The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy
Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown. We invest...
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| creator | Yang, Lei Yu, Di Mo, Ran Zhang, Jiru Hua, Hu Hu, Liang Feng, Yu Wang, Song Zhang, Wei-Yan Yin, Ning Mo, Xu-Ming |
| description | Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.
We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.
Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH. |
| doi_str_mv | 10.1371/journal.pone.0147597 |
| format | Article |
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We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.
Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0147597</identifier><identifier>PMID: 26824665</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Androstadienes - pharmacology ; Anesthesiology ; Animals ; Atrial Natriuretic Factor - genetics ; Atrial Natriuretic Factor - metabolism ; Banding ; Biology and Life Sciences ; Cancer ; Cardiomyocytes ; Cell receptors ; Children & youth ; Diabetes ; Diagnosis ; G protein-coupled receptors ; Gene Expression Regulation ; Genetic aspects ; Genetic markers ; Heart ; Heart failure ; Heart hypertrophy ; Heart surgery ; Heart Ventricles - metabolism ; Heart Ventricles - pathology ; Heart Ventricles - physiopathology ; Hospitals ; Humans ; Hypertension ; Hypertension, Pulmonary - genetics ; Hypertension, Pulmonary - metabolism ; Hypertension, Pulmonary - pathology ; Hypertension, Pulmonary - physiopathology ; Hypertrophy ; Hypertrophy, Right Ventricular - genetics ; Hypertrophy, Right Ventricular - metabolism ; Hypertrophy, Right Ventricular - pathology ; Hypertrophy, Right Ventricular - physiopathology ; Kinases ; Medicine and Health Sciences ; Metabolism ; Metabolites ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Physiological aspects ; Proteins ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Pulmonary arteries ; Pulmonary Artery - metabolism ; Pulmonary Artery - pathology ; Pulmonary Artery - surgery ; Pulmonary hypertension ; Rats ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Rodents ; Signal Transduction ; Signaling ; Stroke Volume ; Succinic Acid - metabolism ; Succinic Acid - pharmacology ; Ventricle ; Wortmannin</subject><ispartof>PloS one, 2016-01, Vol.11 (1), p.e0147597-e0147597</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Yang 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 Yang et al 2016 Yang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-8c37c86e927a1bc9776491c9e03b79323426f028302f2ee68aff4a2fbbecfd523</citedby><cites>FETCH-LOGICAL-c692t-8c37c86e927a1bc9776491c9e03b79323426f028302f2ee68aff4a2fbbecfd523</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/PMC4732750/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732750/$$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/26824665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Lei</creatorcontrib><creatorcontrib>Yu, Di</creatorcontrib><creatorcontrib>Mo, Ran</creatorcontrib><creatorcontrib>Zhang, Jiru</creatorcontrib><creatorcontrib>Hua, Hu</creatorcontrib><creatorcontrib>Hu, Liang</creatorcontrib><creatorcontrib>Feng, Yu</creatorcontrib><creatorcontrib>Wang, Song</creatorcontrib><creatorcontrib>Zhang, Wei-Yan</creatorcontrib><creatorcontrib>Yin, Ning</creatorcontrib><creatorcontrib>Mo, Xu-Ming</creatorcontrib><title>The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.
We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.
Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Androstadienes - pharmacology</subject><subject>Anesthesiology</subject><subject>Animals</subject><subject>Atrial Natriuretic Factor - genetics</subject><subject>Atrial Natriuretic Factor - metabolism</subject><subject>Banding</subject><subject>Biology and Life Sciences</subject><subject>Cancer</subject><subject>Cardiomyocytes</subject><subject>Cell receptors</subject><subject>Children & youth</subject><subject>Diabetes</subject><subject>Diagnosis</subject><subject>G protein-coupled receptors</subject><subject>Gene Expression Regulation</subject><subject>Genetic aspects</subject><subject>Genetic markers</subject><subject>Heart</subject><subject>Heart failure</subject><subject>Heart hypertrophy</subject><subject>Heart surgery</subject><subject>Heart Ventricles - metabolism</subject><subject>Heart Ventricles - pathology</subject><subject>Heart Ventricles - physiopathology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Hypertension, Pulmonary - genetics</subject><subject>Hypertension, Pulmonary - metabolism</subject><subject>Hypertension, Pulmonary - pathology</subject><subject>Hypertension, Pulmonary - physiopathology</subject><subject>Hypertrophy</subject><subject>Hypertrophy, Right Ventricular - genetics</subject><subject>Hypertrophy, Right Ventricular - metabolism</subject><subject>Hypertrophy, Right Ventricular - pathology</subject><subject>Hypertrophy, Right Ventricular - physiopathology</subject><subject>Kinases</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pulmonary arteries</subject><subject>Pulmonary Artery - metabolism</subject><subject>Pulmonary Artery - pathology</subject><subject>Pulmonary Artery - surgery</subject><subject>Pulmonary hypertension</subject><subject>Rats</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Stroke Volume</subject><subject>Succinic Acid - metabolism</subject><subject>Succinic Acid - pharmacology</subject><subject>Ventricle</subject><subject>Wortmannin</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>eNqNk99r2zAQx83YWLtu_8HYDIOxPSTTD1uyXwaldK2hkJJ2fRtCls-JgmK5kh2a_35K45Z49GHoQUL3ua_uTndR9BGjKaYc_1jZ3jXSTFvbwBThhKc5fxUd45ySCSOIvj44H0XvvF8hlNKMsbfREWEZSRhLj6M_t0uIb3qldCM7iOegoO2siy-u5zmOCx8XzcaaDVSxbuJrB973DuLZBpyxspoUTdWrYLyDpnNa9Ua6-HLbguucbZfb99GbWhoPH4b9JPr96_z27HJyNbsozk6vJorlpJtkinKVMcgJl7hUOecsybHKAdGShxxoQliNSEYRqQkAy2RdJ5LUZQmqrlJCT6LPe93WWC-GyniBOcMkoSTNA1HsicrKlWidXku3FVZq8Xhh3UJI12llQFQpJZwQwjOpEsZJCZlivESUAakZy4LWz-G1vlxDpXa5SzMSHVsavRQLuxEJD8opCgLfBgFn73vwnVhrr8AY2YDtH-MmKMSQpgH98g_6cnYDtZAhAd3UNryrdqLiNEkwzzHNdnFPX6DCqmCtVWijWof7kcP3kUNgOnjoFrL3XhQ38_9nZ3dj9usBuwRpuqW3pu-0bfwYTPagctZ7B_VzkTESuyl4qobYTYEYpiC4fTr8oGenp7anfwHUEADv</recordid><startdate>20160129</startdate><enddate>20160129</enddate><creator>Yang, Lei</creator><creator>Yu, Di</creator><creator>Mo, Ran</creator><creator>Zhang, Jiru</creator><creator>Hua, Hu</creator><creator>Hu, Liang</creator><creator>Feng, Yu</creator><creator>Wang, Song</creator><creator>Zhang, Wei-Yan</creator><creator>Yin, Ning</creator><creator>Mo, Xu-Ming</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>20160129</creationdate><title>The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy</title><author>Yang, Lei ; Yu, Di ; Mo, Ran ; Zhang, Jiru ; Hua, Hu ; Hu, Liang ; Feng, Yu ; Wang, Song ; Zhang, Wei-Yan ; Yin, Ning ; Mo, Xu-Ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-8c37c86e927a1bc9776491c9e03b79323426f028302f2ee68aff4a2fbbecfd523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Androstadienes - pharmacology</topic><topic>Anesthesiology</topic><topic>Animals</topic><topic>Atrial Natriuretic Factor - genetics</topic><topic>Atrial Natriuretic Factor - metabolism</topic><topic>Banding</topic><topic>Biology and Life Sciences</topic><topic>Cancer</topic><topic>Cardiomyocytes</topic><topic>Cell receptors</topic><topic>Children & youth</topic><topic>Diabetes</topic><topic>Diagnosis</topic><topic>G protein-coupled receptors</topic><topic>Gene Expression Regulation</topic><topic>Genetic aspects</topic><topic>Genetic markers</topic><topic>Heart</topic><topic>Heart failure</topic><topic>Heart hypertrophy</topic><topic>Heart surgery</topic><topic>Heart Ventricles - metabolism</topic><topic>Heart Ventricles - pathology</topic><topic>Heart Ventricles - physiopathology</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Hypertension, Pulmonary - genetics</topic><topic>Hypertension, Pulmonary - metabolism</topic><topic>Hypertension, Pulmonary - pathology</topic><topic>Hypertension, Pulmonary - 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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>Yang, Lei</au><au>Yu, Di</au><au>Mo, Ran</au><au>Zhang, Jiru</au><au>Hua, Hu</au><au>Hu, Liang</au><au>Feng, Yu</au><au>Wang, Song</au><au>Zhang, Wei-Yan</au><au>Yin, Ning</au><au>Mo, Xu-Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-01-29</date><risdate>2016</risdate><volume>11</volume><issue>1</issue><spage>e0147597</spage><epage>e0147597</epage><pages>e0147597-e0147597</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown.
We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH.
Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26824665</pmid><doi>10.1371/journal.pone.0147597</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-01, Vol.11 (1), p.e0147597-e0147597 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1761243259 |
| 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 | 1-Phosphatidylinositol 3-kinase AKT protein Androstadienes - pharmacology Anesthesiology Animals Atrial Natriuretic Factor - genetics Atrial Natriuretic Factor - metabolism Banding Biology and Life Sciences Cancer Cardiomyocytes Cell receptors Children & youth Diabetes Diagnosis G protein-coupled receptors Gene Expression Regulation Genetic aspects Genetic markers Heart Heart failure Heart hypertrophy Heart surgery Heart Ventricles - metabolism Heart Ventricles - pathology Heart Ventricles - physiopathology Hospitals Humans Hypertension Hypertension, Pulmonary - genetics Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - pathology Hypertension, Pulmonary - physiopathology Hypertrophy Hypertrophy, Right Ventricular - genetics Hypertrophy, Right Ventricular - metabolism Hypertrophy, Right Ventricular - pathology Hypertrophy, Right Ventricular - physiopathology Kinases Medicine and Health Sciences Metabolism Metabolites Myocytes, Cardiac - cytology Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Physiological aspects Proteins Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Pulmonary arteries Pulmonary Artery - metabolism Pulmonary Artery - pathology Pulmonary Artery - surgery Pulmonary hypertension Rats Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Rodents Signal Transduction Signaling Stroke Volume Succinic Acid - metabolism Succinic Acid - pharmacology Ventricle Wortmannin |
| title | The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T07%3A59%3A43IST&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%20Succinate%20Receptor%20GPR91%20Is%20Involved%20in%20Pressure%20Overload-Induced%20Ventricular%20Hypertrophy&rft.jtitle=PloS%20one&rft.au=Yang,%20Lei&rft.date=2016-01-29&rft.volume=11&rft.issue=1&rft.spage=e0147597&rft.epage=e0147597&rft.pages=e0147597-e0147597&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0147597&rft_dat=%3Cgale_plos_%3EA441791388%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=1761243259&rft_id=info:pmid/26824665&rft_galeid=A441791388&rft_doaj_id=oai_doaj_org_article_d532722278ac4672be8c67b036e2f668&rfr_iscdi=true |