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Development of new therapeutics for a highly pathogenic influenza virus infection by inhibition of virus entry and multiplication

Research Project

Project/Area Number 21249061
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Infectious disease medicine
Research InstitutionThe University of Tokushima

Principal Investigator

KIDO Hiroshi  徳島大学, 疾患酵素学研究センター, 教授 (50144978)

Co-Investigator(Renkei-kenkyūsha) CHIDA Junji  徳島大学, 疾患酵素学研究センター, 助教 (20437651)
YOUSSOUF Cisse  徳島大学, 疾患酵素学研究センター, 研究員 (80437649)
MIZUNO Dai  徳島大学, 疾患酵素学研究センター, 助教 (70380061)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥46,150,000 (Direct Cost: ¥35,500,000、Indirect Cost: ¥10,650,000)
Fiscal Year 2011: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2010: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2009: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
Keywords高病原性鳥インフルエンザ / プロセシングプロテアーゼ / 多臓器不全 / サイトカインストーム / トリプシン / MMP-9 / ミトコンドリア膜電位 / ATP産生 / MMP-97 / 高病原も生鳥インフルエンザ
Research Abstract

We found that type II membrane bound serine proteases MSPL/ TMPRSS13 are essential cellular factors for entry into cells of the highly pathogenic avian influenza(HPAI) viruses. To confirm the evidence, we have made TPMRSS13 KO mice and challenged the viruses to the animals. Viral multiplication of the HPAI viruses with the hemagglutinin(HA) cleavage site sequence RKKR partially and the sequence KKKR was completely suppressed in the TPMRSS13 KO mice. The results indicate that MSPL/ TMPRSS13 are essential for the entry of the HPAI virus. Furthermore, we found that viral infection stimulates the influenza. cytokine. protease cycle and the cycle plays an important role in the pathogenicity of multiple organ failure induced by infection.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (62 results)

All 2012 2011 2010 2009

All Journal Article (48 results) (of which Peer Reviewed: 39 results) Presentation (14 results)

  • [Journal Article] Induction and maintenance of anti-influenza antigen-specific nasal secretory IgA levels and serum IgG levels after influenza infection in adult2012

    • Author(s)
      Fujimoto C, Takeda N, Kido H., et al
    • Journal Title

      Influenza Other Respi Viruses

      Volume: Nov;6(6) Issue: 6 Pages: 396-403

    • DOI

      10.1111/j.1750-2659.2011.00330.x

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ脳症の発症機序-CPT2遺伝子多型が解き明かす発症リスク2012

    • Author(s)
      木戸博、千田淳司
    • Journal Title

      医学のあゆみ

      Volume: 241(1) Pages: 23-28

    • Related Report
      2011 Final Research Report
  • [Journal Article] Oseltamiyir reduces hippocampal abnormal EEG activities after influenza A virus infection in isoflurane-anesthetized rats2012

    • Author(s)
      Youssouf Cisse
    • Journal Title

      J Exp Pharmacol

      Volume: (In press)

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An efficient extraction method for quantitation of adenosine triphosphate in mammalian tissues and cells2012

    • Author(s)
      J Chida
    • Journal Title

      Anal Chim Acta

      Volume: (In press) Pages: 8-12

    • DOI

      10.1016/j.aca.2012.03.022

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Induction and maintenance of anti-influenza antigen-specific nasal secretory IgA levels and serum IgG levels after influenza infection in adults2012

    • Author(s)
      C Fujimoto
    • Journal Title

      Influenza Other Respi Viruses

      Volume: (In press)

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children2012

    • Author(s)
      M Kubota
    • Journal Title

      Brain Dev.

      Volume: 34(1) Pages: 20-27

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bezafibrate upregulates carnitine palmitoyltransferase II expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza-associated encephalopathy2011

    • Author(s)
      Yao M, Yao D, Kido H., et al
    • Journal Title

      Mol Genet Metab

      Volume: 104(3) Pages: 265-272

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure2011

    • Author(s)
      Kido H, Okumura Y, Takahashi E., et al
    • Journal Title

      Biochim Biophys Acta

      Volume: 1824(1) Issue: 1 Pages: 186-194

    • DOI

      10.1016/j.bbapap.2011.07.001

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of ectopic trypsins in the myocardium by influenza A virus infection triggers acute myocarditis2011

    • Author(s)
      Pan HY, Yamada H, Kido H, et al.
    • Journal Title

      Casrdiovasc Res

      Volume: 89(3) Pages: 595-603

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] インフルエンザ感染の重症化をもたらすウイルスと宿主の相互関連2011

    • Author(s)
      木戸博、奥村裕司, 他
    • Journal Title

      呼吸と循環

      Volume: 59(10) Pages: 973-981

    • Related Report
      2011 Final Research Report
  • [Journal Article] インフルエンザウイルス感染症の重症化メカニズムと治療戦略2011

