Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear
Long-term drug delivery to the inner ear may be achieved by functionalizing cochlear implant (CI) electrodes with cells providing neuroprotective factors. However, effective strategies in order to coat implant surfaces with cells need to be developed. Our vision is to make benefit of electromagnetic...
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description | Long-term drug delivery to the inner ear may be achieved by functionalizing cochlear implant (CI) electrodes with cells providing neuroprotective factors. However, effective strategies in order to coat implant surfaces with cells need to be developed. Our vision is to make benefit of electromagnetic field attracting forces generated by CI electrodes to bind BDNF-secreting cells that are labelled with magnetic beads (MB) onto the electrode surfaces. Thus, the effect of MB-labelling on cell viability and BDNF production were investigated.
Murine NIH 3T3 fibroblasts-genetically modified to produce BDNF-were labelled with MB.
Atomic force and bright field microscopy illustrated the internalization of MB by fibroblasts after 24 h of cultivation. Labelling cells with MB did not expose cytotoxic effects on fibroblasts and allowed adhesion on magnetic surfaces with sufficient BDNF release.
Our data demonstrate a novel approach for mediating enhanced long-term adhesion of BDNF-secreting fibroblasts on model electrode surfaces for cell-based drug delivery applications in vitro and in vivo. This therapeutic strategy, once transferred to cells suitable for clinical application, may allow the biological modifications of CI surfaces with cells releasing neurotrophic or other factors of interest. |
doi_str_mv | 10.1371/journal.pone.0150057 |
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Murine NIH 3T3 fibroblasts-genetically modified to produce BDNF-were labelled with MB.
Atomic force and bright field microscopy illustrated the internalization of MB by fibroblasts after 24 h of cultivation. Labelling cells with MB did not expose cytotoxic effects on fibroblasts and allowed adhesion on magnetic surfaces with sufficient BDNF release.
Our data demonstrate a novel approach for mediating enhanced long-term adhesion of BDNF-secreting fibroblasts on model electrode surfaces for cell-based drug delivery applications in vitro and in vivo. This therapeutic strategy, once transferred to cells suitable for clinical application, may allow the biological modifications of CI surfaces with cells releasing neurotrophic or other factors of interest.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0150057</identifier><identifier>PMID: 26918945</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adhesion ; Animals ; Atomic force microscopy ; Beads ; Biology and Life Sciences ; Biomedical materials ; Brain research ; Brain-derived neurotrophic factor ; Brain-Derived Neurotrophic Factor - administration & dosage ; Brain-Derived Neurotrophic Factor - genetics ; Cell Survival - drug effects ; Coating effects ; Cochlea ; Cochlear Implants ; Cultivation ; Cytotoxicity ; Data processing ; Drug delivery ; Drug Delivery Systems ; Drug Implants ; Ear, Inner - drug effects ; Electrodes ; Electromagnetic fields ; Emulsion polymerization ; Fibroblasts ; Genetic modification ; Hair ; Hearing impairment ; Hearing loss ; Inner ear ; Internalization ; Labeling ; Labelling ; Magnetics ; Medical schools ; Medicine and Health Sciences ; Mice ; Microscopy ; Neurons ; Neuroprotection ; NIH 3T3 Cells ; Otolaryngology ; Physical Sciences ; Physiological aspects ; Research and Analysis Methods ; Signal transduction ; Studies ; Surgery ; Surgical implants ; Transplants & implants</subject><ispartof>PloS one, 2016-02, Vol.11 (2), p.e0150057-e0150057</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Aliuos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2016 Aliuos et al 2016 Aliuos et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-eb2a37b0d110d7c5b316cc2dc29c2a73d277c5ce75c6e8b2e6be7dab00d34c173</citedby><cites>FETCH-LOGICAL-c692t-eb2a37b0d110d7c5b316cc2dc29c2a73d277c5ce75c6e8b2e6be7dab00d34c173</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/PMC4769079/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769079/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26918945$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Allodi, Silvana</contributor><creatorcontrib>Aliuos, Pooyan</creatorcontrib><creatorcontrib>Schulze, Jennifer</creatorcontrib><creatorcontrib>Schomaker, Markus</creatorcontrib><creatorcontrib>Reuter, Günter</creatorcontrib><creatorcontrib>Stolle, Stefan R O</creatorcontrib><creatorcontrib>Werner, Darja</creatorcontrib><creatorcontrib>Ripken, Tammo</creatorcontrib><creatorcontrib>Lenarz, Thomas</creatorcontrib><creatorcontrib>Warnecke, Athanasia</creatorcontrib><title>Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Long-term drug delivery to the inner ear may be achieved by functionalizing cochlear implant (CI) electrodes with cells providing neuroprotective factors. However, effective strategies in order to coat implant surfaces with cells need to be developed. Our vision is to make benefit of electromagnetic field attracting forces generated by CI electrodes to bind BDNF-secreting cells that are labelled with magnetic beads (MB) onto the electrode surfaces. Thus, the effect of MB-labelling on cell viability and BDNF production were investigated.
