Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions
Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments impl...
Gespeichert in:
Veröffentlicht in: | Proteomics (Weinheim) 2008-06, Vol.8 (12), p.2500-2513 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 2513 |
---|---|
container_issue | 12 |
container_start_page | 2500 |
container_title | Proteomics (Weinheim) |
container_volume | 8 |
creator | Di Girolamo, Francesco Raggi, Carla Birago, Cecilia Pizzi, Elisabetta Lalle, Marco Picci, Leonardo Pace, Tomasino Bachi, Angela de Jong, Joke Janse, Chris J Waters, Andrew P Sargiacomo, Massimo Ponzi, Marta |
description | Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments implicated in protein trafficking in Plasmodium-infected erythrocytes, the contribution of lipid-mediated sorting to this cellular process has been poorly investigated. In this study, we examined the proteome of cholesterol-rich membrane microdomains or lipid rafts, purified from erythrocytes infected by the rodent parasite Plasmodium berghei. Besides structural proteins associated with invasive forms, we detected chaperones, proteins implicated in vesicular trafficking, membrane fusion events and signalling. Interestingly, the raft proteome of mixed P. berghei blood stages included proteins encoded by members of a large family (bir) of putative variant antigens potentially implicated in host immune system interactions and targeted to the surface of the host erythrocytes. The generation of transgenic parasites expressing BIR/GFP fusions confirmed the dynamic association of members of this protein family with membrane microdomains. Our results indicated that lipid rafts in Plasmodium-infected erythrocytes might constitute a route to sort and fold parasite proteins directed to various host cell compartments including the cell surface. |
doi_str_mv | 10.1002/pmic.200700763 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_69242394</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69242394</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4353-de400a7e6527102d6b1c4e92b11ae02c9e2c94391b90d4e5f3d158deafcea573</originalsourceid><addsrcrecordid>eNqFkU2P0zAQhiMEYpfClSP4Aida_JHEzREVKJUWWMGycLOmzqRr1naC7bD01_HXcGlVEBckW7ZHz_vOeKYoHjI6Y5Ty54MzesYplXnV4lZxympWTZt5zW4f75U4Ke7F-JVSJueNvFucsHlVC1k2p8XPcwvR9a0ZHbFmMC0J0KVIdO8TGE-G0Cc0PhLjBms0JGxJDn_HaPRoIZCU-c7oa-M3BHxLotl4sPb3M5IbtHZ3OnRrDJH0HUlXSM5XH0gcBwwdOGO3z8iQs_hksnD7T6arPqYccqNHErcxocvRhAF0Mr2P94s7HdiIDw7npLh4_epi8WZ69n65Wrw4m-pSVGLaYkkpSKwrLhnlbb1musSGrxkDpFw3mHcpGrZuaFti1YmWVfMWodMIlRST4uneNvfj24gxKWeizp8Dj_0YVd3wkovsMClme1CHPsaAnRqCcRC2ilG1m5jaTUwdJ5YFjw7O49ph-wc_jCgDTw4ARA22C-C1iUeO07KWUswz1-y5G2Nx-5-06vztavF3EdO91uQG_zhqIVyrWgpZqc_vlmopX365lLxSl5l_vOc76BVsQq7n00dOmaC0Ydm0FL8ALiHN4w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69242394</pqid></control><display><type>article</type><title>Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions</title><source>Wiley-Blackwell Journals</source><source>MEDLINE</source><creator>Di Girolamo, Francesco ; Raggi, Carla ; Birago, Cecilia ; Pizzi, Elisabetta ; Lalle, Marco ; Picci, Leonardo ; Pace, Tomasino ; Bachi, Angela ; de Jong, Joke ; Janse, Chris J ; Waters, Andrew P ; Sargiacomo, Massimo ; Ponzi, Marta</creator><creatorcontrib>Di Girolamo, Francesco ; Raggi, Carla ; Birago, Cecilia ; Pizzi, Elisabetta ; Lalle, Marco ; Picci, Leonardo ; Pace, Tomasino ; Bachi, Angela ; de Jong, Joke ; Janse, Chris J ; Waters, Andrew P ; Sargiacomo, Massimo ; Ponzi, Marta</creatorcontrib><description>Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments implicated in protein trafficking in Plasmodium-infected erythrocytes, the contribution of lipid-mediated sorting to this cellular process has been poorly investigated. In this study, we examined the proteome of cholesterol-rich membrane microdomains or lipid rafts, purified from erythrocytes infected by the rodent parasite Plasmodium berghei. Besides structural proteins associated with invasive forms, we detected chaperones, proteins implicated in vesicular trafficking, membrane fusion events and signalling. Interestingly, the raft proteome of mixed P. berghei blood stages included proteins encoded by members of a large family (bir) of putative variant antigens potentially implicated in host immune system interactions and targeted to the surface of the host erythrocytes. The generation of transgenic parasites expressing BIR/GFP fusions confirmed the dynamic association of members of this protein family with membrane microdomains. Our results indicated that lipid rafts in Plasmodium-infected erythrocytes might constitute a route to sort and fold parasite proteins directed to various host cell compartments including the cell surface.