Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells

In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promo...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Experimental cell research 2009-06, Vol.315 (10), p.1779-1789
Hauptverfasser: Yamamichi, Nobutake, Inada, Ken-ichi, Furukawa, Chihiro, Sakurai, Kouhei, Tando, Toshio, Ishizaka, Aya, Haraguchi, Takeshi, Mizutani, Taketoshi, Fujishiro, Mitsuhiro, Shimomura, Ryoichi, Oka, Masashi, Ichinose, Masao, Tsutsumi, Yutaka, Omata, Masao, Iba, Hideo
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1789
container_issue 10
container_start_page 1779
container_title Experimental cell research
container_volume 315
creator Yamamichi, Nobutake
Inada, Ken-ichi
Furukawa, Chihiro
Sakurai, Kouhei
Tando, Toshio
Ishizaka, Aya
Haraguchi, Takeshi
Mizutani, Taketoshi
Fujishiro, Mitsuhiro
Shimomura, Ryoichi
Oka, Masashi
Ichinose, Masao
Tsutsumi, Yutaka
Omata, Masao
Iba, Hideo
description In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promoter of human villin. About 1.1 kb upstream of the determined major transcription start site, we identified a highly conserved region (HCR-Cdx) among mammals, which contains two binding sites for Cdx. Expression analyses of 30 human gastrointestinal cell lines suggested that villin is regulated by Cdx2. Introduction of Cdx family genes into colorectal SW480 cells revealed that villin is strongly induced strongly by Cdx2, moderately by Cdx1, and marginally by Cdx4. Knockdown of Cdx2 in SW480 cells caused a clear downregulation of villin, and reporter assays showed that HCR-Cdx is crucial for Cdx2-dependent and Brm-dependent villin expression. Immunohistochemical analyses of gastric intestinal metaplasia and cancer revealed that villin and Cdx2 expression are tightly coupled. GST pull-down assays demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits. Chromatin immunoprecipitation analyses showed the recruitment of Cdx2 and Brm around HCR-Cdx. From these results, we concluded that Cdx2 regulates intestinal villin expression through recruiting Brm-type SWI/SNF complex to the villin promoter.
doi_str_mv 10.1016/j.yexcr.2009.01.006
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67235740</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0014482709000329</els_id><sourcerecordid>67235740</sourcerecordid><originalsourceid>FETCH-LOGICAL-c450t-c5b9f0e177324f2157b04f8454642dc6ff15574bf5adffad64d18a9ea5cb79093</originalsourceid><addsrcrecordid>eNp9kU9r3DAQxUVpaTZpP0GhiB56szOSZck-9NAuTRoIzSEpPQpZHiVa_K-Svex--2q7C4UcchoGfvPm8R4hHxjkDJi83OR73NmQc4A6B5YDyFdkxaCGjAvOX5MVABOZqLg6I-cxbgCgqph8S85YXSgmC7EiT-t2x6kZWjo_If0W-mzeT0jvf99c3v-8onbspw53aY4TBjP7LXZ7GvBx6cyMdOu7zg8Ud1PAGP040LQ9mjiH0Q8zxtkPpqMWuy6-I2-c6SK-P80L8uvq-8P6R3Z7d32z_nqbWVHCnNmyqR0gU6rgwnFWqgaEq0QppOCtlc6xslSicaVpnTOtFC2rTI2mtI2qoS4uyOej7hTGP0uyoHsfDw7MgOMStVS8SAKQwE_PwM24hOQ3alYLqZQQMkHFEbJhjDGg01PwvQl7zUAfWtAb_a8FfWhBA9OphXT18SS9ND22_29OsSfgyxHAlMTWY9DRehwstj6gnXU7-hcf_AXEv5pg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>194677446</pqid></control><display><type>article</type><title>Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Yamamichi, Nobutake ; Inada, Ken-ichi ; Furukawa, Chihiro ; Sakurai, Kouhei ; Tando, Toshio ; Ishizaka, Aya ; Haraguchi, Takeshi ; Mizutani, Taketoshi ; Fujishiro, Mitsuhiro ; Shimomura, Ryoichi ; Oka, Masashi ; Ichinose, Masao ; Tsutsumi, Yutaka ; Omata, Masao ; Iba, Hideo</creator><creatorcontrib>Yamamichi, Nobutake ; Inada, Ken-ichi ; Furukawa, Chihiro ; Sakurai, Kouhei ; Tando, Toshio ; Ishizaka, Aya ; Haraguchi, Takeshi ; Mizutani, Taketoshi ; Fujishiro, Mitsuhiro ; Shimomura, Ryoichi ; Oka, Masashi ; Ichinose, Masao ; Tsutsumi, Yutaka ; Omata, Masao ; Iba, Hideo</creatorcontrib><description>In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promoter of human villin. About 1.1 kb upstream of the determined major transcription start site, we identified a highly conserved region (HCR-Cdx) among mammals, which contains two binding sites for Cdx. Expression analyses of 30 human gastrointestinal cell lines suggested that villin is regulated by Cdx2. Introduction of Cdx family genes into colorectal SW480 cells revealed that villin is strongly induced