Murine NIH 3T3 fibroblasts-genetically modified to produce BDNF-were labelled with MB.
Atomic force and bright field microscopy illustrated the internalization of MB by fibroblasts after 24 h of cultivation. Labelling cells with MB did not expose cytotoxic effects on fibroblasts and allowed adhesion on magnetic surfaces with sufficient BDNF release.
Our data demonstrate a novel approach for mediating enhanced long-term adhesion of BDNF-secreting fibroblasts on model electrode surfaces for cell-based drug delivery applications in vitro and in vivo. This therapeutic strategy, once transferred to cells suitable for clinical application, may allow the biological modifications of CI surfaces with cells releasing neurotrophic or other factors of interest.</description><subject>Adhesion</subject><subject>Animals</subject><subject>Atomic force microscopy</subject><subject>Beads</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>Brain research</subject><subject>Brain-derived neurotrophic factor</subject><subject>Brain-Derived Neurotrophic Factor - administration & dosage</subject><subject>Brain-Derived Neurotrophic Factor - genetics</subject><subject>Cell Survival - drug effects</subject><subject>Coating effects</subject><subject>Cochlea</subject><subject>Cochlear Implants</subject><subject>Cultivation</subject><subject>Cytotoxicity</subject><subject>Data processing</subject><subject>Drug delivery</subject><subject>Drug Delivery Systems</subject><subject>Drug Implants</subject><subject>Ear, Inner - drug effects</subject><subject>Electrodes</subject><subject>Electromagnetic fields</subject><subject>Emulsion polymerization</subject><subject>Fibroblasts</subject><subject>Genetic modification</subject><subject>Hair</subject><subject>Hearing impairment</subject><subject>Hearing loss</subject><subject>Inner ear</subject><subject>Internalization</subject><subject>Labeling</subject><subject>Labelling</subject><subject>Magnetics</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Microscopy</subject><subject>Neurons</subject><subject>Neuroprotection</subject><subject>NIH 3T3 Cells</subject><subject>Otolaryngology</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Research and Analysis Methods</subject><subject>Signal transduction</subject><subject>Studies</subject><subject>Surgery</subject><subject>Surgical implants</subject><subject>Transplants & implants</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11vFCEUhidGY2v1HxglMTF6MSsfM7DTC5O1H3aT1ja29pYwcGaXZhZWYBr7U_y3snbbdE0vDCSQw3Ne4IVTFK8JHhEmyKcrPwSn-tHSOxhhUmNciyfFNmkYLTnF7OmD-VbxIsarTLAx58-LLcobMm6qerv4faJmDpLV6AsoE9GBmyunAU3MHKL1DvkOfZseIXbB0KFtg297FVPcRRN0FrzvytzPgnXaLntAU4cubQoenafB3KDOBzRdLHvlUnkCxqoEBh17NysvICzQfhhmaB96ew3hBiWP0nwl4SCgAxVeFs861Ud4tR53ih-HBxd7R-Xx6dfp3uS41LyhqYSWKiZabAjBRui6ZYRrTY2mjaZKMENFjmoQteYwbinwFoRRLcaGVZoItlO8vdVd9j7KtatREiEIzb2pMzG9JYxXV3IZ7EKFG-mVlX8DPsykCtnCHmTbth3UQjBcqUrXSpGOYWqI5rWg9bjJWp_Xuw3tAowGl4LqN0Q3V5ydy5m_lpXgDRYrgQ9rgeB_DhCTXNiooc8mgx9W5-YNp6LCPKPv_kEfv92amql8Aes6n_fVK1E5qaqKcSYakqnRI1RuBhZW5y_Y2RzfSPi4kZCZBL_STA0xyun59_9nTy832fcP2DmoPs2j74eUP2vcBKtbUAcfY4Du3mSC5aqC7tyQqwqS6wrKaW8ePtB90l3JsD8VKBWg</recordid><startdate>20160226</startdate><enddate>20160226</enddate><creator>Aliuos, Pooyan</creator><creator>Schulze, Jennifer</creator><creator>Schomaker, Markus</creator><creator>Reuter, Günter</creator><creator>Stolle, Stefan R O</creator><creator>Werner, Darja</creator><creator>Ripken, Tammo</creator><creator>Lenarz, Thomas</creator><creator>Warnecke, Athanasia</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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160226</creationdate><title>Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear</title><author>Aliuos, Pooyan ; Schulze, Jennifer ; Schomaker, Markus ; Reuter, Günter ; Stolle, Stefan R O ; Werner, Darja ; Ripken, Tammo ; Lenarz, Thomas ; Warnecke, Athanasia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-eb2a37b0d110d7c5b316cc2dc29c2a73d277c5ce75c6e8b2e6be7dab00d34c173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adhesion</topic><topic>Animals</topic><topic>Atomic force microscopy</topic><topic>Beads</topic><topic>Biology and Life Sciences</topic><topic>Biomedical materials</topic><topic>Brain research</topic><topic>Brain-derived neurotrophic factor</topic><topic>Brain-Derived Neurotrophic Factor - administration & dosage</topic><topic>Brain-Derived Neurotrophic Factor - genetics</topic><topic>Cell Survival - drug effects</topic><topic>Coating effects</topic><topic>Cochlea</topic><topic>Cochlear Implants</topic><topic>Cultivation</topic><topic>Cytotoxicity</topic><topic>Data processing</topic><topic>Drug delivery</topic><topic>Drug Delivery Systems</topic><topic>Drug Implants</topic><topic>Ear, Inner - drug effects</topic><topic>Electrodes</topic><topic>Electromagnetic fields</topic><topic>Emulsion polymerization</topic><topic>Fibroblasts</topic><topic>Genetic modification</topic><topic>Hair</topic><topic>Hearing impairment</topic><topic>Hearing loss</topic><topic>Inner ear</topic><topic>Internalization</topic><topic>Labeling</topic><topic>Labelling</topic><topic>Magnetics</topic><topic>Medical schools</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Microscopy</topic><topic>Neurons</topic><topic>Neuroprotection</topic><topic>NIH 3T3 Cells</topic><topic>Otolaryngology</topic><topic>Physical Sciences</topic><topic>Physiological aspects</topic><topic>Research and Analysis Methods</topic><topic>Signal transduction</topic><topic>Studies</topic><topic>Surgery</topic><topic>Surgical implants</topic><topic>Transplants & implants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Aliuos, Pooyan</creatorcontrib><creatorcontrib>Schulze, Jennifer</creatorcontrib><creatorcontrib>Schomaker, Markus</creatorcontrib><creatorcontrib>Reuter, Günter</creatorcontrib><creatorcontrib>Stolle, Stefan R O</creatorcontrib><creatorcontrib>Werner, Darja</creatorcontrib><creatorcontrib>Ripken, Tammo</creatorcontrib><creatorcontrib>Lenarz, Thomas</creatorcontrib><creatorcontrib>Warnecke, Athanasia</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>Aliuos, Pooyan</au><au>Schulze, Jennifer</au><au>Schomaker, Markus</au><au>Reuter, Günter</au><au>Stolle, Stefan R O</au><au>Werner, Darja</au><au>Ripken, Tammo</au><au>Lenarz, Thomas</au><au>Warnecke, Athanasia</au><au>Allodi, Silvana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-02-26</date><risdate>2016</risdate><volume>11</volume><issue>2</issue><spage>e0150057</spage><epage>e0150057</epage><pages>e0150057-e0150057</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Long-term drug delivery to the inner ear may be achieved by functionalizing cochlear implant (CI) electrodes with cells providing neuroprotective factors. However, effective strategies in order to coat implant surfaces with cells need to be developed. Our vision is to make benefit of electromagnetic field attracting forces generated by CI electrodes to bind BDNF-secreting cells that are labelled with magnetic beads (MB) onto the electrode surfaces. Thus, the effect of MB-labelling on cell viability and BDNF production were investigated.
