Age-related retinopathy in NRF2-deficient mice
Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine...
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| Veröffentlicht in: | PloS one 2011-04, Vol.6 (4), p.e19456-e19456 |
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| creator | Zhao, Zhenyang Chen, Yan Wang, Jian Sternberg, Paul Freeman, Michael L Grossniklaus, Hans E Cai, Jiyang |
| description | Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.
Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD. |
| doi_str_mv | 10.1371/journal.pone.0019456 |
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Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0019456</identifier><identifier>PMID: 21559389</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Age ; Age related diseases ; Aging ; Animals ; Antioxidants ; Antioxidants (Nutrients) ; Antioxidants - metabolism ; Apoptosis ; Autophagy ; Biology ; Cell death ; Deregulation ; Detoxification ; Disruption ; Electron microscopy ; Electroretinograms ; Electroretinography ; Electroretinography - methods ; Enzymes ; Epithelium ; Eye (anatomy) ; Immunofluorescence ; Immunohistochemistry - methods ; Inflammation ; Laboratory animals ; Lipofuscin - metabolism ; Lysosomes - metabolism ; Macular degeneration ; Medical imaging ; Medical research ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular biology ; Neovascularization ; NF-E2-Related Factor 2 - genetics ; NF-E2-Related Factor 2 - physiology ; Oxidative stress ; Pathogenesis ; Pathology ; Phagocytosis ; Phenotype ; Photography ; Protein expression ; Proteins ; Retina ; Retinal Diseases - metabolism ; Retinal pigment epithelium ; Retinopathy ; Rodents ; Smooth muscle ; Time Factors ; Transcription factors ; Vacuoles ; Vascularization</subject><ispartof>PloS one, 2011-04, Vol.6 (4), p.e19456-e19456</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Zhao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Zhao et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-d1752bc9c243cf6b575c4753f597cb7727e57eefc1882f04070fe7e1b44e21d53</citedby><cites>FETCH-LOGICAL-c691t-d1752bc9c243cf6b575c4753f597cb7727e57eefc1882f04070fe7e1b44e21d53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084871/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084871/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21559389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Zhenyang</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>Wang, Jian</creatorcontrib><creatorcontrib>Sternberg, Paul</creatorcontrib><creatorcontrib>Freeman, Michael L</creatorcontrib><creatorcontrib>Grossniklaus, Hans E</creatorcontrib><creatorcontrib>Cai, Jiyang</creatorcontrib><title>Age-related retinopathy in NRF2-deficient mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.
Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD.</description><subject>Accumulation</subject><subject>Age</subject><subject>Age related diseases</subject><subject>Aging</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Antioxidants (Nutrients)</subject><subject>Antioxidants - metabolism</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Biology</subject><subject>Cell death</subject><subject>Deregulation</subject><subject>Detoxification</subject><subject>Disruption</subject><subject>Electron microscopy</subject><subject>Electroretinograms</subject><subject>Electroretinography</subject><subject>Electroretinography - methods</subject><subject>Enzymes</subject><subject>Epithelium</subject><subject>Eye (anatomy)</subject><subject>Immunofluorescence</subject><subject>Immunohistochemistry - methods</subject><subject>Inflammation</subject><subject>Laboratory animals</subject><subject>Lipofuscin - metabolism</subject><subject>Lysosomes - metabolism</subject><subject>Macular degeneration</subject><subject>Medical imaging</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Molecular biology</subject><subject>Neovascularization</subject><subject>NF-E2-Related Factor 2 - genetics</subject><subject>NF-E2-Related Factor 2 - physiology</subject><subject>Oxidative stress</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Phagocytosis</subject><subject>Phenotype</subject><subject>Photography</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Retina</subject><subject>Retinal Diseases - metabolism</subject><subject>Retinal pigment epithelium</subject><subject>Retinopathy</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Time Factors</subject><subject>Transcription factors</subject><subject>Vacuoles</subject><subject>Vascularization</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QHBMWL1iTNR3MjDIurA4sL68dtSNOTmQydZjZpxf33pk53mcpeSC4Skue85yNvlr3EqMClwB-2fgidbou976BACEvK-KPsFMuS5Jyg8vHR-SR7FuMWIVZWnD_NTghmTJaVPM2K5RryAK3uoVkE6F3n97rf3C5ct_h6fUHyBqwzDrp-sXMGnmdPrG4jvJj2s-zHxafv51_yy6vPq_PlZW64xH3eYMFIbaQhtDSW10wwQwUrLZPC1EIQAUwAWIOrilhEkUAWBOCaUiC4YeVZ9vqgu299VFOrUWEieSUoq0ZidSAar7dqH9xOh1vltVN_L3xYKx16Z1pQCJXSipoLbgxtKK8tTrUxzGtuNKpw0vo4ZRvqHTQmdRt0OxOdv3Ruo9b-lypRRSsxCrybBIK_GSD2aueigbbVHfghqjR1wpDkY9lv_iEfbm6i1jrV7zrrU1ozaqolFbyShFGZqOIBKq0G0l8lW1iX7mcB72cBienhd7_WQ4xq9e36_9mrn3P27RG7Ad32m-jboXe-i3OQHkATfIwB7P2MMVKjq--moUZXq8nVKezV8f_cB93ZuPwDlePvrA</recordid><startdate>20110429</startdate><enddate>20110429</enddate><creator>Zhao, Zhenyang</creator><creator>Chen, Yan</creator><creator>Wang, Jian</creator><creator>Sternberg, Paul</creator><creator>Freeman, Michael