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Regulatory mechanisms of exosome production by adiponectin and effect of favine on atherosclerosis and thrombus formation.

Research Project

Project/Area Number 18H02863
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionOsaka University

Principal Investigator

Shimomura Iichiro  大阪大学, 医学系研究科, 教授 (60346145)

Co-Investigator(Kenkyū-buntansha) 福原 淳範  大阪大学, 医学系研究科, 寄附講座准教授 (00437328)
喜多 俊文  大阪大学, 医学系研究科, 寄附講座講師 (10746572)
加藤 恒  大阪大学, 医学系研究科, 助教 (20705214)
前田 法一  大阪大学, 医学系研究科, 寄附講座准教授 (30506308)
小林 祥子  大阪大学, 医学系研究科, 助教 (80649111)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsアディポネクチン / エクソソーム / 幹細胞 / セラミド / カドヘリン / Favine / T-カドヘリン / 間葉系幹細胞 / 受容体 / 動脈硬化 / 血栓
Outline of Final Research Achievements

We identified T-cadherin, a cell-surface membrane protein, as the specific receptor for native adiponectin. Adiponectin enhances exosome biogenesis and secretion from the cells expressing T-cadherin, and protects the endothelium, renal function, stimulates muscle regeneration. Cell therapy based on mesenchymal stem cells needs circulating adiponectin to secrete exosomes and exert therapeutic functions to heart failure models. T-cadherin circulates also as soluble forms and we developed a new EIA system.
We also uncovered the importance of the Favine-regulated pathway in atherosclerosis.

Academic Significance and Societal Importance of the Research Achievements

アディポネクチンの作用はこれまでアディポRという膜タンパクを介するAMPKの活性化作用等で説明されてきたが、T-カドヘリンが主要な結合タンパクであり、エクソソーム産生促進によって多様な生理作用が発揮され得ることが分かった。本成果はCOVID-19治療にも応用されつつある間葉系幹細胞治療にも応用できる。
脂肪・血管分泌因子Favineは動脈硬化の予防治療に有用である可能性を示した。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (51 results)

All 2021 2020 2019 2018

All Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (33 results) (of which Int'l Joint Research: 7 results,  Invited: 4 results) Book (1 results) Patent(Industrial Property Rights) (3 results)

  • [Journal Article] Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin.2021

    • Author(s)
      Tsugawa-Shimizu Y, Fujishima Y, Kita S, Minami S, Sakaue TA, Nakamura Y, Okita T, Kawachi Y, Fukuda S, Namba-Hamano T, Takabatake Y, Isaka Y, Nishizawa H, Ranscht B, Maeda N, Shimomura I.
    • Journal Title

      Am J Physiol Endocrinol Metab.

      Volume: 320 Issue: 2 Pages: E179-E190

    • DOI

      10.1152/ajpendo.00393.2020

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] JB Special Review - Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes.2021

    • Author(s)
      Kita S, Shimomura I.
    • Journal Title

      J Biochem.

      Volume: 169 Issue: 2 Pages: 173-179

    • DOI

      10.1093/jb/mvaa105

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification and clinical associations of three forms of circulating T-cadherin in human serum.2021

    • Author(s)
      Fukuda S, Kita S, Miyashita K, Iioka M, Murai J, Nakamura T, Nishizawa H, Fujishima Y, Morinaga J, Oike Y, Maeda N, Shimomura I.
    • Journal Title

      J Clin Endocrinol Metab.

      Volume: - Issue: 5 Pages: 1333-1344

    • DOI

      10.1210/clinem/dgab066

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice.2020

    • Author(s)
      Nakamura Y, Kita S, Tanaka Y, Fukuda S, Obata Y, Okita T, Nishida H, Takahashi Y, Kawachi Y, Tsugawa-Shimizu Y, Fujishima Y, Nishizawa H, Takakura Y, Miyagawa S, Sawa Y, Maeda N, Shimomura I.
    • Journal Title

      Mol Ther.