Murine NIH 3T3 fibroblasts-genetically modified to produce BDNF-were labelled with MB.
Atomic force and bright field microscopy illustrated the internalization of MB by fibroblasts after 24 h of cultivation. Labelling cells with MB did not expose cytotoxic effects on fibroblasts and allowed adhesion on magnetic surfaces with sufficient BDNF release.
Our data demonstrate a novel approach for mediating enhanced long-term adhesion of BDNF-secreting fibroblasts on model electrode surfaces for cell-based drug delivery applications in vitro and in vivo. This therapeutic strategy, once transferred to cells suitable for clinical application, may allow the biological modifications of CI surfaces with cells releasing neurotrophic or other factors of interest.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26918945</pmid><doi>10.1371/journal.pone.0150057</doi><oa>free_for_read</oa></addata></record> |
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subjects | Adhesion Animals Atomic force microscopy Beads Biology and Life Sciences Biomedical materials Brain research Brain-derived neurotrophic factor Brain-Derived Neurotrophic Factor - administration & dosage Brain-Derived Neurotrophic Factor - genetics Cell Survival - drug effects Coating effects Cochlea Cochlear Implants Cultivation Cytotoxicity Data processing Drug delivery Drug Delivery Systems Drug Implants Ear, Inner - drug effects Electrodes Electromagnetic fields Emulsion polymerization Fibroblasts Genetic modification Hair Hearing impairment Hearing loss Inner ear Internalization Labeling Labelling Magnetics Medical schools Medicine and Health Sciences Mice Microscopy Neurons Neuroprotection NIH 3T3 Cells Otolaryngology Physical Sciences Physiological aspects Research and Analysis Methods Signal transduction Studies Surgery Surgical implants Transplants & implants |
title | Magnetic Beads Enhance Adhesion of NIH 3T3 Fibroblasts: A Proof-of-Principle In Vitro Study for Implant-Mediated Long-Term Drug Delivery to the Inner Ear |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T06%3A37%3A46IST&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=Magnetic%20Beads%20Enhance%20Adhesion%20of%20NIH%203T3%20Fibroblasts:%20A%20Proof-of-Principle%20In%20Vitro%20Study%20for%20Implant-Mediated%20Long-Term%20Drug%20Delivery%20to%20the%20Inner%20Ear&rft.jtitle=PloS%20one&rft.au=Aliuos,%20Pooyan&rft.date=2016-02-26&rft.volume=11&rft.issue=2&rft.spage=e0150057&rft.epage=e0150057&rft.pages=e0150057-e0150057&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0150057&rft_dat=%3Cgale_plos_%3EA444363791%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=1771271295&rft_id=info:pmid/26918945&rft_galeid=A444363791&rft_doaj_id=oai_doaj_org_article_bbbfe577304a4c5aa1f302d1c6572589&rfr_iscdi=true |