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Title:          Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity
Subject:        Nature Communications 7,  (2016). doi:10.1038/ncomms10787
Author:         Ricardo Sant'Anna
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        Title: Results
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        Children: 
         Item: 
          Title: Tolcapone inhibits TTR aggregation
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6
         Item: 
          Title: Tolcapone kinetically stabilizes TTR
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f
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          Title: Tolcapone binds with high affinity to TTR
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        Title: Figure™1Tolcapone and tafamidis effects over WT, V122I-TTR and A25T-TTR aggregation and stability.(a) Chemical structures of the commercially available drugs tolcapone (Tasmar, CAS 134308-13-17) and tafamidis. Anti-amyloidogenic effect of tolcapone and ta
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          Title: Tolcapone stabilizes the TTR dimer-dimer interface
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       Item: 
        Title: Figure™2Interaction of TTR with tolcapone assessed by ITC.Top panels: Thermogram (thermal power versus time) after baseline correction; bottom panel: binding isotherm (normalized heat versus molar ratio of reactants). (a) WT and (b) V122I-TTR. The solid l
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         Item: 
          Title: Tolcapone selectively binds to TTR in human plasma
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        Title: Figure™3Crystal structures of WT-TTRsolligand and V122I-TTRsolligand complexes.(a) Global view of WT-TTR bound to tolcapone (ribbon representation). The electron density map of the two T4-binding sites of tolcapone are depicted. Broken line indicates the 
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         Item: 
          Title: Tolcapone stabilizes WT-TTR and V30M-TTR in human plasma
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71
         Item: 
          Title: Tolcapone prevents TTR-induced cytotoxicity in cell culture
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       Item: 
        Title: Figure™4Tolcapone selectively binds and stabilizes WT and V30M-TTR in human plasma.(a) Human plasma of control or V30M-TTR carriers were incubated with lbrack125IrbrackT4 in the presence or absence of tolcapone or tafamidis (final concentration=1thinspmM)
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         Item: 
          Title: Tolcapone binds to and stabilizes TTR in transgenic mice
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       Item: 
        Title: Figure™5Tolcapone prevents TTR-induced cytotoxicity of TTR variants and inhibits L55P-TTR aggregation under physiological conditions.(a) Tolcapone protects human cardiomyocytes from the toxic effect of V122I-TTR and WT-TTR. AC16 cells were incubated for 2
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        Children: 
         Item: 
          Title: Orally administered tolcapone stabilizes TTR in humans
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee
       Item: 
        Title: Discussion
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       Item: 
        Title: Figure™6Tolcapone is orally available and stabilizes TTR in humans and in transgenic mice expressing the amyloidogenic human V30M-TTR variant.(a) T4 competition was assessed by gel electrophoresis of plasma samples from the transgenic mice expressing huma
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       Item: 
        Title: Table 1 
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       Item: 
        Title: Methods
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89
        Children: 
         Item: 
          Title: Recombinant TTR expression and purification
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9
         Item: 
          Title: TTR in™vitro aggregation inhibition assays
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e
         Item: 
          Title: Sedimentation assay
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         Item: 
          Title: TTR stabilization by tolcapone in the presence of urea
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b
         Item: 
          Title: Isothermal titration calorimetry
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         Item: 
          Title: Crystallography and structure determination
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         Item: 
          Title: Binding competition assays using radioactive T4
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         Item: 
          Title: Stability studies by native PAGE and isoelectric focusing (IEF)
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         Item: 
          Title: Ex vivo stability studies by immunoturbidity
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         Item: 
          Title: Cell toxicity assays
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         Item: 
          Title: Dot-blot filter assay for quantification of TTR aggregation
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3ecd23d9
         Item: 
          Title: Tolcapone oral administration in mice
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@569cfc36
         Item: 
          Title: Tolcapone oral administration in humans
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@43bd930a
         Item: 
          Title: TTR stabilization after oral administrations in humans
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@33723e30
         Item: 
          Title: Tolcapone quantification in human plasma
          Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@64f6106c
       Item: 
        Title: ChitiF.DobsonC. M.Protein misfolding, functional amyloid, and human diseaseAnnu. Rev. Biochem.753333662006CornwellG. G.3rdSlettenK.JohanssonB.WestermarkP.Evidence that the amyloid fibril protein in senile systemic amyloidosis is derived from normal prealb
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@553a3d88
       Item: 
        Title: This work was funded by the Spanish Ministry of Economy and Competitiveness (BFU2013-44763 to S.V., BFU2012-37116 to D.R., RTC-2014-1931-1 to R.I. and BFU2013-47064-P to A.V.-C.), by SUDOE INTERREG IV B (SOE4solP1solE831 to S.V. and A.V.-C.), by the Spani
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a30d1e6
       Item: 
        Title: ACKNOWLEDGEMENTS
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       Item: 
        Title: Author contributions
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       Item: 
        Title: Additional information
        Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8e24743
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