      Volume: 28 Issue: 10 Pages: 2203-2219

    • DOI

      10.1016/j.ymthe.2020.06.026

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A disintegrin and metalloproteinase 12 prevents heart failure by regulating cardiac hypertrophy and fibrosis2020

    • Author(s)
      Nakamura Yuto、Kita Shunbun、Tanaka Yoshimitsu、Fukuda Shiro、Obata Yoshinari、Okita Tomonori、Kawachi Yusuke、Tsugawa-Shimizu Yuri、Fujishima Yuya、Nishizawa Hitoshi、Miyagawa Shigeru、Sawa Yoshiki、Sehara-Fujisawa Atsuko、Maeda Norikazu、Shimomura Iichiro
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: 318 Issue: 2 Pages: H238-H251

    • DOI

      10.1152/ajpheart.00496.2019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] エクソソームを介する代謝調節機構2020

    • Author(s)
      喜多俊文
    • Journal Title

      医学のあゆみ

      Volume: 272 Pages: 325-329

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Interorgan communication by exosomes, adipose tissue, and adiponectin in metabolic syndrome2019

    • Author(s)
      Kita Shunbun、Maeda Norikazu、Shimomura Iichiro
    • Journal Title

      Journal of Clinical Investigation

      Volume: 129 Issue: 10 Pages: 4041-4049

    • DOI

      10.1172/jci129193

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Native adiponectin in serum binds to mammalian cells expressing T-cadherin, but not AdipoRs or calreticulin2019

    • Author(s)
      Kita Shunbun、Fukuda Shiro、Maeda Norikazu、Shimomura Iichiro
    • Journal Title

      eLife

      Volume: 8

    • DOI

      10.7554/elife.48675

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adiponectin promotes muscle regeneration through binding to T-cadherin.2019

    • Author(s)
      Tanaka Y, Kita S, Nishizawa H, Fukuda S, Fujishima Y, Obata Y, Nagao H, Masuda S, Nakamura Y, Shimizu Y, Mineo R, Natsukawa T, Funahashi T, Ranscht B, Fukada SI, Maeda N, Shimomura I.
    • Journal Title

      Sci. Rep.

      Volume: 9 Issue: 1 Pages: 1-12

    • DOI

      10.1038/s41598-018-37115-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release.2018

    • Author(s)
      Obata Y, Kita S, Koyama Y, Fukuda S, Takeda H, Takahashi M, Fujishima Y, Nagao H, Masuda S, Tanaka Y, Nakamura Y, Nishizawa H, Funahashi T, Ranscht B, Izumi Y, Bamba T, Fukusaki E, Hanayama R, Shimada S, Maeda N, Shimomura I.
    • Journal Title

      JCI Insight

      Volume: 3(8) Issue: 8 Pages: 1-18

    • DOI

      10.1172/jci.insight.99680

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes2018

    • Author(s)
      Nishitani S, Fukuhara A, Shin J, Okuno Y, Otsuki M, Shimomura I
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1

    • DOI

      10.1038/s41598-018-27181-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1-Mediated Lipogenic Pathway2018

    • Author(s)
      Okuno Y, Fukuhara A, Hashimoto E, Kobayashi H, Kobayashi S, Otsuki M, Shimomura I
    • Journal Title

      Diabetes

      Volume: 印刷中 Issue: 6 Pages: 1113-1127

    • DOI

      10.2337/db17-1032

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] アディポネクチンの新しい側面2018

    • Author(s)
      下村伊一郎
    • Journal Title

      外科と代謝・栄養

      Volume: 52

    • Related Report
      2018 Annual Research Report
  • [Journal Article] アディポネクチンと動脈硬化2018

    • Author(s)
      前田法一
    • Journal Title

      循環plus

      Volume: 18

    • Related Report
      2018 Annual Research Report
  • [Presentation] アディポネクチンと臓器連関 Up to Date2021

    • Author(s)
      前田法一、下村伊一郎
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アディポネクチンの新たな作用学とその応用2021

    • Author(s)
      喜多俊文、下村伊一郎
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 再生医療におけるアディポネクチン/T-カドヘリンの意義2021

    • Author(s)
      中村勇斗、喜多俊文、前田法一、下村伊一郎
    • Organizer
      第41回日本肥満学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 幹細胞治療におけるアディポネクチン/T-カドヘリンの意義2020

    • Author(s)
      中村勇斗、喜多俊文、小幡佳也、福田士郎、田中紀實、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第93回日本内分泌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アディポネクチンのエクソソーム産生制御と心血管治療応用2020

    • Author(s)
      喜多俊文
    • Organizer
      第5回日本血管不全学会学術集会・総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 血管・脂肪由来分泌因子Favineの機能解析2020