</description><identifier>ISSN: 1615-9853</identifier><identifier>EISSN: 1615-9861</identifier><identifier>DOI: 10.1002/pmic.200700763</identifier><identifier>PMID: 18563749</identifier><language>eng</language><publisher>Weinheim: Wiley-VCH Verlag</publisher><subject>Analytical, structural and metabolic biochemistry ; Animals ; Antigens - genetics ; Antigens - immunology ; Biological and medical sciences ; Erythrocytes - metabolism ; Erythrocytes - parasitology ; Fundamental and applied biological sciences. Psychology ; Host-Parasite Interactions ; Humans ; Life Cycle Stages ; Lipid rafts ; Membrane Microdomains - chemistry ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; Miscellaneous ; Plasmodium ; Plasmodium - chemistry ; Plasmodium - genetics ; Plasmodium - metabolism ; Plasmodium - physiology ; Plasmodium berghei - genetics ; Plasmodium berghei - growth & development ; Plasmodium berghei - parasitology ; Protein Transport ; Proteins ; Proteomics - methods ; Protozoan Proteins - analysis ; Protozoan Proteins - metabolism ; Signal Transduction ; Transport Vesicles - metabolism ; Trypsin - pharmacology ; Vesicular trafficking</subject><ispartof>Proteomics (Weinheim), 2008-06, Vol.8 (12), p.2500-2513</ispartof><rights>Copyright © 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4353-de400a7e6527102d6b1c4e92b11ae02c9e2c94391b90d4e5f3d158deafcea573</citedby><cites>FETCH-LOGICAL-c4353-de400a7e6527102d6b1c4e92b11ae02c9e2c94391b90d4e5f3d158deafcea573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpmic.200700763$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpmic.200700763$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20467738$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18563749$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Girolamo, Francesco</creatorcontrib><creatorcontrib>Raggi, Carla</creatorcontrib><creatorcontrib>Birago, Cecilia</creatorcontrib><creatorcontrib>Pizzi, Elisabetta</creatorcontrib><creatorcontrib>Lalle, Marco</creatorcontrib><creatorcontrib>Picci, Leonardo</creatorcontrib><creatorcontrib>Pace, Tomasino</creatorcontrib><creatorcontrib>Bachi, Angela</creatorcontrib><creatorcontrib>de Jong, Joke</creatorcontrib><creatorcontrib>Janse, Chris J</creatorcontrib><creatorcontrib>Waters, Andrew P</creatorcontrib><creatorcontrib>Sargiacomo, Massimo</creatorcontrib><creatorcontrib>Ponzi, Marta</creatorcontrib><title>Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions</title><title>Proteomics (Weinheim)</title><addtitle>Proteomics</addtitle><description>Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments implicated in protein trafficking in Plasmodium-infected erythrocytes, the contribution of lipid-mediated sorting to this cellular process has been poorly investigated. In this study, we examined the proteome of cholesterol-rich membrane microdomains or lipid rafts, purified from erythrocytes infected by the rodent parasite Plasmodium berghei. Besides structural proteins associated with invasive forms, we detected chaperones, proteins implicated in vesicular trafficking, membrane fusion events and signalling. Interestingly, the raft proteome of mixed P. berghei blood stages included proteins encoded by members of a large family (bir) of putative variant antigens potentially implicated in host immune system interactions and targeted to the surface of the host erythrocytes. The generation of transgenic parasites expressing BIR/GFP fusions confirmed the dynamic association of members of this protein family with membrane microdomains. Our results indicated that lipid rafts in Plasmodium-infected erythrocytes might constitute a route to sort and fold parasite proteins directed to various host cell compartments including the cell surface.