Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates

Mechanical forces play a major role in the regulation of cell adhesion and cytoskeletal organization. In order to explore the molecular mechanism underlying this regulation, we have investigated the relationship between local force applied by the cell to the substrate and the assembly of focal adhes...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature cell biology 2001-05, Vol.3 (5), p.466-472
Hauptverfasser: Balaban, Nathalie Q., Schwarz, Ulrich S., Riveline, Daniel, Goichberg, Polina, Tzur, Gila, Sabanay, Ilana, Mahalu, Diana, Safran, Sam, Bershadsky, Alexander, Addadi, Lia, Geiger, Benjamin
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 472
container_issue 5
container_start_page 466
container_title Nature cell biology
container_volume 3
creator Balaban, Nathalie Q.
Schwarz, Ulrich S.
Riveline, Daniel
Goichberg, Polina
Tzur, Gila
Sabanay, Ilana
Mahalu, Diana
Safran, Sam
Bershadsky, Alexander
Addadi, Lia
Geiger, Benjamin
description Mechanical forces play a major role in the regulation of cell adhesion and cytoskeletal organization. In order to explore the molecular mechanism underlying this regulation, we have investigated the relationship between local force applied by the cell to the substrate and the assembly of focal adhesions. A novel approach was developed for real-time, high-resolution measurements of forces applied by cells at single adhesion sites. This method combines micropatterning of elastomer substrates and fluorescence imaging of focal adhesions in live cells expressing GFP-tagged vinculin. Local forces are correlated with the orientation, total fluorescence intensity and area of the focal adhesions, indicating a constant stress of 5.5 ± 2 nNμm-2. The dynamics of the force-dependent modulation of focal adhesions were characterized by blocking actomyosin contractility and were found to be on a time scale of seconds. The results put clear constraints on the possible molecular mechanisms for the mechanosensory response of focal adhesions to applied force.
doi_str_mv 10.1038/35074532
format Article
fullrecord <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_70810531</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A183279952</galeid><sourcerecordid>A183279952</sourcerecordid><originalsourceid>FETCH-LOGICAL-c507t-4674f4f6dea0d3c14c6a94a8f78429bdb28ea981e72064c364ba54c671590a133</originalsourceid><addsrcrecordid>eNptkV1rFDEUhgdRbK2Cv0CCgujF1nzNZKZ3pdhaKBSqXoczmTPTlJnJmpMB--_NsivLWslFQt7nfLznFMVbwU8FV_UXVXKjSyWfFcdCm2qlK9M837yrcmVUI4-KV0QPnAutuXlZHAmhlKiNPi6GyxAdMpg71gcHI4PuHsmHmQERTu34eMaAuTEQsogjpCzRvV8zSkvnsWML-XlgWaHkHZu8i2ENKWGcs0hLSylCQnpdvOhhJHyzu0-Kn5dff1x8W93cXl1fnN-sXLaQNo3rXvdVh8A75YR2FTQa6t7UWjZt18oaoakFGskr7VSlWygzZETZcMiuToqP27zrGH4tSMlOnhyOI8wYFrKG14KXSmTw_T_gQ1jinHuzUkpVG6V4hj5soQFGtH7uQ3bjNhntuaiVNE1Tykyd_ofKp8M8jzBj7_P_QcDng4DMJPydBliI7PX3u0P205bNgyWK2Nt19BPERyu43Szf_l1-Rt_tLC3thN0e3G17X5eyNA8Y956fJPsDrCGzzQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>222387330</pqid></control><display><type>article</type><title>Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Nature Journals Online</source><creator>Balaban, Nathalie Q. ; Schwarz, Ulrich S. ; Riveline, Daniel ; Goichberg, Polina ; Tzur, Gila ; Sabanay, Ilana ; Mahalu, Diana ; Safran, Sam ; Bershadsky, Alexander ; Addadi, Lia ; Geiger, Benjamin</creator><creatorcontrib>Balaban, Nathalie Q. ; Schwarz, Ulrich S. ; Riveline, Daniel ; Goichberg, Polina ; Tzur, Gila ; Sabanay, Ilana ; Mahalu, Diana ; Safran, Sam ; Bershadsky, Alexander ; Addadi, Lia ; Geiger, Benjamin</creatorcontrib><description>Mechanical forces play a major role in the regulation of cell adhesion and cytoskeletal organization. In order to explore the molecular mechanism underlying this regulation, we have investigated the relationship between local force applied by the cell to the substrate and the assembly of focal adhesions. A novel approach was developed for real-time, high-resolution measurements of forces applied by cells at single adhesion sites. This method combines micropatterning of elastomer substrates and fluorescence imaging of focal adhesions in live cells expressing GFP-tagged vinculin. Local forces are correlated with the orientation, total fluorescence intensity and area of the focal adhesions, indicating a constant stress of 5.5 ± 2 nNμm-2. The dynamics of the force-dependent modulation of focal adhesions were characterized by blocking actomyosin contractility and were found to be on a time scale of seconds. The results put clear constraints on the possible molecular mechanisms for the mechanosensory response of focal adhesions to applied force.