Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia
Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothes...
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| Veröffentlicht in: | PloS one 2014-09, Vol.9 (9), p.e107734-e107734 |
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| description | Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2-/-) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P |
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Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2-/-) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2-/- mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2-/- mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107734</identifier><identifier>PMID: 25226386</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylcholine ; Animals ; Arterioles ; Atherosclerosis ; Bioavailability ; Biology and Life Sciences ; Cardiovascular disease ; Carotid arteries ; Carotid artery ; Cerebral Arteries - drug effects ; Cerebral Arteries - metabolism ; Cerebral blood flow ; Diet ; Disease Models, Animal ; Endothelium ; Endothelium, Vascular - drug effects ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - physiopathology ; Female ; Folic acid ; Gene expression ; Heart diseases ; Homocysteine ; Homocysteine - blood ; Hyperhomocysteinemia ; Hyperhomocysteinemia - genetics ; Hyperhomocysteinemia - metabolism ; Hypotheses ; Internal medicine ; Ischemia ; Laboratory animals ; Male ; Medicine ; Medicine and Health Sciences ; Metabolic disorders ; Methionine ; Methionine - blood ; Mice ; Mice, Knockout ; Myocardial infarction ; Myocardial ischemia ; Myocardial Reperfusion Injury - genetics ; Myocardial Reperfusion Injury - metabolism ; Myocardial Reperfusion Injury - pathology ; Myocardium - metabolism ; Nitric oxide ; Nitric Oxide Synthase Type II - deficiency ; Nitric Oxide Synthase Type II - genetics ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; Occlusion ; Oxidative stress ; Phenotype ; Photochemicals ; Reactive Oxygen Species - metabolism ; Reperfusion ; Rodents ; Smooth muscle ; Studies ; Superoxide ; Thromboembolism ; Thrombosis ; Thrombosis - metabolism ; Vasodilator Agents - pharmacology ; Veins & arteries</subject><ispartof>PloS one, 2014-09, Vol.9 (9), p.e107734-e107734</ispartof><rights>2014. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-68e0487482ae3e6c2f2599f48cc6ceedfc2e524370c5b70c9d04c58de34930a43</citedby><cites>FETCH-LOGICAL-c526t-68e0487482ae3e6c2f2599f48cc6ceedfc2e524370c5b70c9d04c58de34930a43</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/PMC4167199/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167199/$$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/25226386$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dayal, Sanjana</creatorcontrib><creatorcontrib>Blokhin, Ilya O</creatorcontrib><creatorcontrib>Erger, Rochelle A</creatorcontrib><creatorcontrib>Jensen, Melissa</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Stevens, Jeff W</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Faraci, Frank M</creatorcontrib><creatorcontrib>Lentz, Steven R</creatorcontrib><title>Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2-/-) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2-/- mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2-/- mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.</description><subject>Acetylcholine</subject><subject>Animals</subject><subject>Arterioles</subject><subject>Atherosclerosis</subject><subject>Bioavailability</subject><subject>Biology and Life Sciences</subject><subject>Cardiovascular disease</subject><subject>Carotid arteries</subject><subject>Carotid artery</subject><subject>Cerebral Arteries - drug effects</subject><subject>Cerebral Arteries - metabolism</subject><subject>Cerebral blood flow</subject><subject>Diet</subject><subject>Disease Models, Animal</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - drug effects</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - physiopathology</subject><subject>Female</subject><subject>Folic acid</subject><subject>Gene expression</subject><subject>Heart diseases</subject><subject>Homocysteine</subject><subject>Homocysteine - blood</subject><subject>Hyperhomocysteinemia</subject><subject>Hyperhomocysteinemia - genetics</subject><subject>Hyperhomocysteinemia - metabolism</subject><subject>Hypotheses</subject><subject>Internal medicine</subject><subject>Ischemia</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolic disorders</subject><subject>Methionine</subject><subject>Methionine - blood</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Myocardial infarction</subject><subject>Myocardial ischemia</subject><subject>Myocardial Reperfusion Injury - genetics</subject><subject>Myocardial Reperfusion Injury - metabolism</subject><subject>Myocardial Reperfusion Injury - pathology</subject><subject>Myocardium - metabolism</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type II - deficiency</subject><subject>Nitric Oxide Synthase Type II - genetics</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Occlusion</subject><subject>Oxidative stress</subject><subject>Phenotype</subject><subject>Photochemicals</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Reperfusion</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Studies</subject><subject>Superoxide</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Thrombosis - metabolism</subject><subject>Vasodilator Agents - pharmacology</subject><subject>Veins & arteries</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>eNptUk1v1DAQjRCIlsI_QGCJC5dd_B37glRVLVSqBAc4W97JpOtVEi-2s7D_nmw3rVrExR553nvzxnpV9ZbRJRM1-7SJYxp8t9zGAZeU0boW8ll1yqzgC82peP6oPqle5byhVAmj9cvqhCvO9VSfVt33FAtCCTskO59h7HwifmgI-NQEDwTbdmpnElsShmaEsOqQDKGkACT-CQ2SvB_K2mec-qQPgOR3KGuy3m8xrWMfYZ8LhgH74F9XL1rfZXwz32fVz6vLHxdfFzffvlxfnN8sQHFdFtoglaaWhnsUqIG3XFnbSgOgAbFpgaPiUtQU1Go6bEMlKNOgkFZQL8VZ9f6ou-1idvNHZceU5pJzaQ-I6yOiiX7jtin0Pu1d9MHdPcR063wqATp0zCvGOFCFSku03nLKjJFysgqcGZy0Ps_TxlWPDeBQku-eiD7tDGHtbuPOSaZrZu0k8HEWSPHXiLm4PmTArvMDxvHOt6DKUmUm6Id_oP_fTh5RkGLOCdsHM4y6Q3juWe4QHjeHZ6K9e7zIA-k-LeIvTy7D3A</recordid><startdate>20140916</startdate><enddate>20140916</enddate><creator>Dayal, Sanjana</creator><creator>Blokhin, Ilya O</creator><creator>Erger, Rochelle A</creator><creator>Jensen, Melissa</creator><creator>Arning, Erland</creator><creator>Stevens, Jeff W</creator><creator>Bottiglieri, Teodoro</creator><creator>Faraci, Frank M</creator><creator>Lentz, Steven R</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>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>20140916</creationdate><title>Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia</title><author>Dayal, Sanjana ; Blokhin, Ilya O ; Erger, Rochelle A ; Jensen, Melissa ; Arning, Erland ; Stevens, Jeff W ; Bottiglieri, Teodoro ; Faraci, Frank M ; Lentz, Steven R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-68e0487482ae3e6c2f2599f48cc6ceedfc2e524370c5b70c9d04c58de34930a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acetylcholine</topic><topic>Animals</topic><topic>Arterioles</topic><topic>Atherosclerosis</topic><topic>Bioavailability</topic><topic>Biology and Life Sciences</topic><topic>Cardiovascular disease</topic><topic>Carotid arteries</topic><topic>Carotid artery</topic><topic>Cerebral Arteries - drug effects</topic><topic>Cerebral Arteries - metabolism</topic><topic>Cerebral blood flow</topic><topic>Diet</topic><topic>Disease Models, Animal</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - drug effects</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - physiopathology</topic><topic>Female</topic><topic>Folic acid</topic><topic>Gene expression</topic><topic>Heart diseases</topic><topic>Homocysteine</topic><topic>Homocysteine - blood</topic><topic>Hyperhomocysteinemia</topic><topic>Hyperhomocysteinemia - genetics</topic><topic>Hyperhomocysteinemia - metabolism</topic><topic>Hypotheses</topic><topic>Internal medicine</topic><topic>Ischemia</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Metabolic disorders</topic><topic>Methionine</topic><topic>Methionine - blood</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Myocardial infarction</topic><topic>Myocardial ischemia</topic><topic>Myocardial Reperfusion Injury - 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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>Dayal, Sanjana</au><au>Blokhin, Ilya O</au><au>Erger, Rochelle A</au><au>Jensen, Melissa</au><au>Arning, Erland</au><au>Stevens, Jeff W</au><au>Bottiglieri, Teodoro</au><au>Faraci, Frank M</au><au>Lentz, Steven