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Development of the molecular target therapy for the inflammatory bowel disease

Research Project

Project/Area Number 16H05169
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionUniversity of Tsukuba

Principal Investigator

Shibuya Kazuko  筑波大学, 医学医療系, 准教授 (00302406)

Research Collaborator Sato Kazuki  
Kanemaru Yumi (Yamashita Yumi)  
Abe Fumie  
Nakamura Yuho  
Murata Rikito  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2016: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords免疫学 / 免疫受容体 / 制御性T細胞 / 炎症 / 免疫系受容体 / 炎症性腸炎 / 炎症性腸疾患
Outline of Final Research Achievements

The inflammatory bowel disease is an intractable disease with chronic inflammation of the intestinal mucosa. Treg cells play an important role to suppress immune response-induced inflammation. In this study, we show that DNAM-1, an immunoreceptor expressed on Tregs, induces instability in the expression of Foxp3, a master regulator of Tregs, in the inflammatory environment and limits the immunosuppressive capacity of Tregs. Thus, DNAM-1 may be a good therapeutic target for the control of inflammatory bowel disease associated with Treg dysfunction.

Academic Significance and Societal Importance of the Research Achievements

クローン病や潰瘍性大腸炎に代表される炎症性腸疾患は、腸粘膜の慢性炎症を主徴とする原因不明の難治性疾患である。わが国の患者数は年々増加おり、H25年には20万人を超えた。しかし、根治的治療法が未だ確立されていないことより、早急な治療法の開発が望まれている。制御性T細胞 (Treg) は、炎症性腸疾患の病態制御に重要な役割を担っている。本研究において、DNAM-1欠損はAKT-mTORC1経路が抑制し、安定したFoxp3発現を促して、Tregの抑制機能を亢進することが明らかになった。このことは、Tregの機能不全を伴う炎症性疾患の制御にDNAM-1が良い治療標的となりうることを示唆している。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (52 results)

All 2019 2018 2017 2016

All Journal Article (14 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 14 results,  Open Access: 11 results,  Acknowledgement Compliant: 4 results) Presentation (36 results) (of which Int'l Joint Research: 5 results,  Invited: 4 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Exploring the Gut Fungi-Lung Allergy Axis2018

    • Author(s)
      Shibuya Akira、Shibuya Kazuko
    • Journal Title

      Cell Host & Microbe

      Volume: 24 Issue: 6 Pages: 755-757

    • DOI

      10.1016/j.chom.2018.11.012

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation.2018

    • Author(s)
      Nakamura Y, Matsuzaka T, Tahara-Hanaoka S, Shibuya K, Shimano H, Nakahashi-Oda C, Shibuya A.
    • Journal Title

      Cell Death Dis.

      Volume: 9(12) Issue: 12 Pages: 1181-1181

    • DOI

      10.1038/s41419-018-1226-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CD155-Transducing Signaling through TIGIT Plays an Important Role in Transmission of Tolerant State and Suppression Capacity2018

    • Author(s)
      Negishi Naoko、Sato Takehito、Yamashita-Kanemaru Yumi、Shibuya Kazuko、Uchida Koichiro、Kametani Yoshie、Yagita Hideo、Kitaura Jiro、Okumura Ko、Habu Sonoko
    • Journal Title

      ImmunoHorizons

      Volume: 2 Issue: 10 Pages: 338-348

    • DOI

      10.4049/immunohorizons.1800033

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Selective DNAM-1 expression on small peritoneal macrophages contributes to CD4+ T cell costimulation2018

    • Author(s)
      Takenaka Eri、Van Vo Anh、Yamashita-Kanemaru Yumi、Shibuya Akira、Shibuya Kazuko
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 15180-15180

    • DOI

      10.1038/s41598-018-33437-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cutting Edge: Identification of Marginal Reticular Cells as Phagocytes of Apoptotic B Cells in Germinal Centers2018

    • Author(s)
      Sato Kazuki、Honda Shin-ichiro、Shibuya Akira、Shibuya Kazuko
    • Journal Title

      The Journal of Immunology

      Volume: 200 Issue: 11 Pages: 3691-3696

    • DOI

      10.4049/jimmunol.1701293

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TX99 Is a Neutralizing Monoclonal Antibody Against Mouse TIGIT2018

    • Author(s)
      Nakamura Yuho , Naito Keisuke , Yamashita-Kanemaru Yumi , Komori Daisuke , Hirochika Rei , Shibuya Akira , and Shibuya Kazuko
    • Journal Title

      Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

      Volume: 印刷中 Issue: 2 Pages: 105-109

    • DOI

      10.1089/mab.2018.0001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TX99 is a neutralizing monoclonal antibody against mouse TIGIT.2018