</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Antigens - genetics</subject><subject>Antigens - immunology</subject><subject>Biological and medical sciences</subject><subject>Erythrocytes - metabolism</subject><subject>Erythrocytes - parasitology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Host-Parasite Interactions</subject><subject>Humans</subject><subject>Life Cycle Stages</subject><subject>Lipid rafts</subject><subject>Membrane Microdomains - chemistry</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred Strains</subject><subject>Miscellaneous</subject><subject>Plasmodium</subject><subject>Plasmodium - chemistry</subject><subject>Plasmodium - genetics</subject><subject>Plasmodium - metabolism</subject><subject>Plasmodium - physiology</subject><subject>Plasmodium berghei - genetics</subject><subject>Plasmodium berghei - growth & development</subject><subject>Plasmodium berghei - parasitology</subject><subject>Protein Transport</subject><subject>Proteins</subject><subject>Proteomics - methods</subject><subject>Protozoan Proteins - analysis</subject><subject>Protozoan Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Transport Vesicles - metabolism</subject><subject>Trypsin - pharmacology</subject><subject>Vesicular trafficking</subject><issn>1615-9853</issn><issn>1615-9861</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU2P0zAQhiMEYpfClSP4Aida_JHEzREVKJUWWMGycLOmzqRr1naC7bD01_HXcGlVEBckW7ZHz_vOeKYoHjI6Y5Ty54MzesYplXnV4lZxympWTZt5zW4f75U4Ke7F-JVSJueNvFucsHlVC1k2p8XPcwvR9a0ZHbFmMC0J0KVIdO8TGE-G0Cc0PhLjBms0JGxJDn_HaPRoIZCU-c7oa-M3BHxLotl4sPb3M5IbtHZ3OnRrDJH0HUlXSM5XH0gcBwwdOGO3z8iQs_hksnD7T6arPqYccqNHErcxocvRhAF0Mr2P94s7HdiIDw7npLh4_epi8WZ69n65Wrw4m-pSVGLaYkkpSKwrLhnlbb1musSGrxkDpFw3mHcpGrZuaFti1YmWVfMWodMIlRST4uneNvfj24gxKWeizp8Dj_0YVd3wkovsMClme1CHPsaAnRqCcRC2ilG1m5jaTUwdJ5YFjw7O49ph-wc_jCgDTw4ARA22C-C1iUeO07KWUswz1-y5G2Nx-5-06vztavF3EdO91uQG_zhqIVyrWgpZqc_vlmopX365lLxSl5l_vOc76BVsQq7n00dOmaC0Ydm0FL8ALiHN4w</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Di Girolamo, Francesco</creator><creator>Raggi, Carla</creator><creator>Birago, Cecilia</creator><creator>Pizzi, Elisabetta</creator><creator>Lalle, Marco</creator><creator>Picci, Leonardo</creator><creator>Pace, Tomasino</creator><creator>Bachi, Angela</creator><creator>de Jong, Joke</creator><creator>Janse, Chris J</creator><creator>Waters, Andrew P</creator><creator>Sargiacomo, Massimo</creator><creator>Ponzi, Marta</creator><general>Wiley-VCH Verlag</general><general>WILEY-VCH Verlag</general><general>WILEY‐VCH Verlag</general><general>Wiley-VCH</general><scope>FBQ</scope><scope>BSCLL</scope><scope>IQODW</scope><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>7X8</scope></search><sort><creationdate>20080601</creationdate><title>Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions</title><author>Di Girolamo, Francesco ; Raggi, Carla ; Birago, Cecilia ; Pizzi, Elisabetta ; Lalle, Marco ; Picci, Leonardo ; Pace, Tomasino ; Bachi, Angela ; de Jong, Joke ; Janse, Chris J ; Waters, Andrew P ; Sargiacomo, Massimo ; Ponzi, Marta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4353-de400a7e6527102d6b1c4e92b11ae02c9e2c94391b90d4e5f3d158deafcea573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Antigens - genetics</topic><topic>Antigens - immunology</topic><topic>Biological and medical sciences</topic><topic>Erythrocytes - metabolism</topic><topic>Erythrocytes - parasitology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Host-Parasite Interactions</topic><topic>Humans</topic><topic>Life Cycle Stages</topic><topic>Lipid rafts</topic><topic>Membrane Microdomains - chemistry</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred Strains</topic><topic>Miscellaneous</topic><topic>Plasmodium</topic><topic>Plasmodium - chemistry</topic><topic>Plasmodium - genetics</topic><topic>Plasmodium - metabolism</topic><topic>Plasmodium - physiology</topic><topic>Plasmodium berghei - genetics</topic><topic>Plasmodium berghei - growth & development</topic><topic>Plasmodium berghei - parasitology</topic><topic>Protein Transport</topic><topic>Proteins</topic><topic>Proteomics - methods</topic><topic>Protozoan Proteins - analysis</topic><topic>Protozoan Proteins - metabolism</topic><topic>Signal Transduction</topic><topic>Transport Vesicles - metabolism</topic><topic>Trypsin - pharmacology</topic><topic>Vesicular trafficking</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Girolamo, Francesco</creatorcontrib><creatorcontrib>Raggi, Carla</creatorcontrib><creatorcontrib>Birago, Cecilia</creatorcontrib><creatorcontrib>Pizzi, Elisabetta</creatorcontrib><creatorcontrib>Lalle, Marco</creatorcontrib><creatorcontrib>Picci, Leonardo</creatorcontrib><creatorcontrib>Pace, Tomasino</creatorcontrib><creatorcontrib>Bachi, Angela</creatorcontrib><creatorcontrib>de Jong, Joke</creatorcontrib><creatorcontrib>Janse, Chris J</creatorcontrib><creatorcontrib>Waters, Andrew