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Functional interaction between OPC and neural circuits

Planned Research

Project AreaGlial assembly: a new regulatory machinery of brain function and disorders
Project/Area Number 25117007
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 InstitutionNiigata University

Principal Investigator

Hirohide Takebayashi  新潟大学, 医歯学系, 教授 (60353439)

Co-Investigator(Kenkyū-buntansha) 榎戸 靖  愛知県心身障害者コロニー発達障害研究所, 病理学部, 室長 (90263326)
Research Collaborator Horie Masao  鹿児島大学, 大学院医歯学総合研究科 形態科学, 准教授
Yoshioka Nozomu  新潟大学, 超域学術院, 助教
Chiba Yoichi  香川大学, 大学院医学系研究科 炎症病理学, 准教授
Zhou Lei  新潟大学, 大学院医歯学総合研究科, 特任助教
Hossain MD Ibrahim  新潟大学, 大学院医歯学総合研究科, 大学院生
Simankova Anna  新潟大学, 大学院医歯学総合研究科, 大学院生
Mori Yukiko (Ochiai Yukiko)  新潟大学, 医学部, 研究補助員
Imada Yuya  新潟大学, 医学部, 研究補助員
Project Period (FY) 2013-06-28 – 2018-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥62,270,000 (Direct Cost: ¥47,900,000、Indirect Cost: ¥14,370,000)
Fiscal Year 2017: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2016: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2015: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2014: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2013: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Keywordsオリゴデンドロサイト前駆細胞 / オリゴデンドロサイト / ミエリン / 髄鞘 / 分化 / Olig2 / 遺伝子改変マウス / グリアアセンブリ / ミュータントマウス / グリア細胞
Outline of Final Research Achievements

We identified Olig2 binding protein 2 (Obp2) by yeast two hybrid screening. Central nervous system-specific Obp2 conditional knockout (cKO) mice died just after birth and mature oligodendrocyte-specific Obp2 cKO mice died at several weeks old. It was shown that Obp2 is essential factor for maintenance of oligodendrocyte progenitor cells and mature olidogendrocyte.
Dr. Enokido established primary culture system for murine oligodendrocyte progenitor cells. Using this culture system, they investigated on Krabbe disease model mice and then showed accumulation of psycosine in the oligodendrocytes.

Academic Significance and Societal Importance of the Research Achievements

本研究では、オリゴデンドロサイト系譜細胞の維持・分化・細胞死のメカニズムを明らかするとともに、生後マウス脳において、オリゴデンドロサイト前駆細胞の増殖・分化などを制御するマウスを作製し、神経機能への影響を明らかにする。本研究を進めることにより、オリゴデンドロサイトの異常によるミエリン形成不全や多発性硬化症の病態や症状の発現について理解が深まり、治療法開発への基盤となる知識が得られると期待される。

Report

(6 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (50 results)

All 2019 2018 2017 2016 2015 2014 2013 Other

All Int'l Joint Research (1 results) Journal Article (16 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (29 results) (of which Int'l Joint Research: 4 results,  Invited: 5 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] Jahangirnagar University(バングラデシュ)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Deletion of exons encoding carboxypeptidase domain of Nna1 results in Purkinje cell degeneration (pcd) phenotype2018

    • Author(s)
      Zhou Li、Hossain M. Ibrahim、Yamazaki Maya、Abe Manabu、Natsume Rie、Konno Kohtaro、Kageyama Shun、Komatsu Masaaki、Watanabe Masahiko、Sakimura Kenji、Takebayashi Hirohide
    • Journal Title

      Journal of Neurochemistry

      Volume: 147 Issue: 4 Pages: 557-572

    • DOI

      10.1111/jnc.14591

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Developmental defects and aberrant accumulation of endogenous psychosine in oligodendrocytes in a murine model of Krabbe disease.2018