    • Author(s)
      Nakamura Y, Naito K, Yamashita-Kanemaru Y, Komori D, Hirochika R., Shibuya A., Shibuya K.
    • Journal Title

      Monoclon Antib Immunodiagn Immunother

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of marginal reticular cells as phagocytes of apoptotic B cells in germinal centers.2018

    • Author(s)
      Sato K., Honda S., Shibuya A., Shibuya K.
    • Journal Title

      J. Immunol.

      Volume: 印刷中

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development and Characterization of Novel Monoclonal Antibodies Against Human DNAM-12017

    • Author(s)
      Okumura Genki、Abe Fumie、Hirochika Rei、Shibuya Akira、Shibuya Kazuko
    • Journal Title

      Monoclon Antib Immunodiagn Immunother

      Volume: 36 Issue: 3 Pages: 135-139

    • DOI

      10.1089/mab.2016.0049

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Improved protocol for the isolation of naive follicular dendritic cells2016

    • Author(s)
      Sato K, Honda SI, Shibuya A, Shibuya K
    • Journal Title

      Mol Immunol

      Volume: 78 Pages: 140-145

    • DOI

      10.1016/j.molimm.2016.09.011

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10-induced modulation of phagocyte antifungal activity2016

    • Author(s)
      Haraguchi N, Kikuchi N, Morishima Y, Matsuyama M, Sakurai H, Shibuya A, Shibuya K, Taniguchi M, Ishii Y
    • Journal Title

      Eur J Immunol

      Volume: 46 Issue: 7 Pages: 1691-1703

    • DOI

      10.1002/eji.201545987

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Soluble DNAM-1, as a predictive biomarker for acute graft-versus-host disease2016

    • Author(s)
      Kanaya M, Shibuya K, Hirochika R, Kanemoto M, Ohashi K, Okada M, Wagatsuma Y, Cho Y, Kojima H, Teshima T, Imamura M, Sakamaki H, Shibuya A.
    • Journal Title

      PLoS ONE

      Volume: 11 Issue: 6 Pages: e0154173-e0154173

    • DOI

      10.1371/journal.pone.0154173

    • NAID

      120007129409

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling2016

    • Author(s)
      Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K, Nakahashi-Oda C, Tahara-Hanaoka S, Shibuya K, Shibuya A
    • Journal Title

      Nat Commun

      Volume: 7 Issue: 1 Pages: 1-10

    • DOI

      10.1038/ncomms11498

    • NAID

      120007135503

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Increased soluble CD155 in the serum of cancer patients2016

    • Author(s)
      Iguchi-Manaka A, Okumura G, Kojima H, Cho Y, Hirochika R, Bando H, Sato T, Yoshikawa H, Hara H, Shibuya A, Shibuya K.
    • Journal Title

      PLoS One

      Volume: 11(4) Issue: 4 Pages: 1-12

    • DOI

      10.1371/journal.pone.0152982

    • NAID

      120007135543

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 乾癬における免疫受容体CD96の作用機序の解析2019

    • Author(s)
      大岡杏子、渋谷彰、渋谷和子
    • Organizer
      第7回筑波大学・東京理科大学合同リトリート
    • Related Report
      2018 Annual Research Report
  • [Presentation] DNAM-1とTIGITによる制御性T細胞の調節機構2019

    • Author(s)
      佐藤和貴、金丸由美、阿部史枝、中村優歩、村田力斗、伊藤守、渋谷彰、渋谷和子
    • Organizer
      第7回筑波大学・東京理科大学合同リトリート
    • Related Report
      2018 Annual Research Report
  • [Presentation] DNAM-1遺伝子上の一塩基多型による自己免疫疾患への影響2019

    • Author(s)
      村田力斗、金丸由美、渋谷彰、渋谷和子
    • Organizer
      第7回筑波大学・東京理科大学合同リトリート
    • Related Report
      2018 Annual Research Report
  • [Presentation] elective expression and function of DNAM-1 (CD226) expressed on small peritoneal macrophages.2019

    • Author(s)
      Vo AV, Takenaka Yamashita-Kanemaru Y, Shibuya A, Shibuya K.
    • Organizer
      第7回筑波大学・東京理科大学合同リトリート
    • Related Report
      2018 Annual Research Report
  • [Presentation] Involvement of DNAM-1 (CD226) expressed on small peritoneal macrophages in CD4+ T cell priming.2019

    • Author(s)
      Vo AV, Takenaka E, Yamashita-Kanemaru Y, Shibuya A, Shibuya K.
    • Organizer
      Keystone Symposia Conference / Myeloid Cells,
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] DNAM-1 regulates the Foxp3 stability of regulatory T cells under inflammatory conditions.2018

