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時計遺伝子NFIL3によるリンパ組織形成メカニズムの解明

Publicly Offered Research

Project AreaAnalysis and synthesis of multi-dimensional immune organ network
Project/Area Number 15H01162
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo University of Science

Principal Investigator

久保 允人  東京理科大学, 研究推進機構生命医科学研究所, 教授 (40277281)

Project Period (FY) 2015-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2015: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Keywordsリンパ組織形成 / 免疫システム / 発生・分化
Outline of Annual Research Achievements

我々はこれまでのT細胞に焦点を当てた研究から、時計遺伝子として知られる転写因子E4BP4/NFIL-3が、過剰な免疫反応を沈静化する働きを持つことを報告した(Nature Immunology 2011)。この分子を欠くマウスは、腸管内に存在するリンパ組織であるパイエル板の数が激減していた。このパイエル板に与える影響は、Lymphoid tissue inducer ('LTi')の発生過程に障害があることを明らかにした。また、E4BP4/NFIL-3の欠損は腸管内に主に分布する3型自然リンパ球(ILC3)の発生過程でも鍵となる分子として働いていることが分かった。ILCはサイトカインの産生パターンの違いによって、ILC1, ILC2, ILC3に分類できる。E4BP4/NFIL-3は、NK細胞の分化に加え、ILC1とILC2の分化過程,特に初期分化過程において必須の分子であることを見いだした。さらに、エピジェネティックな解析から、E4BP4/NFIL-3はId2遺伝子に結合することで、その発現制御によりILCの初期分化課程を制御していることを明らかにした(Cell Report 2015)。
一方、肺などの末梢組織では、E4BP4欠損下でもILC2細胞が存在していたことから、E4BP4に依存しない分化経路の存在が浮き彫りにされた。しかしながら、E4BP4非依存的ILC2細胞が存在する環境下でも、E4BP4欠損マウスはシステインプロテアーゼで誘導される急性期アレルギー性気道炎症が減弱しているとともに、それに伴うTh2細胞の集積も顕著に減弱した。この炎症後期に集積するTh2細胞は慢性期の反応系を構成しており、その集積にはILC2細胞あるいは好酸球球からのIL-13の産生が必要とされる。E4BP4は、急性期気道炎症時に起こるIL-13の産生を制御することにより、気道炎症の慢性化を制御するE4BP4の新しい役割が、本計画研究から明らかにされることになった。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (44 results)

All 2017 2016 2015

All Journal Article (21 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 19 results,  Acknowledgement Compliant: 14 results,  Open Access: 10 results) Presentation (23 results) (of which Int'l Joint Research: 12 results,  Invited: 17 results)

  • [Journal Article] Innate and adaptive type 2 immunity in lung allergic inflammation2017

    • Author(s)
      Kubo, M
    • Journal Title

      Immunolgical Review

      Volume: - Issue: 1 Pages: 162-172

    • DOI

      10.1111/imr.12557

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Basophil-derived interleukin-4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy2017

    • Author(s)
      Hussain M, Borcard L, Walsh KP, Pena Rodriguez M, Mueller C, Kim BS, Kubo M, Artis D, Noti M
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: - Issue: 1 Pages: 223-234.e5

    • DOI

      10.1016/j.jaci.2017.02.035

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] E3 ubiquitin ligases SIAH1/2 regulates hypoxia-inducible factor 1(HIF1)-mediated TH17 cell differentiation2017

    • Author(s)
      Matsui-Hasumi A, Sato Y, Uto-Konomi A, Yamashita S, Uehori J, Yoshimura A, Yamashita M, Asahara H, Suzuki S, Kubo M
    • Journal Title

      Int.Immunol

      Volume: - Issue: 3 Pages: 133-143

    • DOI

      10.1093/intimm/dxx014

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Differences in the importance of mast cells, basophils, IgE and IgG, versus CD4+ T cells and ILC2 cells, in primary and secondary immunity to Strongyloides venezuelensis2017

    • Author(s)
      Mukai K, Karasuyama H, Kabashima K, Kubo M, Galli SJ
    • Journal Title

      Infect Immun

      Volume: - Issue: 5

    • DOI

      10.1128/iai.00053-17

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] IL4 from T Follicular Helper Cells Downregulates Antitumor Immunity2017

    • Author(s)
      Shirota H, Klinman DM, Ito SE, Ito H, Kubo M, Ishioka C
    • Journal Title

      Cancer Immunology Research

      Volume: 5(1) Pages: 61-71

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Allergin-1 inhibits TLR2-mediated mast cell activation and suppresses dermatitis2016