    • Author(s)
      Inamura N, Kito M, Go S, Kishi S, Hosokawa M, Asai K, Takakura N, Takebayashi H, Matsuda J, Enokido Y.
    • Journal Title

      Neurobiology of Disease

      Volume: 120 Pages: 51-62

    • DOI

      10.1016/j.nbd.2018.08.023

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diencephalic progenitors contribute to the posterior septum through rostral migration along the hippocampal axonal pathway2018

    • Author(s)
      Watanabe Keisuke、Irie Koichiro、Hanashima Carina、Takebayashi Hirohide、Sato Noboru
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s41598-018-30020-9

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduced Proliferation of Oligodendrocyte Progenitor Cells in the Postnatal Brain of Dystonia Musculorum Mice2018

    • Author(s)
      Hossain M. Ibrahim、Horie Masao、Takebayashi Hirohide
    • Journal Title

      Neurochemical Research

      Volume: 43 Issue: 1 Pages: 92-100

    • DOI

      10.1007/s11064-017-2342-5

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Motoneuron degeneration in the trigeminal motor nucleus innervating the masseter muscle in Dystonia musculorum mice2017

    • Author(s)
      Hossain M. Ibrahim、Horie Masao、Yoshioka Nozomu、Kurose Masayuki、Yamamura Kensuke、Takebayashi Hirohide
    • Journal Title

      Neurochem Int

      Volume: - Pages: 159-170

    • DOI

      10.1016/j.neuint.2017.10.009

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear2017

    • Author(s)
      Sato MP, et al.
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 10 Pages: 300-300

    • DOI

      10.3389/fnmol.2017.00300

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BPAG1 in muscles: Structure and function in skeletal, cardiac and smooth muscle2017

    • Author(s)
      Masao Horie, Nozomu Yoshioka, Hirohide Takebayashi
    • Journal Title

      Seminars in Cell and Developmental Biology

      Volume: 69 Pages: 26-33

    • DOI

      10.1016/j.semcdb.2017.07.016

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS).2017

    • Author(s)
      Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, Wakamatsu N.
    • Journal Title

      Oncotarget

      Volume: 8(28) Issue: 28 Pages: 45470-45483

    • DOI

      10.18632/oncotarget.17566

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 単純性表皮水疱症モデルとしての新規Dystonin/Bpag1遺伝子変異マウスの解析2017

    • Author(s)
      栗山桃奈, 吉岡望, 加畑雄大, 牛木辰男, 吉木淳, Thomas J Sproule, 阿部理一郎, 竹林浩秀
    • Journal Title

      新潟医学会雑誌

      Volume: 131 Pages: 655-663

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ジストニア様の運動症状と感覚神経変性を示すdystonia musculorumマウスの病態解析2017

    • Author(s)
      竹林浩秀
    • Journal Title

      生化学

      Volume: 89 Pages: 756-760

    • NAID

      40021377452

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway2017

    • Author(s)
      Morizawa Yosuke M.、Hirayama Yuri、Ohno Nobuhiko、Shibata Shinsuke、Shigetomi Eiji、Sui Yang、Nabekura Junichi、Sato Koichi、Okajima Fumikazu、Takebayashi Hirohide、Okano Hideyuki、Koizumi Schuichi
    • Journal Title

      Nature Communications

      Volume: 8 Issue: 1 Pages: 28-28

    • DOI

      10.1038/s41467-017-00037-1

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histological detection of dynamic glial responses in the dysmyelinating Tabby-jimpy mutant brain.2017

    • Author(s)
      Ikeda M., Hossaim M.I., Zhou L., Horie M., Ikenaka K., Horii A., Takebayashi H.
    • Journal Title

      Anatomical Science International

      Volume: 印刷中 Issue: 1 Pages: 119-127

    • DOI

      10.1007/s12565-016-0383-5

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Oligodendrocyte precursor cells in the mouse optic nerve originate in the preoptic area.2016

