{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:09:17Z","timestamp":1791328157284,"version":"4.3.1"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"39","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,9,28]]},"abstract":"<jats:p>The small molecule thioflavin T (ThT) is a defining probe for the identification and mechanistic study of amyloid fiber formation. As such, ThT is fundamental to investigations of serious diseases such as Alzheimer\u2019s disease, Parkinson disease, and type II diabetes. For each disease, a different protein undergoes conformational conversion to a \u03b2-sheet rich fiber. The fluorescence of ThT exhibits an increase in quantum yield upon binding these fibers. Despite its widespread use, the structural basis for binding specificity and for the changes to the photophysical properties of ThT remain poorly understood. Here, we report the co-crystal structures of ThT with two alternative states of \u03b2-2 microglobulin (\u03b22m); one monomeric, the other an amyloid-like oligomer. In the latter, the dye intercalates between \u03b2-sheets orthogonal to the \u03b2-strands. Importantly, the fluorophore is bound in such a manner that a photophysically relevant torsion is limited to a range of angles generally associated with low, not high, quantum yield. Quantum mechanical assessment of the fluorophore shows the electronic distribution to be strongly stabilized by aromatic interactions with the protein. Monomeric \u03b22m gives little increase in ThT fluorescence despite showing three fluorophores, at two binding sites, in configurations generally associated with high quantum yield. Our efforts fundamentally extend existing understanding about the origins of amyloid-induced photophysical changes. Specifically, the \u03b2-sheet interface that characterizes amyloid acts both sterically and electronically to stabilize the fluorophore\u2019s ground state electronic distribution. By preventing the fluorophore from adopting its preferred excited state configuration, nonradiative relaxation pathways are minimized and quantum yield is increased.<\/jats:p>","DOI":"10.1073\/pnas.1002867107","type":"journal-article","created":{"date-parts":[[2010,9,8]],"date-time":"2010-09-08T22:24:07Z","timestamp":1283984647000},"page":"16863-16868","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":316,"title":["Protein-induced photophysical changes to the amyloid indicator dye thioflavin T"],"prefix":"10.1073","volume":"107","author":[{"given":"Leslie S.","family":"Wolfe","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew F.","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav","family":"Nath","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorottya V.","family":"Blaho","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Miranker","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,9,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.biochem.75.101304.123901","article-title":"Protein misfolding, functional amyloid, and human disease","volume":"75","author":"Chiti F","year":"2006","unstructured":"F Chiti, CM Dobson, Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75, 333\u2013366 (2006).","journal-title":"Annu Rev Biochem"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S0033583506004173","article-title":"Molecular structure of amyloid fibrils: Insights from solid-state NMR","volume":"39","author":"Tycko R","year":"2006","unstructured":"R Tycko, Molecular structure of amyloid fibrils: Insights from solid-state NMR. Q Rev Biophys 39, 1\u201355 (2006).","journal-title":"Q Rev Biophys"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.str.2006.03.011","article-title":"Deposition diseases and 3D domain swapping","volume":"14","author":"Bennett MJ","year":"2006","unstructured":"MJ Bennett, MR Sawaya, D Eisenberg, Deposition diseases and 3D domain swapping. Structure 14, 811\u2013824 (2006).","journal-title":"Structure"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.jmb.2009.09.039","article-title":"The common architecture of cross-beta amyloid","volume":"395","author":"Jahn TR","year":"2010","unstructured":"TR Jahn, et al., The common architecture of cross-beta amyloid. J Mol Biol 395, 717\u2013727 (2010).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"16248","DOI":"10.1073\/pnas.0607815103","article-title":"General structural motifs of amyloid protofilaments","volume":"103","author":"Ferguson N","year":"2006","unstructured":"N Ferguson, et al., General structural motifs of amyloid protofilaments. Proc Natl Acad Sci USA 103, 16248\u201316253 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_6_2","article-title":"Binding modeof Thioflavin T and other molecular probes in the context of amyloid fibrils-current status","author":"Groenning M","year":"2009","unstructured":"M Groenning, Binding modeof Thioflavin T and other molecular probes in the context of amyloid fibrils-current status. J Chem Biol, 2009).","journal-title":"J Chem Biol"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.jmb.2008.11.006","article-title":"Molecular mechanism of thioflavin-T binding to the surface of beta-rich peptide self-assemblies","volume":"385","author":"Biancalana M","year":"2009","unstructured":"M Biancalana, K Makabe, A Koide, S Koide, Molecular mechanism of thioflavin-T binding to the surface of beta-rich peptide self-assemblies. J Mol Biol 385, 1052\u20131063 (2009).