The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes
Dysregulated Toll-Like Receptor (TLR) signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occ...
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| creator | Hold, Georgina L Berry, Susan Saunders, Karin A Drew, Janice Mayer, Claus Brookes, Heather Gay, Nick J El-Omar, Emad M Bryant, Clare E |
| description | Dysregulated Toll-Like Receptor (TLR) signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P |
| doi_str_mv | 10.1371/journal.pone.0111460 |
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We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test) and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0111460</identifier><identifier>PMID: 25365308</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor Proteins, Vesicular Transport - metabolism ; Biology and Life Sciences ; Cell activation ; Cell Line ; Cluster Analysis ; Comparative analysis ; Cytokines ; Disease ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Genes ; Heterozygote ; Humans ; Immune response ; Immune system ; Immunology ; Interferon ; Kinases ; Leukocytes, Mononuclear - metabolism ; Lipid A ; Lipids ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Macrophages ; Medicine and Health Sciences ; Monocytes ; Mutation ; NF-kappa B - metabolism ; NF-κB protein ; Polymorphism, Single Nucleotide ; Proteins ; Reporter gene ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; TLR4 protein ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - metabolism ; Toll-like receptors ; Transcription factors ; Transfection ; Veterinary medicine ; Viral infections</subject><ispartof>PloS one, 2014-11, Vol.9 (11), p.e111460-e111460</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Hold 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>2014 Hold et al 2014 Hold et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-de39795fc96e409ba166adb66e71a274de91114b2952999e7457f2e6e172f4e93</citedby><cites>FETCH-LOGICAL-c692t-de39795fc96e409ba166adb66e71a274de91114b2952999e7457f2e6e172f4e93</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/PMC4218727/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218727/$$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/25365308$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hold, Georgina L</creatorcontrib><creatorcontrib>Berry, Susan</creatorcontrib><creatorcontrib>Saunders, Karin A</creatorcontrib><creatorcontrib>Drew, Janice</creatorcontrib><creatorcontrib>Mayer, Claus</creatorcontrib><creatorcontrib>Brookes, Heather</creatorcontrib><creatorcontrib>Gay, Nick J</creatorcontrib><creatorcontrib>El-Omar, Emad M</creatorcontrib><creatorcontrib>Bryant, Clare E</creatorcontrib><title>The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Dysregulated Toll-Like Receptor (TLR) signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test) and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.</description><subject>Adaptor Proteins, Vesicular Transport - metabolism</subject><subject>Biology and Life Sciences</subject><subject>Cell activation</subject><subject>Cell Line</subject><subject>Cluster Analysis</subject><subject>Comparative analysis</subject><subject>Cytokines</subject><subject>Disease</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation</subject><subject>Gene Regulatory Networks</subject><subject>Genes</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunology</subject><subject>Interferon</subject><subject>Kinases</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Lipid A</subject><subject>Lipids</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Macrophages</subject><subject>Medicine and Health Sciences</subject><subject>Monocytes</subject><subject>Mutation</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Proteins</subject><subject>Reporter gene</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>TLR4 protein</subject><subject>Toll-Like Receptor 4 - genetics</subject><subject>Toll-Like Receptor 4 - metabolism</subject><subject>Toll-like receptors</subject><subject>Transcription factors</subject><subject>Transfection</subject><subject>Veterinary medicine</subject><subject>Viral infections</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9Fu0zAUhiMEYmPwBggsISG4aLEd26lvkKYBo1LF0Fa4tRznJHWVxpmdTNvb49BsatAukC9s2d__H59jnyR5TfCcpBn5tHW9b3Q9b10Dc0wIYQI_SY6JTOlMUJw-PVgfJS9C2GLM04UQz5MjylPBU7w4Tux6A2i9umToC5XyHOmmQOtUyiW6-vEzIO0BGdeEznZ9Z2-gvkPaDAvUOdS3Mw9VX-sOENy2HkKwrkGuRGtvy1kBLTQFNB2qoIHwMnlW6jrAq3E-SX59-7o--z5bXZwvz05XMyMk7aIqlZnkpZECGJa5JkLoIhcCMqJpxgqQQ645lTxeWELGeFZSEEAyWjKQ6Unydu_b1i6osUpBEUEkxzTlA7HcE4XTW9V6u9P-Tjlt1d8N5yulfWdNDQrjUnARoxU5ZfnCaGCMYmMkWTBSUhq9Po_R-nwHhYnpel1PTKcnjd2oyt0oRskio1k0-DAaeHfdQ-jUzgYDda0bcP1wb4p5JFMe0Xf_oI9nN1KVjgnYpnQxrhlM1SkjQgpJ-BB2_ggVRwE7G18cShv3J4KPE0FkOrjtKt2HoJZXl__PXvyesu8P2A3outsEV8ffFr_dFGR70HgXgofyocgEq6Ej7quhho5QY0dE2ZvDB3oQ3bdA-gcRmwNU</recordid><startdate>20141103</startdate><enddate>20141103</enddate><creator>Hold, Georgina