P</creatorcontrib><creatorcontrib>Sargiacomo, Massimo</creatorcontrib><creatorcontrib>Ponzi, Marta</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Proteomics (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Girolamo, Francesco</au><au>Raggi, Carla</au><au>Birago, Cecilia</au><au>Pizzi, Elisabetta</au><au>Lalle, Marco</au><au>Picci, Leonardo</au><au>Pace, Tomasino</au><au>Bachi, Angela</au><au>de Jong, Joke</au><au>Janse, Chris J</au><au>Waters, Andrew P</au><au>Sargiacomo, Massimo</au><au>Ponzi, Marta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions</atitle><jtitle>Proteomics (Weinheim)</jtitle><addtitle>Proteomics</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>8</volume><issue>12</issue><spage>2500</spage><epage>2513</epage><pages>2500-2513</pages><issn>1615-9853</issn><eissn>1615-9861</eissn><abstract>Plasmodium parasites, the causal agents of malaria, dramatically modify the infected erythrocyte by exporting parasite proteins into one or multiple erythrocyte compartments, the cytoplasm and the plasma membrane or beyond. Despite advances in defining signals and specific cellular compartments implicated in protein trafficking in Plasmodium-infected erythrocytes, the contribution of lipid-mediated sorting to this cellular process has been poorly investigated. In this study, we examined the proteome of cholesterol-rich membrane microdomains or lipid rafts, purified from erythrocytes infected by the rodent parasite Plasmodium berghei. Besides structural proteins associated with invasive forms, we detected chaperones, proteins implicated in vesicular trafficking, membrane fusion events and signalling. Interestingly, the raft proteome of mixed P. berghei blood stages included proteins encoded by members of a large family (bir) of putative variant antigens potentially implicated in host immune system interactions and targeted to the surface of the host erythrocytes. The generation of transgenic parasites expressing BIR/GFP fusions confirmed the dynamic association of members of this protein family with membrane microdomains. Our results indicated that lipid rafts in Plasmodium-infected erythrocytes might constitute a route to sort and fold parasite proteins directed to various host cell compartments including the cell surface.</abstract><cop>Weinheim</cop><pub>Wiley-VCH Verlag</pub><pmid>18563749</pmid><doi>10.1002/pmic.200700763</doi><tpages>14</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1615-9853 |
ispartof | Proteomics (Weinheim), 2008-06, Vol.8 (12), p.2500-2513 |
issn | 1615-9853 1615-9861 |
language | eng |
recordid | cdi_proquest_miscellaneous_69242394 |
source | Wiley-Blackwell Journals; MEDLINE |
subjects | Analytical, structural and metabolic biochemistry Animals Antigens - genetics Antigens - immunology Biological and medical sciences Erythrocytes - metabolism Erythrocytes - parasitology Fundamental and applied biological sciences. Psychology Host-Parasite Interactions Humans Life Cycle Stages Lipid rafts Membrane Microdomains - chemistry Mice Mice, Inbred BALB C Mice, Inbred Strains Miscellaneous Plasmodium Plasmodium - chemistry Plasmodium - genetics Plasmodium - metabolism Plasmodium - physiology Plasmodium berghei - genetics Plasmodium berghei - growth & development Plasmodium berghei - parasitology Protein Transport Proteins Proteomics - methods Protozoan Proteins - analysis Protozoan Proteins - metabolism Signal Transduction Transport Vesicles - metabolism Trypsin - pharmacology Vesicular trafficking |
title | Plasmodium lipid rafts contain proteins implicated in vesicular trafficking and signalling as well as members of the PIR superfamily, potentially implicated in host immune system interactions |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T21%3A21%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Plasmodium%20lipid%20rafts%20contain%20proteins%20implicated%20in%20vesicular%20trafficking%20and%20signalling%20as%20well%20as%20members%20of%20the%20PIR%20superfamily,%20potentially%20implicated%20in%20host%20immune%20system%20interactions&rft.jtitle=Proteomics%20(Weinheim)&rft.au=Di%20Girolamo,%20Francesco&rft.date=2008-06-01&rft.volume=8&rft.issue=12&rft.spage=2500&rft.epage=2513&rft.pages=2500-2513&rft.issn=1615-9853&rft.eissn=1615-9861&rft_id=info:doi/10.1002/pmic.200700763&rft_dat=%3Cproquest_cross%3E69242394%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=69242394&rft_id=info:pmid/18563749&rfr_iscdi=true |