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_8_2","first-page":"487","article-title":"Fluorescent stains, with special reference to amyloid and connective tissues","volume":"68","author":"Vassar PS","year":"1959","unstructured":"PS Vassar, CF Culling, Fluorescent stains, with special reference to amyloid and connective tissues. Arch Pathol 68, 487\u2013498 (1959).","journal-title":"Arch Pathol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/pro.5560020312","article-title":"Thioflavine T interaction with synthetic Alzheimer\u2019s disease beta-amyloid peptides: Detection of amyloid aggregation in solution","volume":"2","author":"LeVine H","year":"1993","unstructured":"H LeVine, Thioflavine T interaction with synthetic Alzheimer\u2019s disease beta-amyloid peptides: Detection of amyloid aggregation in solution. Protein Sci 2, 404\u2013410 (1993).","journal-title":"Protein Sci"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/j.bbapap.2010.04.001","article-title":"Molecular mechanism of Thioflavin-T binding to amyloid fibrils.","volume":"1804","author":"Biancalana M","unstructured":"M Biancalana, S Koide, Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta 1804, 1405\u20131412","journal-title":"Biochim Biophys Acta"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1038\/nsmb.1483","article-title":"A regulatable switch mediates self-association in an immunoglobulin fold","volume":"15","author":"Calabrese MF","year":"2008","unstructured":"MF Calabrese, CM Eakin, JM Wang, AD Miranker, A regulatable switch mediates self-association in an immunoglobulin fold. Nat Struct Mol Biol 15, 965\u2013971 (2008).","journal-title":"Nat Struct Mol Biol"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1146\/annurev.cellbio.24.110707.175347","article-title":"Regulation of MHC class I assembly and peptide binding","volume":"24","author":"Peaper DR","year":"2008","unstructured":"DR Peaper, P Cresswell, Regulation of MHC class I assembly and peptide binding. Annu Rev Cell Dev Biol 24, 343\u2013368 (2008).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"7808","DOI":"10.1021\/bi049792q","article-title":"Oligomeric assembly of native-like precursors precedes amyloid formation by beta-2 microglobulin","volume":"43","author":"Eakin CM","year":"2004","unstructured":"CM Eakin, FJ Attenello, CJ Morgan, AD Miranker, Oligomeric assembly of native-like precursors precedes amyloid formation by beta-2 microglobulin. Biochemistry 43, 7808\u20137815 (2004).","journal-title":"Biochemistry"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1006\/jmbi.2001.4661","article-title":"Kidney dialysis-associated amyloidosis: A molecular role for copper in fiber formation","volume":"309","author":"Morgan CJ","year":"2001","unstructured":"CJ Morgan, M Gelfand, C Atreya, AD Miranker, Kidney dialysis-associated amyloidosis: A molecular role for copper in fiber formation. J Mol Biol 309, 339\u2013345 (2001).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1146\/annurev.biophys.050708.133622","article-title":"The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes","volume":"38","author":"Hebda JA","year":"2009","unstructured":"JA Hebda, AD Miranker, The interplay of catalysis and toxicity by amyloid intermediates on lipid bilayers: insights from type II diabetes. Ann Rev Biophys 38, 125\u2013152 (2009).","journal-title":"Ann Rev Biophys"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nsmb1068","article-title":"A native to amyloidogenic transition regulated by a backbone trigger","volume":"13","author":"Eakin CM","year":"2006","unstructured":"CM Eakin, AJ Berman, AD Miranker, A native to amyloidogenic transition regulated by a backbone trigger. Nat Struct Mol Biol 13, 202\u2013208 (2006).","journal-title":"Nat Struct Mol Biol"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/371626a0","article-title":"Three-dimensional structure of a peptide extending from one end of a class I MHC binding site","volume":"371","author":"Collins EJ","year":"1994","unstructured":"EJ Collins, DN Garboczi, DC Wiley, Three-dimensional structure of a peptide extending from one end of a class I MHC binding site. Nature 371, 626\u2013629 (1994).","journal-title":"Nature"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jsb.2005.06.006","article-title":"Mechanism of thioflavin T binding to amyloid fibrils","volume":"151","author":"Khurana R","year":"2005","unstructured":"R Khurana, et