JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21
JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 i...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e34303 |
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| creator | Yang, Xinyi Wang, Wei Qin, Jiang-Jiang Wang, Ming-Hai Sharma, Horrick Buolamwini, John K Wang, Hui Zhang, Ruiwen |
| description | JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy. |
| doi_str_mv | 10.1371/journal.pone.0034303 |
| format | Article |
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In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034303</identifier><identifier>PMID: 22558087</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anticancer properties ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Benzylidene Compounds - chemistry ; Benzylidene Compounds - pharmacology ; Biology ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Cancer ; Cancer therapies ; Cancer treatment ; Carbolines - chemistry ; Carbolines - pharmacology ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cyclin-dependent kinase inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Dose-Response Relationship, Drug ; Drug therapy ; Female ; Fibroblasts ; G1 phase ; G1 Phase Cell Cycle Checkpoints - drug effects ; Gene Expression Regulation - drug effects ; GTP-binding protein ; Harmine - chemistry ; Health aspects ; Health sciences ; Humans ; In Vitro Techniques ; Kinases ; Lung cancer ; Medical prognosis ; Medicine ; Molecular modelling ; Natural products ; p53 Protein ; Panax ginseng ; Pancreatic cancer ; Pharmaceutical sciences ; Pharmacy ; Prostate cancer ; Regulators ; Styrenes - chemistry ; Styrenes - pharmacology ; Therapy ; Transcription ; Tumor proteins ; Tumors ; Xenografts</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34303</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Yang 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>Yang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7c387de398753da8f5e6c4df308f8b45cd9014db184ea6f97e7afd6eb26113963</citedby><cites>FETCH-LOGICAL-c692t-7c387de398753da8f5e6c4df308f8b45cd9014db184ea6f97e7afd6eb26113963</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/PMC3338851/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338851/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22558087$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Wu, Gen Sheng</contributor><creatorcontrib>Yang, Xinyi</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Qin, Jiang-Jiang</creatorcontrib><creatorcontrib>Wang, Ming-Hai</creatorcontrib><creatorcontrib>Sharma, Horrick</creatorcontrib><creatorcontrib>Buolamwini, John K</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Zhang, Ruiwen</creatorcontrib><title>JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>JKA97, a benzylidene analog of harmine, has been found to be a promising drug candidate for human cancer therapy, although the underlying molecular mechanisms have not been fully demonstrated. In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.</description><subject>Anticancer properties</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Benzylidene Compounds - chemistry</subject><subject>Benzylidene Compounds - pharmacology</subject><subject>Biology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Carbolines - chemistry</subject><subject>Carbolines - pharmacology</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclin-dependent kinase inhibitor p21</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>G1 phase</subject><subject>G1 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Gene Expression Regulation - drug effects</subject><subject>GTP-binding protein</subject><subject>Harmine - chemistry</subject><subject>Health aspects</subject><subject>Health sciences</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Molecular modelling</subject><subject>Natural products</subject><subject>p53 Protein</subject><subject>Panax ginseng</subject><subject>Pancreatic cancer</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Prostate cancer</subject><subject>Regulators</subject><subject>Styrenes - chemistry</subject><subject>Styrenes - pharmacology</subject><subject>Therapy</subject><subject>Transcription</subject><subject>Tumor proteins</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk-1qFDEUhgdRbK3egWhAEITOmkxmJpM_wlK0rhYKfv0N2eRkNmU2GZOZ0vU2vGGz3WnZBQUJJOGc57xJXnKy7DnBM0IZeXvlx-BkN-u9gxnGtKSYPsiOCadFXheYPtzbH2VPYrzCuKJNXT_OjoqiqhrcsOPs96fPc85OkUTOX0OHluB-bTqrwQGSSd63yBu0kmFtHZwiuIEwxJQZbK6kUxAQGAMqxZYbZJ0elXUtOidIhgBxSMK97wcfbUxbp1Ff0Txh0EOa3IDGPg_Qjp0crHfbo_qCPM0eGdlFeDatJ9n3D--_nX3MLy7PF2fzi1zVvBhypmjDNFDesIpq2ZgKalVqQ3FjmmVZKc0xKfWSNCXI2nAGTBpdw7KoCaG8pifZy51u3_koJj-jILQoq5S-JRY7Qnt5Jfpg1zJshJdW3AZ8aIUMg1UdiJJBZSSpVcGrklDMS8V4A9QwXSlidNJ6N502LtegVXp9kN2B6GHG2ZVo_bWglDZNRZLAq0kg-J9jMvcfV56oVqZbWWd8ElNrG5WYl4xhSjnniZr9hUpDw9qq9KOMTfGDgjcHBYkZ4GZo5RijWHz98v_s5Y9D9vUeuwLZDavou3H7HeIhWO5AFXyMAcy9cwSLbUPcuSG2DSGmhkhlL_Zdvy-66wD6B3ljBiI</recordid><startdate>20120427</startdate><enddate>20120427</enddate><creator>Yang, Xinyi</creator><creator>Wang, Wei</creator><creator>Qin, Jiang-Jiang</creator><creator>Wang, Ming-Hai</creator><creator>Sharma, Horrick</creator><creator>Buolamwini, John