    • Author(s)
      Katsuhiko Ono, Kengo Yoshii, Hiroyuki Tominaga, Hitoshi Gotoh, Tadashi Nomura, Hirohide Takebayashi, Kazuhiro Ikenaka
    • Journal Title

      Brain structure and function

      Volume: - Issue: 5 Pages: 2441-2448

    • DOI

      10.1007/s00429-017-1394-2

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Disruption of actin-binding domain-containing Dystonin protein causes dystonia musculorum in mice.2014

    • Author(s)
      Horie, M., Watanabe, K., Bepari, A. K., Nashimoto, J., Araki, K., Sano, H., Chiken, S., Nambu, A., Ono, K., Ikenaka, K., Kakita, A., Yamamura, K. and Takebayashi, H.
    • Journal Title

      Eur. J Neurosci.

      Volume: 40 Issue: 10 Pages: 3458-3471

    • DOI

      10.1111/ejn.12711

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 佐藤和彦、堀江正男、竹林浩秀、高橋均、柿田明美2014

    • Author(s)
      ヒト脳病理切片におけるin situ hybridization 法を利用したニューロンおよびグリア細胞の同定
    • Journal Title

      新潟医学会雑誌

      Volume: 128 Pages: 625-634

    • Related Report
      2014 Annual Research Report
    • Acknowledgement Compliant
  • [Journal Article] グリア細胞発生・分化機構の解析と生体内細胞系譜追跡実験系の確立・応用2014

    • Author(s)
      竹林浩秀
    • Journal Title

      神経化学

      Volume: 53 Pages: 41-46

    • Related Report
      2014 Annual Research Report
  • [Presentation] 新規Olig2結合因子によるオリゴデンドロサイト前駆細胞維持機構の解明2019

    • Author(s)
      備前典久、矢野真人、周麗、阿部学、﨑村建司、竹林浩秀
    • Organizer
      第124回日本解剖学会総会全国学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] カルボキシペプチターゼドメインをコードするエクソンを欠失するNna1ノックアウトマウスはプルキンエ細胞変性を引き起こす2019

    • Author(s)
      周麗、山崎真弥、阿部学、夏目里恵、今野幸太郎、渡辺雅彦、﨑村建司、竹林浩秀
    • Organizer
      第124回日本解剖学会総会全国学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Analysis of the effect of a novel Olig2-Binding Factor on the oligodendrocyte differentiation and myelination in central nervous system2019

    • Author(s)
      Norihisa Bizen, Anna Simankova, Nobuhiro Ohno, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
    • Organizer
      The 66th NIBB Conference ABiS International Symposium
    • Related Report
      2017 Annual Research Report
  • [Presentation] Effects of a novel Olig2-binding protein 2 (Obp2) deficiency on the oligodendrocytes differentiation and myelination in murine spinal cord.2019

    • Author(s)
      Anna Simankova, Norihisa Bizen, Manabu Abe, Kenji Sakimura, Hirohide Takebayashi
    • Organizer
      N-hybrid conference
    • Related Report
      2017 Annual Research Report
  • [Presentation] Myelin lipid分解経路の破綻がもたらす脳白質脳症の病態解析とその治療応用2018

    • Author(s)
      榎戸靖、鬼頭もも子、郷慎司、細川昌則、浅井清文、竹林浩秀、松田純子、稲村直子
    • Organizer
      第61回日本神経化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] マウスNna1遺伝子のcarboxypeptidaseドメインをコードするエクソンを欠失するとプルキ二エ細胞変性の表現型を示す2018

    • Author(s)
      竹林浩秀、周麗、ホサイン MDイブラヒム、山崎真弥、阿部学、夏目理恵、今野幸太郎、渡辺雅彦、﨑村建司
    • Organizer
      第61回日本神経化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Semaphorins and their transcriptional regulators limit axonal regeneration after spinal cord injury.2018

