibrosis and?hypophysitis with antecedent respiratory disease followed by spontaneous remission and?recurrence2023

    • Author(s)
      Sakai Masato、Ohno Yuta、Kozuki Nana、Kawasaki Yuki、Yoshida Michiko、Ikeda Hiroyuki、Konishi Junji、Maeda Toshiki、Sugano Motoki、Kawakami Satoshi、Ito Isao、Yamaguchi Aina、Naiki Hironobu、Notohara Kenji、Akamizu Takashi、Kawano Mitsuhiro、Yoshida Haruyoshi
    • Journal Title

      Modern Rheumatology Case Reports

      Volume: 8 Issue: 1 Pages: 163-171

    • DOI

      10.1093/mrcr/rxad040

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] アミロイドーシスと質量分析イメージング2023

    • Author(s)
      堂本 裕加子, 内木 宏延
    • Journal Title

      医学のあゆみ

      Volume: 287 Pages: 715-721

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Renoprotective effects of extracellular fibroblast specific protein 1 via nuclear factor erythroid 2-related factor-mediated antioxidant activity2023

    • Author(s)
      Takahashi Naoki、Yokoi Seiji、Kimura Hideki、Naiki Hironobu、Matsusaka Taiji、Yamamoto Yasuhiko、Nakatani Kimihiko、Kasuno Kenji、Iwano Masayuki
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 22540-22540

    • DOI

      10.1038/s41598-023-49863-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fanconi syndrome in an elderly patient with membranous nephropathy during treatment with the immunosuppressant mizoribine.2023

    • Author(s)
      Nishikawa Sho ,Takahashi Naoki ,Nishikawa Yudai ,Yokoi Seiji ,Morita Sayu ,Shimamoto Yuki ,Sakashita Sayumi ,Nishimori Kazuhisa ,Kobayashi Mamiko ,Fukushima Sachiko
    • Journal Title

      CEN Case Reports

      Volume: 12 Issue: 1 Pages: 32-38

    • DOI

      10.1007/s13730-022-00715-0

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 肝胆膵疾患領域における医療関連死解析に寄与する介在死因データベース2023

    • Author(s)
      宇野 美雪, 樋口 翔平, 八田 聡美, 木下 一之, 法木 左近, 後藤 伸之, 内木 宏延, 稲井邦博
    • Journal Title

      医療の質・安全会誌

      Volume: 18 Pages: 3-16

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Elderly onset congenital hepatic fibrosis with portal hypertension diagnosed after recurrent cholangitis: a case report2022

    • Author(s)
      Takahashi Kazuto、Ofuji Kazuya、Nosaka Takuto、Naito Tatsushi、Matsuda Hidetaka、Ohtani Masahiro、Hiramatsu Katsushi、Harada Kenichi、Naiki Hironobu、Nakamoto Yasunari
    • Journal Title

      Clinical Journal of Gastroenterology

      Volume: 15 Issue: 3 Pages: 611-616

    • DOI

      10.1007/s12328-022-01620-w

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis2022

    • Author(s)
      Nakajima Kichitaro、Yamaguchi Keiichi、Noji Masahiro、Aguirre Cesar、Ikenaka Kensuke、Mochizuki Hideki、Zhou Lianjie、Ogi Hirotsugu、Ito Toru、Narita Ichiei、Gejyo Fumitake、Naiki Hironobu、Yamamoto Suguru、Goto Yuji
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 5689-5689

    • DOI

      10.1038/s41467-022-33247-3

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] いまさら聞けない アミロイドーシスって何?2022

    • Author(s)
      内木 宏延
    • Journal Title

      Medical Technology

      Volume: 50 Pages: 996-1000

    • Related Report
      2022 Research-status Report
  • [Journal Article] プロテオーム解析2022

    • Author(s)
      羽深 将人, 山本 卓, 内木 宏延, 山本 格, 成田 一衛
    • Journal Title

      日腎会誌

      Volume: 64 Pages: 863-867

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pathological evaluation of human pancreatic tissue injuries by machine compression for computer-aided safe pancreatic compression.2022

    • Author(s)
      K. Inai, D. Kim, N. Takano, M. Uno, S. Noriki, H. Naiki, E. Kobayashi
    • Journal Title