    • Author(s)
      小林祥子, 加藤恒, 福原淳範, 喜多俊文, 大月道夫, 森井英一, 下村伊一郎
    • Organizer
      第93回日本内分泌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Native adiponectin in serum binds to cells expressing T-cadherin, but not AdipoRs or calreticulin2020

    • Author(s)
      Shunbun Kita, Shiro Fukuda, Yuto Nakamura, Yoshinari Obata, Yoshimitsu Tanaka, Tomonori Okita, Shigeki Masuda, Yuri Shimizu, Yusuke Kawachi, Emi Horitani, Takaaki Sakaue, Yuya Fujishima, Hitoshi Nishizawa, Norikazu Maeda, and Iichiro Shimomura
    • Organizer
      Keystone Symposia, Diabetes: Glucose Control and Beyond
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Action mechanism of high-molecular weight multimer adiponectin - possible role of stem cells, T-cadherin, and exosomes for organ protections2020

    • Author(s)
      Yuto Nakamura, Shunbun Kita, Yoshinari Obata, Shiro Fukuda, Yoshimitsu Tanaka, Yuya Fujishima, Hitoshi Nishizawa, Norikazu Maeda, and Iichiro Shimomura
    • Organizer
      Keystone Symposia, Obesity and NAFLD: Mechanisms and Therapeutics
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 肥満・糖尿病病態における血中ならびに組織T-カドヘリンの関連2019

    • Author(s)
      福田士郎、喜多俊文、宮下かずや、中村勇斗、川知祐介、沖田朋憲、清水有理、田中紀實、増田重樹、小幡佳也、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アディポネクチン/TカドヘリンシステムとERストレスに関する検討2019

    • Author(s)
      沖田朋憲、喜多俊文、中村勇斗、嶺尾良平、福田士郎、小幡佳也、川知祐介、田中紀實、増田重樹、清水有理、西澤 均、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 慢性心不全モデルにおけるアディポネクチン/T-カドヘリンシステム2019

    • Author(s)
      中村勇斗、喜多俊文、福田士郎、小幡佳也、田中紀實、増田重樹、清水有理、沖田朋憲、川知祐介、西澤 均、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Keeping homeostasis;organ cross-talks by adiponectin, T-cadherin, and exosomes2019

    • Author(s)
      喜多俊文、福田士郎、沖田朋憲、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Exosome Secretion by Adiponectin Contributes to MSC Transplantation in Pressure Overload Heart Failure Models2019

    • Author(s)
      喜多俊文、中村勇斗、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] アディポネクチンのT-カドヘリンを介する骨格筋再生促進作用2019

    • Author(s)
      田中紀實、喜多俊文、西澤 均、福田士郎、藤島裕也、小幡佳也、長尾博文、増田重樹、中村勇斗、清水有理、嶺尾良平、ランシュット バーバラ、深田宗一郎、前田法一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脂肪組織・血管由来分泌因子Favineの機能探索2019

    • Author(s)
      小林祥子、早川友朗、林令子 、奥野陽亮、福原淳範、大月道夫、森井英一、下村伊一郎
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アディポネクチンのエクソソーム産生制御と再生医療への応用2019

    • Author(s)
      喜多俊文、下村伊一郎
    • Organizer
      日本内分泌学会 第37回内分泌代謝学サマーセミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Exosome Secretion by Adiponectin Contributes to MSC-Transplantation on Pressure Overload Heart Failure Mice2019

    • Author(s)
      Shunbun Kita, Iichiro Shimomura
    • Organizer
      Asia-Pacific Diabetes and Obesity Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 幹細胞治療におけるアディポネクチン/T-カドヘリンの意義2019

    • Author(s)
      中村勇斗、喜多俊文、小幡佳也、福田士郎、田中紀實、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第40回日本肥満学会 第37回日本肥満症治療学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Molecular regulation of the GPI-anchored adiponectin receptor T-cadherin2019

    • Author(s)
      Shiro Fukuda, Shunbun Kita, Iichiro Shimomura
    • Organizer
      Keystone Symposia, Obesity and Adipose Tissue Biology 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Stimulated Exosome Secretion by Adiponectin Contributes to Effectiveness of Mesenchymal Stem Cell Transplantation on Pressure Overload Heart Failure Models2019