    • Author(s)
      Yuka Nakamura, Masaki Ueno, Hiroshi Nakagawa, Jesse Niehaus, Hirohide Takebayashi, Qing R Lu, Masahiro Takada, Yutaka Yoshida
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Diencephalic progenitors contribute to the posterior septum through rostral migration along the hippocampal axonal pathway.2018

    • Author(s)
      Keisuke Watanabe, Hirohide Takebayashi, Noboru Sato
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Motoneuron degeneration in the trigeminal motor nucleus and atrophy of the masseter muscle in Dystonia musculorum mice.2018

    • Author(s)
      Hirohide Takebayashi, MD Ibrahim Hossain, Masao Horie, Nozomu Yoshioka, Masayuki Kurose, Kensuke Yamamura
    • Organizer
      FENS2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Neural and systemic pathogenesis of dystonia musculorum mice.2018

    • Author(s)
      Hirohide Takebayashi
    • Organizer
      2018 Korea-Japan Joint Symposium on Neurodevelopment
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新規Olig2結合因子によるオリゴデンドロサイト発生機構の解明2018

    • Author(s)
      備前典久、周麗、﨑村建司、竹林浩秀
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Presentation] 恐怖・不安行動に関わる後方中隔核の新たな産生領域2018

    • Author(s)
      渡辺啓介、佐藤航士、竹林浩秀、佐藤昇
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] マウスとニワトリ間での、視神経オリゴデンドロサイトの起源の違いはなぜ生じるか2018

    • Author(s)
      栗田菜花、後藤仁志、野村真、竹林浩秀、小野勝彦
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] 髄鞘形成不全マウスにおけるミクログリア分布及び形態の解析2018

    • Author(s)
      五十嵐恵介、吉岡望、竹林浩秀、目黒玲子
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] 視神経オリゴデンドロサイトの起源の種差2018

    • Author(s)
      小野勝彦、栗田菜花、後藤仁志、野村真、竹林浩秀
    • Organizer
      第123回日本解剖学会総会・全国学術集会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Migration and differentiation of V-SVZ-derived oligodendrocyte progenitors in the injured cortex2017

    • Author(s)
      Mayaka Hashimoto, Naoko Kaneko, Seiya Yamamoto, Takuya Miyamoto, Hirohide Takebayashi, Kazuhiro Ikenaka, Kazunobu Sawamoto
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] A novel Olig2-binding factor is indispensable for oligodendrocyte development in central nervous system2017

    • Author(s)
      Hirohide Takebayashi, Norihisa Bizen
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Identification and characterization of novel dystonia musculorum mutant mice.2017

    • Author(s)
      Hirohide Takebayashi, Masao Horie, Kazuyuki Mekada, Hiromi Sano, Yoshiaki Kikkawa, Satomi Chiken, Takuro Someya, Keisuke Saito, M Ibrahim Hossain, Masaaki Nameta, Kuniya Abe, Kenji Sakimura, Katsuhiko Ono, Atsushi Nambu, Atsushi Yoshiki
    • Organizer
      2017 ISN-ESN meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] GABAergic neuron progenitors differentiate to mature GABAergic neuron strictly but small number of them differentiate to glial cells during forebrain development.2017

    • Author(s)
      Shigeyuki Esumi, Yuchio Yanagawa, Kenji Sakimura, Tetsushi Kagawa, Tatsunori Seki, Hirohide Takebayashi, Nobuaki Tamamaki
    • Organizer
      he 40th Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2017 Annual Research Report
  • [Presentation] Dystonia musculorumマウスの生後脳におけるオリゴデンドロサイト前駆細胞の増殖低下2017

    • Author(s)
      MD Ibrahim Hossain、堀江正男、竹林浩秀
    • Organizer
      第3回日本ミエリン研究会
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Presentation] Optic nerve oligodendrocyte precursor cells originate in the preoptic area in the mouse fetus.2017