    • Author(s)
      Tsurusaki S, Tahara-Hanaoka S, Shibagaki S, Miyake S, Imai M, Shibayama S, Kubo M, Shibuya A
    • Journal Title

      International Immunology

      Volume: 28(12) Issue: 12 Pages: 605-609

    • DOI

      10.1093/intimm/dxw046

    • NAID

      120007135029

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Mathematical modeling of atopic dermatitis reveals “double switch” mechanisms underlying 4 common disease phenotypes2016

    • Author(s)
      Domínguez-Hüttinger E, Christodoulides P, Miyauchi K, Irvine AD, Okada-Hatakeyama M, Kubo M, Tanaka RJ
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: - Issue: 6 Pages: 1861-1872.e7

    • DOI

      10.1016/j.jaci.2016.10.026

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Protective neutralizing influenza antibody response in the absence of T follicular helper cells2016

    • Author(s)
      Miyauchi K, Sugimoto-Ishige A, Harada Y, Adachi Y, Usami Y, Kaji T, Inoue K, Hasegawa H, Watanabe T, Hijikata A, Fukuyama S, Maemura T, Okada-Hatakeyama M, Ohara O, Kawaoka Y, Takahashi Y, Takemori T, Kubo M
    • Journal Title

      Nature Immunology

      Volume: 17(12) Issue: 12 Pages: 1447-1458

    • DOI

      10.1038/ni.3563

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis2016

    • Author(s)
      Yasuda T, Fukada T, Nishida K, Nakayama M, Matsuda M, Miura I, Dainichi T, Fukuda S, Kabashima K, Nakaoka S, Bin BH, Kubo M, Ohno H, Hasegawa T, Ohara O, Koseki H, Wakana S, Yoshida H
    • Journal Title

      J. Clin. Invest

      Volume: 126(6) Issue: 6 Pages: 2064-76

    • DOI

      10.1172/jci82887

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] CRTAM determines the CD4+ cytotoxic T lymphocyte lineage.2016

    • Author(s)
      Takeuchi, A., Badr Mel, S., Miyauchi, K., Ishihara, C., Onishi, R., Guo, Z., Sasaki. Y., Ike, H., Takumi, A., Tsuji, NM., Murakami, Y., Katakai, T., Kubo, M. and Saito, T.
    • Journal Title

      J. Exp. Med.

      Volume: 213 Issue: 1 Pages: 123-138

    • DOI

      10.1084/jem.20150519

    • Related Report
      2016 Annual Research Report 2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Oncolytic reovirus synergizes with chemotherapeutic agents to promote cell death in canine mammary gland tumor2016

    • Author(s)
      Igase M, Hwang CC, Kambayashi S, Kubo M, Coffey M, Miyama TS, Baba K, Okuda M, Noguchi S, Mizuno T
    • Journal Title

      Can J Vet Res

      Volume: 80(1) Pages: 21-31

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway2015

    • Author(s)
      Hara Y, Tashiro Y, Murakami A, Nishimura M, Shimizu T, Kubo M, Burrows PD, Azuma T
    • Journal Title

      Mol Immunol

      Volume: 68(2 Pt C) Issue: 2 Pages: 617-27

    • DOI

      10.1016/j.molimm.2015.10.003

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] PU.1 Suppresses Th2 Cytokine Expression via Silencing of GATA3 Transcription in Dendritic Cells2015

    • Author(s)
      Yashiro T, Kubo M, Ogawa H, Okumura K, Nishiyama C
    • Journal Title

      PLoS One

      Volume: 10(9) Issue: 9 Pages: e0137699-e0137699

    • DOI

      10.1371/journal.pone.0137699

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TCF-1 and LEF-1 help launch the T(FH) program2015

    • Author(s)
      Kubo M
    • Journal Title

      Nat Immunol

      Volume: 16(9) Issue: 9 Pages: 900-1

    • DOI

      10.1038/ni.3254

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.2015

    • Author(s)
      Morita H, Arae K, Unno H, Miyauchi K, Toyama S, Nambu A, Oboki K, Ohno T, Motomura K, Matsuda A, Yamaguchi S, Narushima S, Kajiwara N, Iikura M, Suto H, McKenzie AN, Takahashi T, Karasuyama H, Okumura K, Azuma M, Moro K, Akdis CA, Galli SJ, Koyasu S, Kubo M, Sudo K, Saito H, Matsumoto K, Nakae S.
    • Journal Title

      Immunity

      Volume: 43 Issue: 1 Pages: 175-86

    • DOI

      10.1016/j.immuni.2015.06.021

    • NAID

      40020962854

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Notch signaling enhances FceRI-mediated cytokine production by mast cells through direct and indirect mechanisms2015