      Int J CARS

      Volume: suppl1 Issue: S1 Pages: 54-55

    • DOI

      10.1007/s11548-022-02635-x

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] 心アミロイドーシス2022

    • Author(s)
      池田 善彦, 内木 宏延
    • Journal Title

      病理と臨床

      Volume: 39(10) Pages: 988-992

    • Related Report
      2021 Research-status Report
  • [Journal Article] Development of Myeloperoxidase Anti-neutrophil Cytoplasmic Antibody-positive Necrotizing Crescentic Glomerulonephritis in an Elderly Patient with Immunological Kidney Disease2021

    • Author(s)
      Haruyoshi Yoshida, Naoki Takahashi, Takayasu Horiguchi, Hiroki Yasuhara, Tokuharu Tanaka, Yuhao Chen, Toshikazu Takasaki, Hitokazu Tsukao, Michiko Yoshida, Satoshi Kawakami, Makoto Ohta, Hironobu Naiki, Satoshi Konishi, Isao Ito, Masayuki Iwano
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 24 Pages: 3927-3935

    • DOI

      10.2169/internalmedicine.7252-21

    • NAID

      130008129501

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-12-15
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathological review of cardiac amyloidosis using autopsy cases in a single Japanese institution.2021

    • Author(s)
      Tateishi Y, Yamada Y, Katsuki M, Nagata T, Yamamoto H, Kohashi K, Koga Y, Hashisako M, Kiyozawa D, Mori T, Kuboyama Y, Kakinokizono A, Miyazaki Y, Yamaguchi A, Tsutsui H, Ninomiya T, Naiki H, Oda Y.
    • Journal Title

      Pathol Res Pract

      Volume: 227 Pages: 153635-153635

    • DOI

      10.1016/j.prp.2021.153635

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Case With Transthyretin Amyloid Cardiomyopathy Complicated With Rapidly Progressive Aortic Stenosis Possibly Caused by Amyloid Deposition in the Aortic Valve. Circ Cardiovasc Imaging.2021

    • Author(s)
      Fujimoto T, Yamano T, Miyagawa-Hayashino A, Naiki H, Ueda M, Tasaki M, Yamano M, Zen K, Numata S, Matoba S.
    • Journal Title

      Circ Cardiovasc Imaging

      Volume: 14 Issue: 11

    • DOI

      10.1161/circimaging.121.013357

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gastrointestinal AA amyloidosis secondary to chronic pyelonephritis presenting with refractory diarrhea and severe hypoalbuminemia2021

    • Author(s)
      Tanaka Tomoko、Naito Tatsushi、Midori Yohei、Nosaka Takuto、Takahashi Kazuto、Ofuji Kazuya、Matsuda Hidetaka、Ohtani Masahiro、Hiramatsu Katsushi、Imamura Yoshiaki、Yokoyama Osamu、Naiki Hironobu、Nakamoto Yasunari
    • Journal Title

      Clinical Journal of Gastroenterology

      Volume: 14 Issue: 6 Pages: 1642-1648

    • DOI

      10.1007/s12328-021-01508-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autopsy case with concurrent transthyretin and immunoglobulin amyloidosis2021

    • Author(s)
      Shintani‐Domoto Yukako、Ishino Kousuke、Naiki Hironobu、Sakatani Takashi、Ohashi Ryuji
    • Journal Title

      Pathology International

      Volume: 72 Issue: 1 Pages: 65-71

    • DOI

      10.1111/pin.13179

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 蓄積病・アミロイドーシス2021

    • Author(s)
      内木 宏延
    • Journal Title

      病理と臨床

      Volume: 39(臨増) Pages: 266-269

    • Related Report
      2021 Research-status Report
  • [Presentation] アミロイドーシス学会を代表して2023

    • Author(s)
      内木 宏延
    • Organizer
      第10回日本アミロイドーシス学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 日本病理剖検輯報に基づく全身性アミロイドーシス各病型頻度の疫学調査2023

    • Author(s)
      山口 愛奈, 田崎 雅義, 植田 光晴, 安東 由喜雄, 内木 宏延
    • Organizer
      第10回日本アミロイドーシス学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 剖検例による造血器疾患の死因経過および感染症の検討2023

    • Author(s)
      稲井 邦博, 宇野 美雪, 法木 左近, 大越 忠和, 岩崎 博道, 内木 宏延
    • Organizer
      第112回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Deep learningを用いた病理組織AIの関心領域2023

    • Author(s)
      八田 聡美, 一氏 良仁, 間普 真吾, 本谷 秀堅, 木戸 尚治, 今村 好章, 大越 忠和, 内木 宏延, 稲井 邦博
    • Organizer
      第112回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] アミロイドーシス概論とシンポジウムの概要2023