    • Author(s)
      木戸博、千田淳司、山根一彦
    • Journal Title

      呼吸器病

      Volume: 15(1) Pages: 37-39

    • Related Report
      2011 Final Research Report
  • [Journal Article] Characterization of compound missense mutation and deletion of carnitine palmitoyltransferase II in a patient with adenovirus-associated encep halopathy2011

    • Author(s)
      D Yao
    • Journal Title

      J Med Invest

      Volume: 58(3-4) Pages: 210-218

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bezafibrate upregulates carnitine palmitoyltransferase II expression and promotes mitochondrial energy crisis dissipation in fibroblasts with influenza-associated encephalopathy2011

    • Author(s)
      M Yao
    • Journal Title

      Mol Genet Metab

      Volume: 104(3) Pages: 265-272

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle are principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches2011

    • Author(s)
      J Chida
    • Journal Title

      Influenza Other Respi Viruses

      Volume: 5(1) Pages: 284-286

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of the highly pathogenic avian influenza virus replication by membrane-bound protease MSPL and TMPRSS 13 andits inhibition by the protease inhibitors2011

    • Author(s)
      E Takahashi
    • Journal Title

      Influenza Other Respi Viruses

      Volume: 5(1) Pages: 276-279

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Attenuation of respiratory immune responses by antiviral neuramirsidase inhibitor treatment and boost of mucosal immunoglobulin A response by co-administration of immunomodulator clarithromycin in paediatric influenza2011

    • Author(s)
      H Kido
    • Journal Title

      Influenza Other Respi Viruses

      Volume: 5(1) Pages: 240-243

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virius replication and upregulation of cellular factors in cardiomyocytes2011

    • Author(s)
      Hai-Yan Pan
    • Journal Title

      J.Med.Invest.

      Volume: 58(1,2) Pages: 19-28

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of ectopic trypsins in the myocardium by influenza A virus infection triggers acute myocarditis2011

    • Author(s)
      Hai-Yan Pan
    • Journal Title

      Cardiovasc Res

      Volume: 89(3) Pages: 595-603

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure2011

    • Author(s)
      Hiroshi kido
    • Journal Title

      Biochemica Biophysica Acta-Proteins and Proteomics

      Volume: (In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virius replication and upregulation of cellular factors in cardiomyocytes.2011

    • Author(s)
      Hai-Yan Pan
    • Journal Title

      J.Med.Invest.

      Volume: 58(1,2) Pages: 19-28

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children.2011

    • Author(s)
      Masaya Kubota
    • Journal Title

      Brain Dev.

      Volume: (In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Upregulation of ectopic trypsins in the myocardium by influenza A virus infection triggers acute myocarditis.2011

    • Author(s)
      Hai-Yan Pan
    • Journal Title

      Cardiovasc.Res.

      Volume: 89(3) Pages: 595-603

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza2010

    • Author(s)
      Wang S, Le TQ, Kido H, et al.
    • Journal Title

      J Infect Dis

      Volume: 202(7) Pages: 991-1001

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Attenuation of inducible respiratory immune responses by oseltamivir treatment in mice infected with influenza A virus2010

    • Author(s)
      Takahashi E, Kataoka K, Kido H, et al.
    • Journal Title

      Microbes Infect

      Volume: 12(10) Pages: 778-783

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Novel type II transmembrane serine proteases, MSPL and TMPRSS13, proteolytically activate membrane fusion activity of hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication.2010

    • Author(s)
      Okumura Y, Takahashi E, Kido H. et al.
    • Journal Title

      J Virol

      Volume: 84(10) Pages: 5089-5096

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] 遺伝子多型が解き明かすインフルエンザ脳症と多臓器不全2010

    • Author(s)
      木戸博、千田淳司, 他
    • Journal Title

      実験医学

      Volume: 28(18) Pages: 2927-2933

    • Related Report
      2011 Final Research Report
  • [Journal Article] インフルエンザ感染の重症化、多臓器不全の発症メカニズム2010

    • Author(s)
      木戸博、千田淳司, 他
    • Journal Title

      日本臨床

      Volume: 68(8) Pages: 1565-1573

    • Related Report
      2011 Final Research Report
  • [Journal Article] インフルエンザ脳症の発症原因-ミトコンドリア脂肪酸代謝障害と血管内皮細胞の膜透過性の亢進-2010

    • Author(s)
      木戸博、千田淳司、Cisse Y, 他
    • Journal Title

      最新医学

      Volume: 65(1) Pages: 52-60

    • Related Report
      2011 Final Research Report
  • [Journal Article] 経鼻ワクチンの開発状況2010