    • Author(s)
      Katsuhiko Ono、Kengo Yoshii、Hitoshi Gotoh、Tadashi Nomura、Hiroyuki Yominaga、Hirohide Takebayashi、Kazuhiro Ikenaka
    • Organizer
      The 40th Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2016 Annual Research Report
  • [Presentation] A novel Olig2-binding factor is indispensable for oligodendrocyte development in central nervous system2017

    • Author(s)
      Hirohide Takebayashi、Norihisa Bizen
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Preoptic area generates oligodendrocyte precursor cells in the mouse optic nerve.2016

    • Author(s)
      Ono K, Yoshii K, Gotoh H, Nomura T, Tominaga H, Takebayashi H, Ikenaka K
    • Organizer
      Cold Spring Harbor Asia Conference
    • Place of Presentation
      Suzhou, China
    • Year and Date
      2016-12-05
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Mouse model of dystonia with sensory neuropathy2015

    • Author(s)
      Hirohide Takebayashi
    • Organizer
      解剖生理合同大会
    • Place of Presentation
      神戸国際会議場
    • Year and Date
      2015-03-21 – 2015-03-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Oligodendrogenesis in the adult brain and abnormal proliferation of oligodendrocyte progenitor cells in neuropathological condition.2015

    • Author(s)
      Hirohide Takebayashi
    • Organizer
      新学術グリアアセンブリ 国際シンポジウム
    • Place of Presentation
      東京大学 伊藤謝恩ホール
    • Year and Date
      2015-01-23
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ジストニア症状を示す遺伝性神経難病モデルマウスの作製と解析2014

    • Author(s)
      竹林浩秀
    • Organizer
      第703回 新潟医学会
    • Place of Presentation
      有壬記念館(新潟)
    • Year and Date
      2014-11-15
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] グリア細胞発生・分化機構の解析と生体内細胞系譜追跡実験系の確立・応用2014

    • Author(s)
      竹林浩秀
    • Organizer
      第57回 日本神経化学会大会
    • Place of Presentation
      奈良県文化会館
    • Year and Date
      2014-09-29 – 2014-10-01
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ジストニア症状と感覚性ニューロパチーを示す新規遺伝子改変マウスの作製と解析2014

    • Author(s)
      竹林浩秀、堀江正男、渡辺啓介、荒木喜美、佐野裕美、知見聡美、南部篤、小野勝彦、池中一裕、柿田明美、山村研一
    • Organizer
      第57回 日本神経化学会大会
    • Place of Presentation
      奈良県文化会館
    • Year and Date
      2014-09-29 – 2014-10-01
    • Related Report
      2014 Annual Research Report
  • [Presentation] グリア細胞の発生について2013

    • Author(s)
      竹林浩秀
    • Organizer
      第37回峠の会(形態学セミナー)
    • Place of Presentation
      福島猪苗代町
    • Year and Date
      2013-08-02 – 2013-08-03
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Book] 脳神経化学 脳はいま化学の言葉でどこまで語れるか (第一章担当)2018

    • Author(s)
      竹林浩秀
    • Total Pages
      380
    • Publisher
      化学同人
    • Related Report
      2017 Annual Research Report
  • [Book] 脳神経化学 ー脳はいま化学の言葉でどこまで語れるか(第1章)2018

    • Author(s)
      森 泰生、尾藤 晴彦
    • Total Pages
      368
    • Publisher
      化学同人
    • ISBN
      9784759817263
    • Related Report
      2016 Annual Research Report
  • [Remarks] 新潟大学大学院医歯学総合研究科 神経生物・解剖学分野

    • URL

      https://www.med.niigata-u.ac.jp/an2/index.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 新潟大学大学院医歯学総合研究科 神経生物・解剖学分野

    • URL

      http://www.med.niigata-u.ac.jp/an2/index.html

    • Related Report
      2016 Annual Research Report

URL: 

Published: 2013-07-10   Modified: 2020-03-30  

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