R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-09-16</date><risdate>2014</risdate><volume>9</volume><issue>9</issue><spage>e107734</spage><epage>e107734</epage><pages>e107734-e107734</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Diet-induced hyperhomocysteinemia produces endothelial and cardiac dysfunction and promotes thrombosis through a mechanism proposed to involve oxidative stress. Inducible nitric oxide synthase (iNOS) is upregulated in hyperhomocysteinemia and can generate superoxide. We therefore tested the hypothesis that iNOS mediates the adverse oxidative, vascular, thrombotic, and cardiac effects of hyperhomocysteinemia. Mice deficient in iNOS (Nos2-/-) and their wild-type (Nos2+/+) littermates were fed a high methionine/low folate (HM/LF) diet to induce mild hyperhomocysteinemia, with a 2-fold increase in plasma total homocysteine (P<0.001 vs. control diet). Hyperhomocysteinemic Nos2+/+ mice exhibited endothelial dysfunction in cerebral arterioles, with impaired dilatation to acetylcholine but not nitroprusside, and enhanced susceptibility to carotid artery thrombosis, with shortened times to occlusion following photochemical injury (P<0.05 vs. control diet). Nos2-/- mice had decreased rather than increased dilatation responses to acetylcholine (P<0.05 vs. Nos2+/+ mice). Nos2-/- mice fed control diet also exhibited shortened times to thrombotic occlusion (P<0.05 vs. Nos2+/+ mice), and iNOS deficiency failed to protect from endothelial dysfunction or accelerated thrombosis in mice with hyperhomocysteinemia. Deficiency of iNOS did not alter myocardial infarct size in mice fed the control diet but significantly increased infarct size and cardiac superoxide production in mice fed the HM/LF diet (P<0.05 vs. Nos2+/+ mice). These findings suggest that endogenous iNOS protects from, rather than exacerbates, endothelial dysfunction, thrombosis, and hyperhomocysteinemia-associated myocardial ischemia-reperfusion injury. In the setting of mild hyperhomocysteinemia, iNOS functions to blunt cardiac oxidative stress rather than functioning as a source of superoxide.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25226386</pmid><doi>10.1371/journal.pone.0107734</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1562422494 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Acetylcholine Animals Arterioles Atherosclerosis Bioavailability Biology and Life Sciences Cardiovascular disease Carotid arteries Carotid artery Cerebral Arteries - drug effects Cerebral Arteries - metabolism Cerebral blood flow Diet Disease Models, Animal Endothelium Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - physiopathology Female Folic acid Gene expression Heart diseases Homocysteine Homocysteine - blood Hyperhomocysteinemia Hyperhomocysteinemia - genetics Hyperhomocysteinemia - metabolism Hypotheses Internal medicine Ischemia Laboratory animals Male Medicine Medicine and Health Sciences Metabolic disorders Methionine Methionine - blood Mice Mice, Knockout Myocardial infarction Myocardial ischemia Myocardial Reperfusion Injury - genetics Myocardial Reperfusion Injury - metabolism Myocardial Reperfusion Injury - pathology Myocardium - metabolism Nitric oxide Nitric Oxide Synthase Type II - deficiency Nitric Oxide Synthase Type II - genetics Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase Occlusion Oxidative stress Phenotype Photochemicals Reactive Oxygen Species - metabolism Reperfusion Rodents Smooth muscle Studies Superoxide Thromboembolism Thrombosis Thrombosis - metabolism Vasodilator Agents - pharmacology Veins & arteries |
| title | Protective vascular and cardiac effects of inducible nitric oxide synthase in mice with hyperhomocysteinemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T14%3A07%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Protective%20vascular%20and%20cardiac%20effects%20of%20inducible%20nitric%20oxide%20synthase%20in%20mice%20with%20hyperhomocysteinemia&rft.jtitle=PloS%20one&rft.au=Dayal,%20Sanjana&rft.date=2014-09-16&rft.volume=9&rft.issue=9&rft.spage=e107734&rft.epage=e107734&rft.pages=e107734-e107734&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0107734&rft_dat=%3Cproquest_plos_%3E3434093651%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1562422494&rft_id=info:pmid/25226386&rft_doaj_id=oai_doaj_org_article_1a5112c05e564e9a92018844526c218e&rfr_iscdi=true |