L</creator><creator>Berry, Susan</creator><creator>Saunders, Karin A</creator><creator>Drew, Janice</creator><creator>Mayer, Claus</creator><creator>Brookes, Heather</creator><creator>Gay, Nick J</creator><creator>El-Omar, Emad M</creator><creator>Bryant, Clare E</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>20141103</creationdate><title>The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes</title><author>Hold, Georgina L ; Berry, Susan ; Saunders, Karin A ; Drew, Janice ; Mayer, Claus ; Brookes, Heather ; Gay, Nick J ; El-Omar, Emad M ; Bryant, Clare E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-de39795fc96e409ba166adb66e71a274de91114b2952999e7457f2e6e172f4e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adaptor Proteins, Vesicular Transport - metabolism</topic><topic>Biology and Life Sciences</topic><topic>Cell activation</topic><topic>Cell Line</topic><topic>Cluster Analysis</topic><topic>Comparative analysis</topic><topic>Cytokines</topic><topic>Disease</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation</topic><topic>Gene Regulatory Networks</topic><topic>Genes</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunology</topic><topic>Interferon</topic><topic>Kinases</topic><topic>Leukocytes, Mononuclear - metabolism</topic><topic>Lipid A</topic><topic>Lipids</topic><topic>Lipopolysaccharides</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Macrophages</topic><topic>Medicine and Health Sciences</topic><topic>Monocytes</topic><topic>Mutation</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Proteins</topic><topic>Reporter gene</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Single nucleotide polymorphisms</topic><topic>Single-nucleotide polymorphism</topic><topic>TLR4 protein</topic><topic>Toll-Like Receptor 4 - genetics</topic><topic>Toll-Like Receptor 4 - metabolism</topic><topic>Toll-like receptors</topic><topic>Transcription factors</topic><topic>Transfection</topic><topic>Veterinary medicine</topic><topic>Viral infections</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hold, Georgina L</creatorcontrib><creatorcontrib>Berry, Susan</creatorcontrib><creatorcontrib>Saunders, Karin A</creatorcontrib><creatorcontrib>Drew, Janice</creatorcontrib><creatorcontrib>Mayer, Claus</creatorcontrib><creatorcontrib>Brookes, Heather</creatorcontrib><creatorcontrib>Gay, Nick J</creatorcontrib><creatorcontrib>El-Omar, Emad M</creatorcontrib><creatorcontrib>Bryant, Clare E</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>Hold, Georgina L</au><au>Berry, Susan</au><au>Saunders, Karin A</au><au>Drew, Janice</au><au>Mayer, Claus</au><au>Brookes, Heather</au><au>Gay, Nick J</au><au>El-Omar, Emad M</au><au>Bryant, Clare E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-11-03</date><risdate>2014</risdate><volume>9</volume><issue>11</issue><spage>e111460</spage><epage>e111460</epage><pages>e111460-e111460</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Dysregulated Toll-Like Receptor (TLR) signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test) and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25365308</pmid><doi>10.1371/journal.pone.0111460</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Vesicular Transport - metabolism Biology and Life Sciences Cell activation Cell Line Cluster Analysis Comparative analysis Cytokines Disease Gene expression Gene Expression Profiling Gene Expression Regulation Gene Regulatory Networks Genes Heterozygote Humans Immune response Immune system Immunology Interferon Kinases Leukocytes, Mononuclear - metabolism Lipid A Lipids Lipopolysaccharides Lipopolysaccharides - pharmacology Macrophages Medicine and Health Sciences Monocytes Mutation NF-kappa B - metabolism NF-κB protein Polymorphism, Single Nucleotide Proteins Reporter gene Signal transduction Signal Transduction - drug effects Signaling Single nucleotide polymorphisms Single-nucleotide polymorphism TLR4 protein Toll-Like Receptor 4 - genetics Toll-Like Receptor 4 - metabolism Toll-like receptors Transcription factors Transfection Veterinary medicine Viral infections |
| title | The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T02%3A28%3A34IST&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=The%20TLR4%20D299G%20and%20T399I%20SNPs%20are%20constitutively%20active%20to%20up-regulate%20expression%20of%20Trif-dependent%20genes&rft.jtitle=PloS%20one&rft.au=Hold,%20Georgina%20L&rft.date=2014-11-03&rft.volume=9&rft.issue=11&rft.spage=e111460&rft.epage=e111460&rft.pages=e111460-e111460&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0111460&rft_dat=%3Cgale_plos_%3EA416969157%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=1619502359&rft_id=info:pmid/25365308&rft_galeid=A416969157&rft_doaj_id=oai_doaj_org_article_00f6564b2db24b8cae4420cc91841f22&rfr_iscdi=true |