    • Author(s)
      内木 宏延
    • Organizer
      第112回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 大動脈弁狭窄症に対する弁置換術で摘出された大動脈弁でのトランスサイレチン型アミロイドの同定2023

    • Author(s)
      本田 行平, 宮川 文, 田崎 雅義, 山野 哲弘, 長峯 理子, 森永 友紀子, 田中 顕之, 内木 宏延, 植田 光晴, 小西 英一
    • Organizer
      第112回日本病理学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] アルツハイマー病βアミロイド蛋白質の脳内での生理濃度であるnMレベルでのアミロイド線維の増減を検出する新規反応系の開発2023

    • Author(s)
      長谷川 一浩, 内木 宏延
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Pathological evaluation of human pancreatic tissue injuries by machine compression for computer-aided safe \npancreatic compression devices2022

    • Author(s)
      K. Inai, D. Kim, N. Takano, M. Uno, S. Noriki, H. Naiki, E. Kobayashi
    • Organizer
      36th International Congress and Exhibition, CARS 2022 Computer Assist Radiology and Surgery
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒトアミロイドーシス発症の分子機構2022

    • Author(s)
      内木 宏延
    • Organizer
      第101回福井県医学会総会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 抗がん剤性肝硬変の鑑別における鑑別における肝体積萎縮速度の活用に関する検討2022

    • Author(s)
      宇野美雪、稲井邦博、西島昭彦、法木左近、内木宏延、後藤伸之
    • Organizer
      第32回日本医療薬学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 左室肥大を認めない心アミロイドーシスの一例2022

    • Author(s)
      川口樹里、有馬直輝、越智友梨、馬場裕一、久保亨、山崎直仁、内木宏延、北岡裕章
    • Organizer
      第9回日本アミロイドーシス学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] 心アミロイドーシス診断のピットフォール2022

    • Author(s)
      池田 善彦, 岡田 厚, 雨宮 妃, 松本 学, 大郷 恵子, 内木 宏延, 畠山 金太
    • Organizer
      第111回日本病理学会総会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 深層学習を用いた甲状腺癌の識別2022

    • Author(s)
      八田 聡美, 樋口 翔平, 稲井 邦博, 今村 好章, 一氏 良仁, 間普 真吾, 本谷 秀堅, 木戸 尚治, 内木 宏延
    • Organizer
      第111回日本病理学会総会
    • Related Report
      2022 Research-status Report
  • [Presentation] 他施設甲状腺標本に対する機械識別のための色調補正深層学習の活用法2022

    • Author(s)
      八田 聡美, 樋口 翔平, 稲井 邦博, 一氏 良仁, 間普 真吾, 本谷 秀堅, 木戸 尚治, 内木 宏延, 今村 好章
    • Organizer
      第9回日本甲状腺病理学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] アミロイドーシス発症の分子機構2022

    • Author(s)
      内木 宏延
    • Organizer
      第41回日本画像医学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] ヒト全身性アミロイドーシス:発症の分子機構と病理組織学的診断2021

    • Author(s)
      内木 宏延
    • Organizer
      第110回日本病理学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 心アミロイドーシスの病理組織学的診断:免疫染色の重要性とアミロイドーシスに関する調査研究班のコンサルテーション体制について2021

    • Author(s)
      内木 宏延
    • Organizer
      第42回心筋生検研究会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 大型放射光施設SPring-8のX線位差CTを用いた心・腎アミロイドーシス組織の構造解析とイメージング質量分析法を用いた組織プロテオーム解析の統合2021

    • Author(s)
      武笠 結天, 袴田 圭祐, 升本 英利, 新谷 祈, 外山 友美子, 辻 崇, 徳平 壮一郎, 星野 真人, 八木 直人, 杉山 将大, 韮澤 崇, Jean-Paul Duong Van Huyen, Marion Rabant, Patrick Bruneval, 内木 宏延, 湊谷 謙司, 植田 初江, 池川 雅哉
    • Organizer
      第42回心筋生検研究会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] Ai研究を基盤に確立した推定法を用いた肝重量の経時的解析2021

    • Author(s)
      宇野 美雪, 西島 昭彦, 法木 左近, 後藤 伸之, 内木 宏延, 稲井 邦博
    • Organizer
      第19回オートプシー・イメージング(Ai)学会学術総会
    • Related Report
      2021 Research-status Report
  • [Remarks] 分子病理学

    • URL

      https://www.med.u-fukui.ac.jp/laboratory/molecular-pathology/

    • Related Report
      2023 Annual Research Report 2022 Research-status Report 2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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