    • Author(s)
      木戸博、水野大、武井恒知
    • Journal Title

      インフルエンザ

      Volume: 11(2) Pages: 184-190

    • Related Report
      2011 Final Research Report
  • [Journal Article] インフルエンザ感染の重症化機序2010

    • Author(s)
      木戸博、千田淳司
    • Journal Title

      神経感染症

      Volume: 15(1) Pages: 66-73

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] 粘膜免疫機能とインフルエンザ感染2010

    • Author(s)
      木戸博、水野大, 、木本貴士
    • Journal Title

      小児内科

      Volume: 42(9) Pages: 1541-1545

    • Related Report
      2011 Final Research Report
  • [Journal Article] Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza.2010

    • Author(s)
      Siye Wang
    • Journal Title

      J.Infect.Dis.

      Volume: 202(7) Pages: 991-1001

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Attenuation of inducible respiratory immune responses by oseltamivir treatment in mice infected with influenza A virus.2010

    • Author(s)
      Etsuhisa Takahashi
    • Journal Title

      Microbes Infect

      Volume: 12(10) Pages: 778-783

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel type II transmembrane serine protease, MSPL and TMPRSS13, proteolytically activate membrane fusion activation of hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication.2010

    • Author(s)
      Yuushi Okumura
    • Journal Title

      The Journal Virology

      Volume: 84 Pages: 5089-5096

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms of matrix metalloprotease-9 upregulation and tissue destruction in various organs in influenza A virus infection.2010

    • Author(s)
      Siye Wang
    • Journal Title

      J.Med.Invest.

      Volume: 57(1,2) Pages: 26-34

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rat model of influenza-associated encephalopathy (IAE) : stidies of electroencephalogram (EEG) in vivo.2010

    • Author(s)
      Youssouf Cisse
    • Journal Title

      Neuroscience

      Volume: 165 Pages: 1127-1137

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel type II transmembrane serine protease, MSPL and TMPRSS13, proteolytically activate membrane fusion activation of hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication.2010

    • Author(s)
      Yuushi Okumura
    • Journal Title

      The Journal Virology 84

      Pages: 5089-5096

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza.2010

    • Author(s)
      Siye Wang
    • Journal Title

      Journal of Infectious Diseases (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms of matrix metalloprotease-9 upregulation and tissue destruction in various organs in influenza A virus infection.2010

    • Author(s)
      Siye Wang
    • Journal Title

      J.Med.Invest. 57(1,2)

      Pages: 26-34

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rat model of influenza-associated encephalopathy(IAE) : stidies of electroencephalogram(EEG)in vivo.2010

    • Author(s)
      Youssouf Cisse
    • Journal Title

      Neuroscience 165

      Pages: 1127-1137

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro2009

    • Author(s)
      Kam YW, Okumura Y, Kido H, et al.
    • Journal Title

      PLoS One

      Volume: 4(11)

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Boost of mucosal secretory immunoglobilin A response by clarithromycin in paediatric influenza2009

    • Author(s)
      Sawabuchi T, Suzuki S, Kido H, et al.
    • Journal Title

      Respirology

      Volume: 14(8) Pages: 1173-1179

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses2009

    • Author(s)
      Kido H, Okumura Y, Takahashi E, et al.
    • Journal Title

      J Mol Genet Med

      Volume: 3(1) Pages: 176-175

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] 酵素学からみえてくるインフルエンザ感染とインフルエンザ脳症2009

    • Author(s)
      木戸博
    • Journal Title

      インフルエンザ

      Volume: 10(2) Pages: 101-103

    • Related Report
      2011 Final Research Report
  • [Journal Article] Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro.2009

    • Author(s)
      Yiu-Wing Kam
    • Journal Title

      PLoS One 4(11)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Boost of mucosal secretoty immunoglobulin A response by clarithromycin in paediatric influenza.2009

    • Author(s)
      Takako Sawabuchi
    • Journal Title

      Respirology 14(8)

      Pages: 1173-1179

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Influenza vaccine with Surfaeten, a modified pulmonary surfactant, induces systemic and mucosal immune responses without side effects in minipigs.2009

    • Author(s)
      Maki Nishino
    • Journal Title

      Vaccine 27

      Pages: 5620-5627

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Host envelope glycoprotein processing proteases are indispensable for entry into human cells by seasonal and highly pathogenic avian influenza viruses.2009

    • Author(s)
      Hiroshi Kido
    • Journal Title

      J.Mol.Genet.Med. 3(1)

      Pages: 165-175

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] 肺サーファクタントの新たな医学応用の可能性-粘膜アジュバントへの応用とワクチン開発2011