    • Author(s)
      Nakano, N., Nishiyama, C., Yagita, H., Hara, M., Motomura, Y., Kubo, M., Okumura, K., and Ogawa, H
    • Journal Title

      J. Immunol

      Volume: 194(9) Issue: 9 Pages: 4535-44

    • DOI

      10.4049/jimmunol.1301850

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Zinc-binding metallothioneins are key modulators of IL-4 production by basophils2015

    • Author(s)
      Ugajin T, Nishida K, Yamasaki S, Suzuki J, Mita M, Kubo M, Yokozeki H, Hirano T
    • Journal Title

      Mol Immunol

      Volume: 66 Issue: 2 Pages: 180-188

    • DOI

      10.1016/j.molimm.2015.03.002

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors2015

    • Author(s)
      Wei Xu, Rita G. Domingues, Diogo Fonseca-Pereira, Manuela Ferreira, Hélder Ribeiro, Silvia Lopez-Lastra, Yasutaka Motomura, Lara Moreira-Santos, Franck Bihl4, Véronique Braud, Barbara Kee, Hugh Brady, Mark C.Coles, Christian Vosshenrich, Kubo, M., James P. Di Santo and Henrique Veiga-Fernandes
    • Journal Title

      Cell Report

      Volume: 10(12) Issue: 12 Pages: 2043-54

    • DOI

      10.1016/j.celrep.2015.02.057

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Helios enhances regulatory T cell function in cooperation with Foxp32015

    • Author(s)
      Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K, Suto A, Suzuki K, Kagami S, Hirose K, Kubo M, Hori S, Nakajima H
    • Journal Title

      Arthritis Rheumatol

      Volume: 67 Issue: 6 Pages: 1491-502

    • DOI

      10.1002/art.39091

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 新たなアレルギー発症メカニズム2015

    • Author(s)
      久保允人
    • Journal Title

      ファルマシア

      Volume: 51(6) Pages: 526-531

    • NAID

      130007448190

    • Related Report
      2015 Annual Research Report
  • [Journal Article] 好塩基球による免疫応答制御2015

    • Author(s)
      久保允人
    • Journal Title

      感染・炎症・免疫

      Volume: 45-2 Pages: 63-67

    • Related Report
      2015 Annual Research Report
  • [Presentation] Role of T follicular helper (Tfh) and Th1 cells in anti-viral immunity2017

    • Author(s)
      Kubo Masato
    • Organizer
      7th International Workshop of Kyoto T Cell Conference
    • Place of Presentation
      Shiran Kaikan, Kyoto University(Kyoto City, Kyoto)
    • Year and Date
      2017-03-13
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] New therapeutic approach for atopic dermatitis (AD) using comprehensive analysis and system biology2017

    • Author(s)
      Kubo Masato
    • Organizer
      2017 INTERNATIONAL BIOMEDICAL INTERFACE SYMPOSIUM
    • Place of Presentation
      Taipei Medical University(Taipei, Taiwan)
    • Year and Date
      2017-03-04
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 皮膚恒常性制御機構とアトピー性皮膚炎2017

    • Author(s)
      久保允人
    • Organizer
      アトピー疾患研究センター学術セミナー
    • Place of Presentation
      順天堂大学(東京都・文京区)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Essential role of E4BP4 in effector function of lung ILC22016

    • Author(s)
      SUZUKI Narumi, OMI Ai, MIYAUCHI Kosuke, KUBO Masato
    • Organizer
      The 45th Annual Meeting of the Japanese Society for Immunology
    • Place of Presentation
      Okinawa Convention Center, Laguna Garden Hotel(Ginowan City, Okinawa)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] IFNg and IL-6-dependent production of influenza virus specific IgA2016

    • Author(s)
      MIYAUCHI Kosuke, TAKEMORI Toshitada, KUBO Masato
    • Organizer
      45th Annual Meeting of the Japanese Society for Immunology
    • Place of Presentation
      Okinawa Convention Center, Laguna Garden Hotel(Ginowan City, Okinawa)
    • Year and Date
      2016-12-05
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of T follicular helper (TFH) in humoral immunity2016

    • Author(s)
      Kubo Masato
    • Organizer
      The 13th International Workshop on Autoantibodies and Autoimmunity (IWAA2016)
    • Place of Presentation
      The Westin Miyako Kyoto(Kyoto City, Kyoto)
    • Year and Date
      2016-10-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] サイトカインシグナルと皮膚恒常性2016

    • Author(s)
      久保允人
    • Organizer
      NEXT Lecture Meeting in Chiba
    • Place of Presentation
      千葉大学(千葉県・千葉市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 免疫疾患における細胞内シグナル伝達・サイトカインの基礎から応用へ2016