al., Mechanism of thioflavin T binding to amyloid fibrils. J Struct Biol 151, 229\u2013238 (2005).","journal-title":"J Struct Biol"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.jsb.2007.06.004","article-title":"Binding modeof Thioflavin T in insulin amyloid fibrils","volume":"159","author":"Groenning M","year":"2007","unstructured":"M Groenning, et al., Binding modeof Thioflavin T in insulin amyloid fibrils. J Struct Biol 159, 483\u2013497 (2007).","journal-title":"J Struct Biol"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1021\/jp070590o","article-title":"Computational study of thioflavin T torsional relaxation in the excited state","volume":"111","author":"Stsiapura VI","year":"2007","unstructured":"VI Stsiapura, AA Maskevich, VA Kuzmitsky, KK Turoverov, IM Kuznetsova, Computational study of thioflavin T torsional relaxation in the excited state. J Phys Chem A 111, 4829\u20134835 (2007).","journal-title":"J Phys Chem A"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"15893","DOI":"10.1021\/jp805822c","article-title":"Thioflavin T as a molecular rotor: Fluorescent properties of thioflavin T in solvents with different viscosity","volume":"112","author":"Stsiapura VI","year":"2008","unstructured":"VI Stsiapura, et al., Thioflavin T as a molecular rotor: Fluorescent properties of thioflavin T in solvents with different viscosity. J Phys Chem B 112, 15893\u201315902 (2008).","journal-title":"J Phys Chem B"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"7856","DOI":"10.1021\/ja7109822","article-title":"Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site","volume":"130","author":"Harel M","year":"2008","unstructured":"M Harel, LK Sonoda, I Silman, JL Sussman, TL Rosenberry, Crystal structure of thioflavin T bound to the peripheral site of Torpedo californica acetylcholinesterase reveals how thioflavin T acts as a sensitive fluorescent reporter of ligand binding to the acylation site. J Am Chem Soc 130, 7856\u20137861 (2008).","journal-title":"J Am Chem Soc"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1073\/pnas.0912654107","article-title":"Minimalist design of water-soluble cross-{beta} architecture","volume":"107","author":"Biancalana M","year":"2010","unstructured":"M Biancalana, K Makabe, S Koide, Minimalist design of water-soluble cross-{beta} architecture. Proc Natl Acad Sci USA 107, 3469\u20133474 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jmb.2008.09.062","article-title":"The binding of thioflavin T and its neutral analog BTA-1 to protofibrils of the Alzheimer\u2019s disease Abeta(16-22) peptide probed by molecular dynamics simulations","volume":"384","author":"Wu C","year":"2008","unstructured":"C Wu, et al., The binding of thioflavin T and its neutral analog BTA-1 to protofibrils of the Alzheimer\u2019s disease Abeta(16-22) peptide probed by molecular dynamics simulations. J Mol Biol 384, 718\u2013729 (2008).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1021\/jp070590o","article-title":"Computational study of thioflavin T torsional relaxation in the excited state","volume":"111","author":"Stsiapura VI","year":"2007","unstructured":"VI Stsiapura, AA Maskevich, VA Kuzmitsky, KK Turoverov, IM Kuznetsova, Computational study of thioflavin T torsional relaxation in the excited state. J Phys Chem A 111, 4829\u20134835 (2007).","journal-title":"J Phys Chem A"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nmeth.1432","article-title":"Exploring the sequence determinants of amyloid structure using position-specific scoring matrices","volume":"7","author":"Maurer-Stroh S","year":"2010","unstructured":"S Maurer-Stroh, et al., Exploring the sequence determinants of amyloid structure using position-specific scoring matrices. Nat Methods 7, 237\u2013242 (2010).","journal-title":"Nat Methods"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"3899","DOI":"10.1021\/cr940745l","article-title":"Structural changes accompanying intramolecular electron transfer: Focus on twisted intramolecular charge-transfer states and structures","volume":"103","author":"Grabowski ZR","year":"2003","unstructured":"ZR Grabowski, K Rotkiewicz, W Rettig, Structural changes accompanying intramolecular electron transfer: Focus on twisted intramolecular charge-transfer states and structures. Chem Rev 103, 3899\u20134031 (2003).","journal-title":"Chem Rev"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"6601","DOI":"10.1016\/j.febslet.2005.10.048","article-title":"Chiral bias of amyloid fibrils revealed by the twisted conformation of Thioflavin T: An induced circular dichroism\/DFT study","volume":"579","author":"Dzwolak W","year":"2005","unstructured":"W Dzwolak, M Pecul, Chiral bias of amyloid fibrils revealed by the twisted conformation of Thioflavin T: An induced circular dichroism\/DFT study. FEBS Lett 579, 6601\u20136603 (2005).","journal-title":"FEBS Lett"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jmb.2008.03.057","article-title":"Chiral bifurcation in aggregating insulin: An induced circular dichroism study","volume":"379","author":"Loksztejn A","year":"2008","unstructured":"A Loksztejn, W Dzwolak, Chiral bifurcation in aggregating insulin: An induced circular dichroism study. J Mol Biol 379, 9\u201316 (2008).