K</creator><creator>Wang, Hui</creator><creator>Zhang, Ruiwen</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>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120427</creationdate><title>JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21</title><author>Yang, Xinyi ; Wang, Wei ; Qin, Jiang-Jiang ; Wang, Ming-Hai ; Sharma, Horrick ; Buolamwini, John K ; Wang, Hui ; Zhang, Ruiwen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-7c387de398753da8f5e6c4df308f8b45cd9014db184ea6f97e7afd6eb26113963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Anticancer properties</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Benzylidene Compounds - chemistry</topic><topic>Benzylidene Compounds - pharmacology</topic><topic>Biology</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>Carbolines - chemistry</topic><topic>Carbolines - pharmacology</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclin-dependent kinase inhibitor p21</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>G1 phase</topic><topic>G1 Phase Cell Cycle Checkpoints - drug effects</topic><topic>Gene Expression Regulation - drug effects</topic><topic>GTP-binding protein</topic><topic>Harmine - chemistry</topic><topic>Health aspects</topic><topic>Health sciences</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Kinases</topic><topic>Lung cancer</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Molecular modelling</topic><topic>Natural products</topic><topic>p53 Protein</topic><topic>Panax ginseng</topic><topic>Pancreatic cancer</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacy</topic><topic>Prostate cancer</topic><topic>Regulators</topic><topic>Styrenes - chemistry</topic><topic>Styrenes - pharmacology</topic><topic>Therapy</topic><topic>Transcription</topic><topic>Tumor proteins</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Xinyi</creatorcontrib><creatorcontrib>Wang, Wei</creatorcontrib><creatorcontrib>Qin, Jiang-Jiang</creatorcontrib><creatorcontrib>Wang, Ming-Hai</creatorcontrib><creatorcontrib>Sharma, Horrick</creatorcontrib><creatorcontrib>Buolamwini, John K</creatorcontrib><creatorcontrib>Wang, Hui</creatorcontrib><creatorcontrib>Zhang, Ruiwen</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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In this study, we evaluated the effects of JKA97 on human breast cancer cells in vitro and in vivo. JKA97 inhibited the growth and proliferation of MCF7 (p53 wild-type), MCF7 (p53 knockdown), and MDA-MB-468 (p53 mutant) cells in a dose-dependent manner. Treatment with JKA97 arrested breast cancer cells in G1 phase and induced apoptosis. JKA97 also significantly suppressed the growth of MCF7 and MDA-MB-468 xenograft tumors. It regulated the expression levels of G1 phase regulators, such as p21, p27, cyclinE, and cylinD1. JKA97 activated p21 transcription, independent of p53, but had little effect on p21 protein stability/degradation. In summary, our results suggest that JKA97 inhibits human breast cancer cell growth through activating p21, independent of p53, which provides a basis for developing this compound as a novel drug for human breast cancer therapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22558087</pmid><doi>10.1371/journal.pone.0034303</doi><tpages>e34303</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2012-04, Vol.7 (4), p.e34303 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1324596396 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Anticancer properties Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Benzylidene Compounds - chemistry Benzylidene Compounds - pharmacology Biology Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cancer Cancer therapies Cancer treatment Carbolines - chemistry Carbolines - pharmacology Cell cycle Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cyclin-dependent kinase inhibitor p21 Cyclin-Dependent Kinase Inhibitor p21 - metabolism Dose-Response Relationship, Drug Drug therapy Female Fibroblasts G1 phase G1 Phase Cell Cycle Checkpoints - drug effects Gene Expression Regulation - drug effects GTP-binding protein Harmine - chemistry Health aspects Health sciences Humans In Vitro Techniques Kinases Lung cancer Medical prognosis Medicine Molecular modelling Natural products p53 Protein Panax ginseng Pancreatic cancer Pharmaceutical sciences Pharmacy Prostate cancer Regulators Styrenes - chemistry Styrenes - pharmacology Therapy Transcription Tumor proteins Tumors Xenografts |
| title | JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-13T23%3A28%3A40IST&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=JKA97,%20a%20novel%20benzylidene%20analog%20of%20harmine,%20exerts%20anti-cancer%20effects%20by%20inducing%20G1%20arrest,%20apoptosis,%20and%20p53-independent%20up-regulation%20of%20p21&rft.jtitle=PloS%20one&rft.au=Yang,%20Xinyi&rft.date=2012-04-27&rft.volume=7&rft.issue=4&rft.spage=e34303&rft.pages=e34303-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0034303&rft_dat=%3Cgale_plos_%3EA477033999%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=1324596396&rft_id=info:pmid/22558087&rft_galeid=A477033999&rft_doaj_id=oai_doaj_org_article_47e5fa16c295413094c798e3f7d5c1fd&rfr_iscdi=true |