    • Author(s)
      木戸博
    • Organizer
      第47回日本肺サーファクタント・界面医学会
    • Place of Presentation
      徳島大学青藍会館(徳島県)
    • Year and Date
      2011-10-29
    • Related Report
      2011 Annual Research Report
  • [Presentation] Attenuation of respiratory immune responses by antiviral neuraminidase inhibitor treatment and boost of mucosal immunoglobulin A response by administration of immunomodulator Clarithromycin in pediatric influenza2011

    • Author(s)
      Kido H
    • Organizer
      Options for the Control of Influenza VII
    • Place of Presentation
      Hong Kong, China
    • Year and Date
      2011-09-07
    • Related Report
      2011 Final Research Report
  • [Presentation] Potent mucosal antigen delivery vehicle SF-10, mimicking pulmonary surfactant, for nasal influenza vaccination : safety and efficacy2011

    • Author(s)
      Kido H
    • Organizer
      International Conference & Exhibition on Vaccines & Vaccination.
    • Place of Presentation
      Philadelphia, USA
    • Related Report
      2011 Final Research Report
  • [Presentation] Potent Mucosal Antigen Delivery Vehicle SF-10, Mimicking Pulmonary Surfactant, for Nasal Influenza Vaccination : Safety and Efficacy2011

    • Author(s)
      H Kido
    • Organizer
      International Cinference & Exhibition on Vaccines & Vaccination
    • Place of Presentation
      Philadelphia
    • Related Report
      2011 Annual Research Report
  • [Presentation] "Influenza-Cytokine-Protease Cycle" in the pathogenesis of vascular hyperpermeability in severe influenza and its possible treatments2010

    • Author(s)
      木戸博
    • Organizer
      第83回日本生化学会大会
    • Place of Presentation
      神戸市
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] Attenuation of respiratory immune responses by antiviral neuraminidase inhibitor treatment and boost of mucosal immunoglobulin A response by caadministration of immunomodulator Clarithromycin in pediatric influenza2010

    • Author(s)
      木戸博
    • Organizer
      Options for the Control of Influenza VII
    • Place of Presentation
      Hong Kong SAR, China
    • Year and Date
      2010-09-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] インフルエンザはなぜ怖い-重症化機序における宿主因子のプロテアーゼとエネルギー代謝-2010

    • Author(s)
      木戸博
    • Organizer
      第15回日本病態プロテアーゼ学会
    • Place of Presentation
      大阪府豊中市
    • Year and Date
      2010-08-21
    • Related Report
      2010 Annual Research Report
  • [Presentation] 抗インフルエンザ薬のタミフル、リレンザの服用で気道粘膜の抗ウイルスIgA抗体の産生は抑制されるが、マクロライドの併用はこれを回復させる2010

    • Author(s)
      木戸博
    • Organizer
      第17回マクロライド新作用研究会
    • Place of Presentation
      東京
    • Year and Date
      2010-07-16
    • Related Report
      2010 Annual Research Report
  • [Presentation] インフルエンザ感染に伴う体内代謝の変動と感染重症化の機序、診断マーカーと治療2010

    • Author(s)
      木戸博
    • Organizer
      第58回日本化学療法学会
    • Place of Presentation
      長崎市
    • Year and Date
      2010-06-03
    • Related Report
      2010 Annual Research Report
  • [Presentation] インフルエンザの重症化機序と、その予防と治療2010

    • Author(s)
      木戸博
    • Organizer
      日本薬学会130年会
    • Place of Presentation
      岡山市
    • Year and Date
      2010-03-30
    • Related Report
      2010 Annual Research Report
  • [Presentation] Pathogenesis of severe influenza and its prevention and treatments2010

    • Author(s)
      Hiroshi Kido
    • Organizer
      第83回日本薬理学会
    • Place of Presentation
      大阪
    • Year and Date
      2010-03-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] Role of the host cellular processing proteases in influenza virus infection.2009

    • Author(s)
      Yuushi Okumura
    • Organizer
      International Proteolysis Society
    • Place of Presentation
      Gold Coast, Australia
    • Year and Date
      2009-10-27
    • Related Report
      2009 Annual Research Report
  • [Presentation] Immune responses to nasal vaccination of HA Vaccine with new mucosal adjuvants, pulmonary surfactant medicine Surfacten and its synthetic compound in mice and mini-pigs2009

    • Author(s)
      Kido H
    • Organizer
      Influenza vaccine for the world
    • Place of Presentation
      Canne, France
    • Year and Date
      2009-05-29
    • Related Report
      2011 Final Research Report
  • [Presentation] Immune responses to nasal vaccination of HA vaccine with new mucosal adjuvants, pulmonary surfactant medicine Surfacten and its synthetic compound, in mice and mini-pigs2009

    • Author(s)
      Hiroshi Kido
    • Organizer
      Influenza vaccine for the World
    • Place of Presentation
      Canne, France
    • Year and Date
      2009-05-29
    • Related Report
      2009 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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