    • Author(s)
      Shunbun Kita, Yuto Nakamura, Iichiro Shimomura
    • Organizer
      Keystone Symposia, Obesity and Adipose Tissue Biology 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Proteolytic shedding by metalloprotease ADAM12 regulates abundance of T-cadherin in pressure overload heart failure models2019

    • Author(s)
      Yuto Nakamura, Shunbun Kita, Iichiro Shimomura
    • Organizer
      Keystone Symposia, Obesity and Adipose Tissue Biology 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] T-カドヘリンに特有のプロドメインはアディポネクチンとの結合において重要な役割を持つ2018

    • Author(s)
      福田士郎、喜多俊文、小幡佳也、藤島裕也、長尾博文、増田重樹、田中紀實、西澤 均、船橋 徹、前田法一、下村伊一郎
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Exosome biogenesis mediated vascular protection by adiponectin/ T-cadherin system2018

    • Author(s)
      喜多俊文、前田法一、下村伊一郎
    • Organizer
      第66回日本心臓病学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 骨格筋再生におけるアディポネクチン・T-カドヘリンの役割についての検討2018

    • Author(s)
      田中紀實、喜多俊文、深田宗一朗、西澤 均、中村勇斗、清水有理、嶺尾良平、増田重樹、小幡佳也、長尾博文、福田士郎、藤島裕也、前田法一、下村伊一郎
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アディポネクチンのT-カドヘリンを介した新たな臓器保護作用メカニズム2018

    • Author(s)
      小幡佳也、福田士郎、喜多俊文、前田法一、下村伊一郎
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脂肪組織・血管由来分泌因子Favineの機能解析2018

    • Author(s)
      小林祥子、福原淳範、大月道夫、森井英一、下村伊一郎
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メタボリックシンドロームとアディポネクチンそして高尿酸血症2018

    • Author(s)
      下村伊一郎
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] T-カドヘリンにおけるアディポネクチン結合ドメインの同定およびT-カドヘリンプロドメインの重要性について2018

    • Author(s)
      福田士郎、喜多俊文、小幡佳也、藤島裕也、長尾博文、増田重樹、田中紀實、西澤 均、船橋 徹、前田法一、下村伊一郎
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アディポネクチン結合蛋白T-カドヘリンのメタロプロテアーゼADAM12による切断制御2018

    • Author(s)
      喜多俊文、中村勇斗、福田士郎、小幡佳也、嶺尾良平、清水有理、田中紀實、長尾博文、増田重樹、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アディポネクチン/TカドヘリンシステムとERストレスの関連2018

    • Author(s)
      嶺尾良平、喜多俊文、中村勇斗、福田士郎、小幡佳也、田中紀實、長尾博文、増田重樹、清水有理、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 慢性心不全モデルにおけるアディポネクチン/T-カドヘリンシステム2018

    • Author(s)
      中村勇斗、喜多俊文、嶺尾良平、福田士郎、小幡佳也、田中紀實、長尾博文、増田重樹、清水有理、藤島裕也、西澤 均、前田法一、下村伊一郎
    • Organizer
      第91回日本内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] アディポネクチンの新しい側面2018

    • Author(s)
      下村伊一郎
    • Organizer
      第55回日本外科代謝栄養学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Adiponectine/T-cadherin exrts vascular protection partly through exosome biogenesis and secretion2018

    • Author(s)
      Iichiro Shimomura
    • Organizer
      APDO(Asia-Pacific Diabetes and Obesity Study Group) SYMPOSIUM 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
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    • Author(s)
      喜多俊文、下村伊一郎
    • Publisher
      Diabetes Journal社
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 糖尿病治療剤2021

    • Inventor(s)
      喜多 俊文、下村 伊一郎、前田 法一、西田 浩之
    • Industrial Property Rights Holder
      喜多 俊文、下村 伊一郎、前田 法一、西田 浩之
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-026666
    • Filing Date
      2021
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 動脈硬化性疾患予防用組成物、血小板凝集抑制用組成物及び血栓形成抑制用組成物2019

    • Inventor(s)
      小林祥子、加藤 恒、森井英一、福原淳範、喜多俊文、下村伊一郎
    • Industrial Property Rights Holder
      国立大学法人大阪大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 幹細胞治療増強方法2019

    • Inventor(s)
      喜多俊文 他
    • Industrial Property Rights Holder
      ロート製薬株式会社、国立大学法人大阪大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2024-01-30  

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