strongly by Cdx2, moderately by Cdx1, and marginally by Cdx4. Knockdown of Cdx2 in SW480 cells caused a clear downregulation of villin, and reporter assays showed that HCR-Cdx is crucial for Cdx2-dependent and Brm-dependent villin expression. Immunohistochemical analyses of gastric intestinal metaplasia and cancer revealed that villin and Cdx2 expression are tightly coupled. GST pull-down assays demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits. Chromatin immunoprecipitation analyses showed the recruitment of Cdx2 and Brm around HCR-Cdx. From these results, we concluded that Cdx2 regulates intestinal villin expression through recruiting Brm-type SWI/SNF complex to the villin promoter.</description><identifier>ISSN: 0014-4827</identifier><identifier>EISSN: 1090-2422</identifier><identifier>DOI: 10.1016/j.yexcr.2009.01.006</identifier><identifier>PMID: 19371634</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Base Sequence ; Binding Sites ; Blotting, Western ; Brm ; Cdx2 ; CDX2 Transcription Factor ; Cell Line, Tumor ; Cellular biology ; Chromatin Assembly and Disassembly ; Conserved Sequence ; Digestive system ; Gastric cancer ; Gastrointestinal Tract - cytology ; Gastrointestinal Tract - metabolism ; Gene expression ; Gene Expression Regulation ; Genes, Reporter ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Microfilament Proteins - genetics ; Molecular Sequence Data ; Promoter Regions, Genetic - genetics ; Protein Binding ; Protein Subunits - metabolism ; Proteins ; SWI/SNF complex ; Transcription Factors - metabolism ; Transcription Initiation Site ; Villin</subject><ispartof>Experimental cell research, 2009-06, Vol.315 (10), p.1779-1789</ispartof><rights>2009 Elsevier Inc.</rights><rights>Copyright © 2009 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-c5b9f0e177324f2157b04f8454642dc6ff15574bf5adffad64d18a9ea5cb79093</citedby><cites>FETCH-LOGICAL-c450t-c5b9f0e177324f2157b04f8454642dc6ff15574bf5adffad64d18a9ea5cb79093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0014482709000329$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19371634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamamichi, Nobutake</creatorcontrib><creatorcontrib>Inada, Ken-ichi</creatorcontrib><creatorcontrib>Furukawa, Chihiro</creatorcontrib><creatorcontrib>Sakurai, Kouhei</creatorcontrib><creatorcontrib>Tando, Toshio</creatorcontrib><creatorcontrib>Ishizaka, Aya</creatorcontrib><creatorcontrib>Haraguchi, Takeshi</creatorcontrib><creatorcontrib>Mizutani, Taketoshi</creatorcontrib><creatorcontrib>Fujishiro, Mitsuhiro</creatorcontrib><creatorcontrib>Shimomura, Ryoichi</creatorcontrib><creatorcontrib>Oka, Masashi</creatorcontrib><creatorcontrib>Ichinose, Masao</creatorcontrib><creatorcontrib>Tsutsumi, Yutaka</creatorcontrib><creatorcontrib>Omata, Masao</creatorcontrib><creatorcontrib>Iba, Hideo</creatorcontrib><title>Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells</title><title>Experimental cell research</title><addtitle>Exp Cell Res</addtitle><description>In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promoter of human villin. About 1.1 kb upstream of the determined major transcription start site, we identified a highly conserved region (HCR-Cdx) among mammals, which contains two binding sites for Cdx. Expression analyses of 30 human gastrointestinal cell lines suggested that villin is regulated by Cdx2. Introduction of Cdx family genes into colorectal SW480 cells revealed that villin is strongly induced strongly by Cdx2, moderately by Cdx1, and marginally by Cdx4. Knockdown of Cdx2 in SW480 cells caused a clear downregulation of villin, and reporter assays showed that HCR-Cdx is crucial for Cdx2-dependent and Brm-dependent villin expression. Immunohistochemical analyses of gastric intestinal metaplasia and cancer revealed that villin and Cdx2 expression are tightly coupled. GST pull-down assays demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits. Chromatin immunoprecipitation analyses showed the recruitment of Cdx2 and Brm around HCR-Cdx. From these results, we concluded that Cdx2 regulates intestinal villin expression through recruiting Brm-type SWI/SNF complex to the villin promoter.