L</creator><creator>Grossniklaus, Hans E</creator><creator>Cai, Jiyang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110429</creationdate><title>Age-related retinopathy in NRF2-deficient mice</title><author>Zhao, Zhenyang ; Chen, Yan ; Wang, Jian ; Sternberg, Paul ; Freeman, Michael L ; Grossniklaus, Hans E ; Cai, Jiyang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-d1752bc9c243cf6b575c4753f597cb7727e57eefc1882f04070fe7e1b44e21d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Accumulation</topic><topic>Age</topic><topic>Age related diseases</topic><topic>Aging</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants (Nutrients)</topic><topic>Antioxidants - metabolism</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Biology</topic><topic>Cell death</topic><topic>Deregulation</topic><topic>Detoxification</topic><topic>Disruption</topic><topic>Electron microscopy</topic><topic>Electroretinograms</topic><topic>Electroretinography</topic><topic>Electroretinography - methods</topic><topic>Enzymes</topic><topic>Epithelium</topic><topic>Eye (anatomy)</topic><topic>Immunofluorescence</topic><topic>Immunohistochemistry - methods</topic><topic>Inflammation</topic><topic>Laboratory animals</topic><topic>Lipofuscin - metabolism</topic><topic>Lysosomes - metabolism</topic><topic>Macular degeneration</topic><topic>Medical imaging</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Molecular biology</topic><topic>Neovascularization</topic><topic>NF-E2-Related Factor 2 - genetics</topic><topic>NF-E2-Related Factor 2 - physiology</topic><topic>Oxidative stress</topic><topic>Pathogenesis</topic><topic>Pathology</topic><topic>Phagocytosis</topic><topic>Phenotype</topic><topic>Photography</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Retina</topic><topic>Retinal Diseases - metabolism</topic><topic>Retinal pigment epithelium</topic><topic>Retinopathy</topic><topic>Rodents</topic><topic>Smooth muscle</topic><topic>Time Factors</topic><topic>Transcription factors</topic><topic>Vacuoles</topic><topic>Vascularization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Zhenyang</creatorcontrib><creatorcontrib>Chen, Yan</creatorcontrib><creatorcontrib>Wang, Jian</creatorcontrib><creatorcontrib>Sternberg, Paul</creatorcontrib><creatorcontrib>Freeman, Michael L</creatorcontrib><creatorcontrib>Grossniklaus, Hans E</creatorcontrib><creatorcontrib>Cai, Jiyang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Zhenyang</au><au>Chen, Yan</au><au>Wang, Jian</au><au>Sternberg, Paul</au><au>Freeman, Michael L</au><au>Grossniklaus, Hans E</au><au>Cai, Jiyang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Age-related retinopathy in NRF2-deficient mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-04-29</date><risdate>2011</risdate><volume>6</volume><issue>4</issue><spage>e19456</spage><epage>e19456</epage><pages>e19456-e19456</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.
Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21559389</pmid><doi>10.1371/journal.pone.0019456</doi><tpages>e19456</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Accumulation Age Age related diseases Aging Animals Antioxidants Antioxidants (Nutrients) Antioxidants - metabolism Apoptosis Autophagy Biology Cell death Deregulation Detoxification Disruption Electron microscopy Electroretinograms Electroretinography Electroretinography - methods Enzymes Epithelium Eye (anatomy) Immunofluorescence Immunohistochemistry - methods Inflammation Laboratory animals Lipofuscin - metabolism Lysosomes - metabolism Macular degeneration Medical imaging Medical research Medicine Mice Mice, Inbred C57BL Mice, Transgenic Molecular biology Neovascularization NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - physiology Oxidative stress Pathogenesis Pathology Phagocytosis Phenotype Photography Protein expression Proteins Retina Retinal Diseases - metabolism Retinal pigment epithelium Retinopathy Rodents Smooth muscle Time Factors Transcription factors Vacuoles Vascularization |
| title | Age-related retinopathy in NRF2-deficient mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T11%3A42%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Age-related%20retinopathy%20in%20NRF2-deficient%20mice&rft.jtitle=PloS%20one&rft.au=Zhao,%20Zhenyang&rft.date=2011-04-29&rft.volume=6&rft.issue=4&rft.spage=e19456&rft.epage=e19456&rft.pages=e19456-e19456&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0019456&rft_dat=%3Cgale_plos_%3EA476892549%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1296874585&rft_id=info:pmid/21559389&rft_galeid=A476892549&rft_doaj_id=oai_doaj_org_article_0039f7b676cc4d46bf1bc9516b6ca081&rfr_iscdi=true |