    • Author(s)
      Sato K, Yamashita-Kanemaru Y, Abe F, Nakamura Y, Murata R, Ito M, Shibuya A, Shibuya K.
    • Organizer
      第47回日本免疫学会総会・学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Involvement of DNAM-1 (CD226) expressed on small peritoneal macrophages in CD4+ T cell priming.2018

    • Author(s)
      Vo AV, Takenaka E, Yamashita-Kanemaru Y, Shibuya A, Shibuya K.
    • Organizer
      第47回日本免疫学会総会・学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性化受容体DNAM-1は炎症時の制御性T細胞の機能を抑制する2018

    • Author(s)
      佐藤和貴、金丸由美、阿部史枝、中村優歩、村田力斗、伊藤守、渋谷彰、渋谷和子
    • Organizer
      第10回血液・疾患免疫療法学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 腫瘍免疫応答における可溶型CD155の役割2018

    • Author(s)
      奥村元紀、村田力斗、井口研子、渋谷彰、渋谷和子
    • Organizer
      第10回血液・疾患免疫療法学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Development of molecular target therapy for human acute GVHD in humanized mice.2018

    • Author(s)
      Murata R, Okumura G, Abe F, Sato K, Yamashita-Kanemaru Y, Ito M, Shibuya A, Shibuya K.
    • Organizer
      Tsukuba Global Science Week 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Allergin-1 immunoreceptor suppresses house dust mite-induced allergic Th2 responses2018

    • Author(s)
      田原聡子、三木春香、人見香織、Almeida Mariana、柴垣翔平、金丸和正、岩田佳奈子、柴山史朗、住田孝之、渋谷和子、渋谷彰
    • Organizer
      第83回日本インターフェロン・サイトカイン学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性化受容体DNAM-1は炎症時の制御性T細胞の機能を抑制する2018

    • Author(s)
      佐藤和貴、金丸(山下)由美、阿部史枝、中村優歩、村田力斗、伊藤守、渋谷彰、渋谷和子
    • Organizer
      第33回自己免疫研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性化受容体DNAM-1 は炎症時の制御性T 細胞の機能を抑制する2018

    • Author(s)
      佐藤 和貴、金丸 由美、阿部 史枝、中村 優歩、村田 力斗、伊藤 守、渋谷 彰、渋谷 和子
    • Organizer
      第6回筑波大学・東京理科大学合同リトリート
    • Related Report
      2017 Annual Research Report
  • [Presentation] DSS 誘導性腸炎モデルにおける活性化受容体DNAM-1 の役割2018

    • Author(s)
      中村 優歩、金丸 由美、渋谷 彰、渋谷 和子
    • Organizer
      第6回筑波大学・東京理科大学合同リトリート
    • Related Report
      2017 Annual Research Report
  • [Presentation] DNAM-1 遺伝子上の一塩基多型による自己免疫疾患への影響2018

    • Author(s)
      村田 力斗、金丸 由美、渋谷 彰、渋谷 和子
    • Organizer
      第6回筑波大学・東京理科大学合同リトリート
    • Related Report
      2017 Annual Research Report
  • [Presentation] DNAM-1 limits Treg cell function via TIGIT-dependent manner.2017

    • Author(s)
      Yamashita-Kanemaru Y, Sato K, Abe F, Nakamura Y, Murata R, Shibuya A, Shibuya K.
    • Organizer
      第46回日本免疫学会総会・学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The role of soluble CD155 in tumor immune response and metastasis.2017

    • Author(s)
      Okumura G., Iguchi-Manaka A., Shibuya A., Shibuya K.,
    • Organizer
      第46回日本免疫学会総会・学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Marginal reticular cells act as a non-professional phagocyte for clearance of apoptotic B cells.2017

    • Author(s)
      Sato K. Honda S., Shibuya A., Shibuya K.
    • Organizer
      第46回日本免疫学会総会・学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] CD155-mediated signaling through TIGIT is involved in serial transfer of tolerant state into naive T cells.2017

    • Author(s)
      Negishi N., Sato T., Kanemaru Y., Shibuya K., Uchida K., Kametani Y., Okumura K., Habu S.
    • Organizer
      第46回日本免疫学会総会・学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Escape from tumor immunity by soluble CD155.2017

    • Author(s)
      Shibuya K.
    • Organizer
      The 5th Annual Meeting of the International Cytokine and Interferon Society
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 免疫受容体によるヘルパーT細胞の機能分化と活性化制御2017

    • Author(s)
      渋谷 和子
    • Organizer
      第4回ベーシックリサーチカンファレンス
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] DNAM-1はヒト急性GVHD治療の分子標的となりうる2017

    • Author(s)
      金丸(山下)由美、佐藤 和貴、阿部 史枝、奥村 元紀、伊藤 守、渋谷 彰、渋谷 和子
    • Organizer
      第9回血液・疾患免疫療法学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 急性GVHDにおけるsoluble DNAM-1 dynamicsの解析2017