</description><subject>Base Sequence</subject><subject>Binding Sites</subject><subject>Blotting, Western</subject><subject>Brm</subject><subject>Cdx2</subject><subject>CDX2 Transcription Factor</subject><subject>Cell Line, Tumor</subject><subject>Cellular biology</subject><subject>Chromatin Assembly and Disassembly</subject><subject>Conserved Sequence</subject><subject>Digestive system</subject><subject>Gastric cancer</subject><subject>Gastrointestinal Tract - cytology</subject><subject>Gastrointestinal Tract - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genes, Reporter</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Microfilament Proteins - genetics</subject><subject>Molecular Sequence Data</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein Binding</subject><subject>Protein Subunits - metabolism</subject><subject>Proteins</subject><subject>SWI/SNF complex</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription Initiation Site</subject><subject>Villin</subject><issn>0014-4827</issn><issn>1090-2422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9r3DAQxUVpaTZpP0GhiB56szOSZck-9NAuTRoIzSEpPQpZHiVa_K-Svex--2q7C4UcchoGfvPm8R4hHxjkDJi83OR73NmQc4A6B5YDyFdkxaCGjAvOX5MVABOZqLg6I-cxbgCgqph8S85YXSgmC7EiT-t2x6kZWjo_If0W-mzeT0jvf99c3v-8onbspw53aY4TBjP7LXZ7GvBx6cyMdOu7zg8Ud1PAGP040LQ9mjiH0Q8zxtkPpqMWuy6-I2-c6SK-P80L8uvq-8P6R3Z7d32z_nqbWVHCnNmyqR0gU6rgwnFWqgaEq0QppOCtlc6xslSicaVpnTOtFC2rTI2mtI2qoS4uyOej7hTGP0uyoHsfDw7MgOMStVS8SAKQwE_PwM24hOQ3alYLqZQQMkHFEbJhjDGg01PwvQl7zUAfWtAb_a8FfWhBA9OphXT18SS9ND22_29OsSfgyxHAlMTWY9DRehwstj6gnXU7-hcf_AXEv5pg</recordid><startdate>20090610</startdate><enddate>20090610</enddate><creator>Yamamichi, Nobutake</creator><creator>Inada, Ken-ichi</creator><creator>Furukawa, Chihiro</creator><creator>Sakurai, Kouhei</creator><creator>Tando, Toshio</creator><creator>Ishizaka, Aya</creator><creator>Haraguchi, Takeshi</creator><creator>Mizutani, Taketoshi</creator><creator>Fujishiro, Mitsuhiro</creator><creator>Shimomura, Ryoichi</creator><creator>Oka, Masashi</creator><creator>Ichinose, Masao</creator><creator>Tsutsumi, Yutaka</creator><creator>Omata, Masao</creator><creator>Iba, Hideo</creator><general>Elsevier Inc</general><general>Elsevier BV</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>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20090610</creationdate><title>Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells</title><author>Yamamichi, Nobutake ; Inada, Ken-ichi ; Furukawa, Chihiro ; Sakurai, Kouhei ; Tando, Toshio ; Ishizaka, Aya ; Haraguchi, Takeshi ; Mizutani, Taketoshi ; Fujishiro, Mitsuhiro ; Shimomura, Ryoichi ; Oka, Masashi ; Ichinose, Masao ; Tsutsumi, Yutaka ; Omata, Masao ; Iba, Hideo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c450t-c5b9f0e177324f2157b04f8454642dc6ff15574bf5adffad64d18a9ea5cb79093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Base Sequence</topic><topic>Binding Sites</topic><topic>Blotting, Western</topic><topic>Brm</topic><topic>Cdx2</topic><topic>CDX2 Transcription Factor</topic><topic>Cell Line, Tumor</topic><topic>Cellular biology</topic><topic>Chromatin Assembly and Disassembly</topic><topic>Conserved Sequence</topic><topic>Digestive system</topic><topic>Gastric cancer</topic><topic>Gastrointestinal Tract - cytology</topic><topic>Gastrointestinal Tract - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genes, Reporter</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Microfilament Proteins - genetics</topic><topic>Molecular Sequence Data</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Protein Binding</topic><topic>Protein Subunits - metabolism</topic><topic>Proteins</topic><topic>SWI/SNF complex</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription Initiation Site</topic><topic>Villin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamamichi, Nobutake</creatorcontrib><creatorcontrib>Inada, Ken-ichi</creatorcontrib><creatorcontrib>Furukawa, Chihiro</creatorcontrib><creatorcontrib>Sakurai, Kouhei</creatorcontrib><creatorcontrib>Tando, Toshio</creatorcontrib><creatorcontrib>Ishizaka, Aya</creatorcontrib><creatorcontrib>Haraguchi, Takeshi</creatorcontrib><creatorcontrib>Mizutani, Taketoshi</creatorcontrib><creatorcontrib>Fujishiro, Mitsuhiro</creatorcontrib><creatorcontrib>Shimomura, Ryoichi</creatorcontrib><creatorcontrib>Oka, Masashi</creatorcontrib><creatorcontrib>Ichinose, Masao</creatorcontrib><creatorcontrib>Tsutsumi, Yutaka</creatorcontrib><creatorcontrib>Omata, Masao</creatorcontrib><creatorcontrib>Iba, Hideo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental cell research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamamichi, Nobutake</au><au>Inada, Ken-ichi</au><au>Furukawa, Chihiro</au><au>Sakurai, Kouhei</au><au>Tando, Toshio</au><au>Ishizaka, Aya</au><au>Haraguchi, Takeshi</au><au>Mizutani, Taketoshi</au><au>Fujishiro, Mitsuhiro</au><au>Shimomura, Ryoichi</au><au>Oka, Masashi</au><au>Ichinose, Masao</au><au>Tsutsumi, Yutaka</au><au>Omata, Masao</au><au>Iba, Hideo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells</atitle><jtitle>Experimental cell research</jtitle><addtitle>Exp Cell Res</addtitle><date>2009-06-10</date><risdate>2009</risdate><volume>315</volume><issue>10</issue><spage>1779</spage><epage>1789</epage><pages>1779-1789</pages><issn>0014-4827</issn><eissn>1090-2422</eissn><abstract>In our recent study showing a correlation between Brm-deficiency and undifferentiated status of gastric cancer, we found that the Brm-type SWI/SNF complex is required for villin expression. To elucidate intestinal villin regulation more precisely, we here analyzed structure and function of the promoter of human villin. About 1.1 kb upstream of the determined major transcription start site, we identified a highly conserved region (HCR-Cdx) among mammals, which contains two binding sites for Cdx. Expression analyses of 30 human gastrointestinal cell lines suggested that villin is regulated by Cdx2. Introduction of Cdx family genes into colorectal SW480 cells revealed that villin is strongly induced strongly by Cdx2, moderately by Cdx1, and marginally by Cdx4. Knockdown of Cdx2 in SW480 cells caused a clear downregulation of villin, and reporter assays showed that HCR-Cdx is crucial for Cdx2-dependent and Brm-dependent villin expression. Immunohistochemical analyses of gastric intestinal metaplasia and cancer revealed that villin and Cdx2 expression are tightly coupled. GST pull-down assays demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits. Chromatin immunoprecipitation analyses showed the recruitment of Cdx2 and Brm around HCR-Cdx. From these results, we concluded that Cdx2 regulates intestinal villin expression through recruiting Brm-type SWI/SNF complex to the villin promoter.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19371634</pmid><doi>10.1016/j.yexcr.2009.01.006</doi><tpages>11</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0014-4827
ispartof Experimental cell research, 2009-06, Vol.315 (10), p.1779-1789
issn 0014-4827
1090-2422
language eng
recordid cdi_proquest_miscellaneous_67235740
source MEDLINE; Elsevier ScienceDirect Journals
subjects Base Sequence
Binding Sites
Blotting, Western
Brm
Cdx2
CDX2 Transcription Factor
Cell Line, Tumor
Cellular biology
Chromatin Assembly and Disassembly
Conserved Sequence
Digestive system
Gastric cancer
Gastrointestinal Tract - cytology
Gastrointestinal Tract - metabolism
Gene expression
Gene Expression Regulation
Genes, Reporter
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Microfilament Proteins - genetics
Molecular Sequence Data
Promoter Regions, Genetic - genetics
Protein Binding
Protein Subunits - metabolism
Proteins
SWI/SNF complex
Transcription Factors - metabolism
Transcription Initiation Site
Villin
title Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T18%3A16%3A30IST&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=Cdx2%20and%20the%20Brm-type%20SWI/SNF%20complex%20cooperatively%20regulate%20villin%20expression%20in%20gastrointestinal%20cells&rft.jtitle=Experimental%20cell%20research&rft.au=Yamamichi,%20Nobutake&rft.date=2009-06-10&rft.volume=315&rft.issue=10&rft.spage=1779&rft.epage=1789&rft.pages=1779-1789&rft.issn=0014-4827&rft.eissn=1090-2422&rft_id=info:doi/10.1016/j.yexcr.2009.01.006&rft_dat=%3Cproquest_cross%3E67235740%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=194677446&rft_id=info:pmid/19371634&rft_els_id=S0014482709000329&rfr_iscdi=true