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.jsb.2008.02.002","article-title":"On the binding of Thioflavin-T to HET-s amyloid fibrils assembled at pH 2","volume":"162","author":"Sabate R","year":"2008","unstructured":"R Sabate, I Lascu, SJ Saupe, On the binding of Thioflavin-T to HET-s amyloid fibrils assembled at pH 2. J Struct Biol 162, 387\u2013396 (2008).","journal-title":"J Struct Biol"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.jsb.2006.12.010","article-title":"Study on the binding of Thioflavin T to beta-sheet-rich and non-beta-sheet cavities","volume":"158","author":"Groenning M","year":"2007","unstructured":"M Groenning, et al., Study on the binding of Thioflavin T to beta-sheet-rich and non-beta-sheet cavities. J Struct Biol 158, 358\u2013369 (2007).","journal-title":"J Struct Biol"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jsb.2004.08.002","article-title":"The binding of thioflavin-T to amyloid fibrils: Localisation and implications","volume":"149","author":"Krebs MR","year":"2005","unstructured":"MR Krebs, EH Bromley, AM Donald, The binding of thioflavin-T to amyloid fibrils: Localisation and implications. J Struct Biol 149, 30\u201337 (2005).","journal-title":"J Struct Biol"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1107\/S0907444906045975","article-title":"Solving structures of protein complexes by molecular replacement with Phaser","volume":"63","author":"McCoy AJ","year":"2007","unstructured":"AJ McCoy, Solving structures of protein complexes by molecular replacement with Phaser. Acta Crystallogr D 63, 32\u201341 (2007).","journal-title":"Acta Crystallogr D"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1107\/S0907444996012255","article-title":"Refinement of macromolecular structures by the maximum-likelihood method","volume":"53","author":"Murshudov GN","year":"1997","unstructured":"GN Murshudov, AA Vagin, EJ Dodson, Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D 53, 240\u2013255 (1997).","journal-title":"Acta Crystallogr D"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1107\/S0907444904019158","article-title":"Coot: Model-building tools for molecular graphics","volume":"60","author":"Emsley P","year":"2004","unstructured":"P Emsley, K Cowtan, Coot: Model-building tools for molecular graphics. Acta Crystallogr D 60, 2126\u20132132 (2004).","journal-title":"Acta Crystallogr D"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1107\/S0907444994003112","article-title":"The CCP4 suite: Programs for protein crystallography","volume":"50","year":"1994","unstructured":", The CCP4 suite: Programs for protein crystallography. Acta Crystallogr D 50, 760\u2013763 (1994).","journal-title":"Acta Crystallogr D"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1107\/S0907444902016657","article-title":"PHENIX: Building new software for automated crystallographic structure determination","volume":"58","author":"Adams PD","year":"2002","unstructured":"PD Adams, et al., PHENIX: Building new software for automated crystallographic structure determination. Acta Crystallogr D 58, 1948\u20131954 (2002).","journal-title":"Acta Crystallogr D"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/jcc.540141112","article-title":"General atomic and molecular electronic-structure system","volume":"14","author":"Schmidt MW","year":"1993","unstructured":"MW Schmidt, et al., General atomic and molecular electronic-structure system. J Comput Chem 14, 1347\u20131363 (1993).","journal-title":"J Comput Chem"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1063\/1.1747632","article-title":"On the non-orthogonality problem connected with the use of atomic wave functions in the theory of molecules and crystals","volume":"18","author":"Lowdin PO","year":"1950","unstructured":"PO Lowdin, On the non-orthogonality problem connected with the use of atomic wave functions in the theory of molecules and crystals. J Chem Phys 18, 365\u2013375 (1950).","journal-title":"J Chem Phys"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1002867107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:08:40Z","timestamp":1654571320000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1002867107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,8]]},"references-count":39,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2010,9,28]]}},"alternative-id":["10.1073\/pnas.1002867107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1002867107","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,8]]},"assertion":[{"value":"2010-09-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}