    • Author(s)
      五島 祐樹、渋谷 和子、渋谷 彰、中岡 慎治
    • Organizer
      第9回血液・疾患免疫療法学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 癌患者血清における可溶型CD1552017

    • Author(s)
      井口 研子、渋谷 彰、渋谷 和子
    • Organizer
      第9回血液・疾患免疫療法学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 腫瘍免疫応答とがん転移における可溶型CD155の役割2017

    • Author(s)
      奥村 元紀、井口 研子、村田 力斗、渋谷 彰、渋谷 和子
    • Organizer
      第9回血液・疾患免疫療法学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 新規抗TIGIT抗体の樹立と特性評価2017

    • Author(s)
      中村 優歩、内藤 惠介、金丸(山下)由美、渋谷 彰、渋谷 和子
    • Organizer
      第9回血液・疾患免疫療法学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 乳癌における可溶型CD155の発現解析2017

    • Author(s)
      井口 研子、渋谷 和子、市岡 恵美香、都島 由希子、池田 達彦、坂東 裕子、渋谷 彰、原 尚人
    • Organizer
      日本乳癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] アレルギー疾患におけるヘルパーT細胞の役割2017

    • Author(s)
      渋谷 和子
    • Organizer
      第44回日本毒性学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 免疫系受容体DNAM-1を分子標的とした病態制御2017

    • Author(s)
      渋谷 和子
    • Organizer
      Co-stimulator’s Assembly
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Involvement of DNAM-1 (CD226) expressed on small peritoneal macrophages in antigen presentation.2016

    • Author(s)
      Vo AV, Takenaka E, Yamashita-Kanemaru Y, Shibuya A, Shibuya K.
    • Organizer
      第45回日本免疫学会総会学術集会
    • Place of Presentation
      沖縄コンベンションセンター(沖縄県宜野湾市)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
  • [Presentation] Development of molecular targeted therapy for human acute GVHD in humanized mice.2016

    • Author(s)
      Okumura G, Abe F, Ito M, Shibuya A, Shibuya K.
    • Organizer
      第45回日本免疫学会総会学術集会
    • Place of Presentation
      沖縄コンベンションセンター(沖縄県宜野湾市)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
  • [Presentation] Apoptotic epithelial cells control the abundance of regulatory T cells at barrier surfaces.2016

    • Author(s)
      Nakahashi-Oda C, Udayanga K. G. S, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, Iino S, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A.
    • Organizer
      International Congress of Immunology 2016
    • Place of Presentation
      Melbourne (Australia)
    • Year and Date
      2016-08-22
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] CD155 (PVR/Necl5) mediates a costimulatory signal in CD4+ T cells and regulates allergic inflammation.2016

    • Author(s)
      Yamashita-Kanemaru Y, Bernhardt G, Shibuya A, Shibuya K.
    • Organizer
      International Congress of Immunology 2016
    • Place of Presentation
      Melbourne (Australia)
    • Year and Date
      2016-08-22
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] “今後の基礎医学教育のあり方”に関するアンケート調査2016

    • Author(s)
      岸美紀子、井内康輝、坂井建雄、高桑雄一、堤寛、柳澤輝行、鯉淵典之、渋谷和子、中島昭、熊ノ郷淳
    • Organizer
      第48回日本医学教育学会大会
    • Place of Presentation
      大阪市立大学(大阪府大阪市)
    • Year and Date
      2016-07-29
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒト化マウスを用いた抗ヒトDNAM-1抗体によるヒト急性GVHDの治療法開発2016

    • Author(s)
      渋谷和子、阿部史枝、伊藤守、渋谷彰
    • Organizer
      第8回血液疾患免疫療法学会学術集会
    • Place of Presentation
      北海道大学(北海道札幌市)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 筑波大学における臨地実習前OSCEの開発に向けた取組2016

    • Author(s)
      會田 雄一、山内一由、上妻行則、渋谷和子、上杉憲子、中川嘉、吉田文代、山下年晴、小池朗、二宮治彦
    • Organizer
      第11回日本臨床検査学教育学会学術大会
    • Place of Presentation
      神戸常盤大学(兵庫県神戸市)
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 制御性T細胞の活性化剤及びその使用2017

    • Inventor(s)
      渋谷 彰、渋谷 和子、阿部 史枝、広近 玲、奥村 元紀
    • Industrial Property Rights Holder
      筑波大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 抗ヒトDNAM-1モノクローナル抗体及びその使用2016

    • Inventor(s)
      渋谷彰、渋谷和子、阿部史枝、広近玲、奥村元紀
    • Industrial Property Rights Holder
      渋谷彰、渋谷和子、阿部史枝、広近玲、奥村元紀
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-084170
    • Filing Date
      2016-04-16
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2024-01-30  

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