    • Author(s)
      久保允人
    • Organizer
      Cytokine Network Seminar ~免疫シグナル伝達の解明・進展~
    • Place of Presentation
      大阪大学(大阪府・吹田市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] アレルギーにおける自然免疫と獲得免疫のクロストーク2016

    • Author(s)
      久保允人
    • Organizer
      第65回日本アレルギー学会学術大会
    • Place of Presentation
      東京国際フォーラム (東京都・千代田区)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Humoral Immunity against Influenza virus infection2015

    • Author(s)
      KUBO Masato
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Most of the CD8+TIL are tumor-reactive in spontaneously regressing or progressing murine gastric cancer2015

    • Author(s)
      NAGAOKA Koji, HOSOI Akihiro, MATSUSHITA Hirokazu, KUBO Masato, TAKEDA Kazuyoshi, KAKIMI Kazuhiro
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Germinal centers and follicular helper T cells are dispensable for a protective antibody response to acute influenza A virus infection2015

    • Author(s)
      MIYAUCHI Kosuke, SUGIMOTO-ISHIGE Akiko, TAKAHASHI Yoshimasa, HASEGAWA Hideki, TAKEMORI Toshitada, KUBO Masato
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pathogenic effect of PM2.5 and nanoparticle in Lung inflammation2015

    • Author(s)
      THARMALINGAM Jayaraman, MIYAUCHI Kosuke, KUBO Masato
    • Organizer
      The 44th Annual Meeting of the Japanese Society for Immunology (JSI)
    • Place of Presentation
      札幌コンベンションセンター(北海道札幌市)
    • Year and Date
      2015-11-18
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Innate and acquired immunity in influenza virus infection2015

    • Author(s)
      KUBO Masato
    • Organizer
      2015 Fall Conference of The Korean Association of the Immunologists
    • Place of Presentation
      Sejong University Convention Center(Soul, Korea)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Innate and acquired immunity in influenza virus infection2015

    • Author(s)
      KUBO Masato
    • Organizer
      International Symposium on Allergy and Inflammation 2015
    • Place of Presentation
      大洗パークホテル(茨城県東茨城郡)
    • Year and Date
      2015-10-29
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アレルギーにおける白血球・リンパ球の役割2015

    • Author(s)
      久保允人
    • Organizer
      鹿児島呼吸器セミナー
    • Place of Presentation
      鹿児島大学(鹿児島県鹿児島市)
    • Year and Date
      2015-09-15
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Host defense mechanisms against Influenza virus infection2015

    • Author(s)
      KUBO Masato
    • Organizer
      International Symposium of Center for Animal Disease Model (CADMIS) 2015
    • Place of Presentation
      学士会館(東京都千代田区)
    • Year and Date
      2015-07-21
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 転写因子E4BP4と自然リンパ球によるアレルギー性気道炎症の制御2015

    • Author(s)
      KUBO Masato
    • Organizer
      第80回日本インターフェロン・サイトカイン学会学術集会
    • Place of Presentation
      東京工業大学(東京都目黒区)
    • Year and Date
      2015-07-17
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 皮膚の恒常と炎症の制御2015

    • Author(s)
      久保允人
    • Organizer
      第22回四国四大学皮膚科研究会
    • Place of Presentation
      ザ クラウンパレス新阪急高知(高知県高知市)
    • Year and Date
      2015-07-11
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] インフルエンザ感染における気道炎症制御と抗体産生制御について2015

    • Author(s)
      久保允人
    • Organizer
      ヘルスバイオサイエンス研究部 免疫学セミナー
    • Place of Presentation
      徳島大学(徳島県徳島市)
    • Year and Date
      2015-07-10
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] マスト細胞・好塩基球欠損マウスシステムの構築とサイトカイン産生能2015

    • Author(s)
      久保允人
    • Organizer
      第64回日本アレルギー学会学術大会
    • Place of Presentation
      グランドプリンスホテル新高輪(東京都港区)
    • Year and Date
      2015-05-28
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 転写因子E4BP4 と自然リンパ球によるアレルギー性気道炎症の制御2015

    • Author(s)
      久保允人
    • Organizer
      第64回日本アレルギー学会学術大会
    • Place of Presentation
      グランドプリンスホテル新高輪(東京都港区)
    • Year and Date
      2015-05-26
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] アレルギー性気道炎症における自然免疫細胞2015

    • Author(s)
      久保允人
    • Organizer
      SCIENCE in Shinagawa
    • Place of Presentation
      ガーデンシティ品川(東京都港区)
    • Year and Date
      2015-04-18
    • Related Report
      2015 Annual Research Report
    • Invited

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Published: 2015-04-16   Modified: 2018-03-28  

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