</description><identifier>ISSN: 1465-7392</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/35074532</identifier><identifier>PMID: 11331874</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Adhesion ; Animals ; Biology ; Biomedical and Life Sciences ; Cancer Research ; Cell Adhesion ; Cell adhesion &amp; migration ; Cell adhesion molecules ; Cell Biology ; Cells, Cultured ; Developmental Biology ; Diagnostic Imaging - methods ; Elastomers - metabolism ; Fibroblasts ; Fibroblasts - ultrastructure ; Fluorescence ; Focal Adhesions - metabolism ; Green Fluorescent Proteins ; Humans ; Life Sciences ; Luminescent Proteins - metabolism ; Microscopy ; Microscopy, Electron ; Microscopy, Fluorescence ; Microscopy, Phase-Contrast ; Morphogenesis ; Myocardium - cytology ; Physiological aspects ; Rats ; Recombinant Fusion Proteins - metabolism ; Semiconductor research ; Space life sciences ; Stem Cells ; Stress, Mechanical ; Substrates ; Time Factors ; Vinculin - metabolism</subject><ispartof>Nature cell biology, 2001-05, Vol.3 (5), p.466-472</ispartof><rights>Springer Nature Limited 2001</rights><rights>COPYRIGHT 2001 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c507t-4674f4f6dea0d3c14c6a94a8f78429bdb28ea981e72064c364ba54c671590a133</citedby><cites>FETCH-LOGICAL-c507t-4674f4f6dea0d3c14c6a94a8f78429bdb28ea981e72064c364ba54c671590a133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/35074532$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/35074532$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11331874$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Balaban, Nathalie Q.</creatorcontrib><creatorcontrib>Schwarz, Ulrich S.</creatorcontrib><creatorcontrib>Riveline, Daniel</creatorcontrib><creatorcontrib>Goichberg, Polina</creatorcontrib><creatorcontrib>Tzur, Gila</creatorcontrib><creatorcontrib>Sabanay, Ilana</creatorcontrib><creatorcontrib>Mahalu, Diana</creatorcontrib><creatorcontrib>Safran, Sam</creatorcontrib><creatorcontrib>Bershadsky, Alexander</creatorcontrib><creatorcontrib>Addadi, Lia</creatorcontrib><creatorcontrib>Geiger, Benjamin</creatorcontrib><title>Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates</title><title>Nature cell biology</title><addtitle>Nat Cell Biol</addtitle><addtitle>Nat Cell Biol</addtitle><description>Mechanical forces play a major role in the regulation of cell adhesion and cytoskeletal organization. In order to explore the molecular mechanism underlying this regulation, we have investigated the relationship between local force applied by the cell to the substrate and the assembly of focal adhesions. A novel approach was developed for real-time, high-resolution measurements of forces applied by cells at single adhesion sites. This method combines micropatterning of elastomer substrates and fluorescence imaging of focal adhesions in live cells expressing GFP-tagged vinculin. Local forces are correlated with the orientation, total fluorescence intensity and area of the focal adhesions, indicating a constant stress of 5.5 ± 2 nNμm-2. The dynamics of the force-dependent modulation of focal adhesions were characterized by blocking actomyosin contractility and were found to be on a time scale of seconds. The results put clear constraints on the possible molecular mechanisms for the mechanosensory response of focal adhesions to applied force.</description><subject>Adhesion</subject><subject>Animals</subject><subject>Biology</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer Research</subject><subject>Cell Adhesion</subject><subject>Cell adhesion &amp; migration</subject><subject>Cell adhesion molecules</subject><subject>Cell Biology</subject><subject>Cells, Cultured</subject><subject>Developmental Biology</subject><subject>Diagnostic Imaging - methods</subject><subject>Elastomers - metabolism</subject><subject>Fibroblasts</subject><subject>Fibroblasts - ultrastructure</subject><subject>Fluorescence</subject><subject>Focal Adhesions - metabolism</subject><subject>Green Fluorescent Proteins</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Luminescent Proteins - metabolism</subject><subject>Microscopy</subject><subject>Microscopy, Electron</subject><subject>Microscopy, Fluorescence</subject><subject>Microscopy, Phase-Contrast</subject><subject>Morphogenesis</subject><subject>Myocardium - cytology</subject><subject>Physiological aspects</subject><subject>Rats</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Semiconductor research</subject><subject>Space life sciences</subject><subject>Stem Cells</subject><subject>Stress, Mechanical</subject><subject>Substrates</subject><subject>Time Factors</subject><subject>Vinculin - metabolism</subject><issn>1465-7392</issn><issn>1476-4679</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkV1rFDEUhgdRbK2Cv0CCgujF1nzNZKZ3pdhaKBSqXoczmTPTlJnJmpMB--_NsivLWslFQt7nfLznFMVbwU8FV_UXVXKjSyWfFcdCm2qlK9M837yrcmVUI4-KV0QPnAutuXlZHAmhlKiNPi6GyxAdMpg71gcHI4PuHsmHmQERTu34eMaAuTEQsogjpCzRvV8zSkvnsWML-XlgWaHkHZu8i2ENKWGcs0hLSylCQnpdvOhhJHyzu0-Kn5dff1x8W93cXl1fnN-sXLaQNo3rXvdVh8A75YR2FTQa6t7UWjZt18oaoakFGskr7VSlWygzZETZcMiuToqP27zrGH4tSMlOnhyOI8wYFrKG14KXSmTw_T_gQ1jinHuzUkpVG6V4hj5soQFGtH7uQ3bjNhntuaiVNE1Tykyd_ofKp8M8jzBj7_P_QcDng4DMJPydBliI7PX3u0P205bNgyWK2Nt19BPERyu43Szf_l1-Rt_tLC3thN0e3G17X5eyNA8Y956fJPsDrCGzzQ</recordid><startdate>20010501</startdate><enddate>20010501</enddate><creator>Balaban, Nathalie Q.</creator><creator>Schwarz, Ulrich S.</creator><creator>Riveline, Daniel</creator><creator>Goichberg, Polina</creator><creator>Tzur, Gila</creator><creator>Sabanay, Ilana</creator><creator>Mahalu, Diana</creator><creator>Safran, Sam</creator><creator>Bershadsky, Alexander</creator><creator>Addadi, Lia</creator><creator>Geiger, Benjamin</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</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>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20010501</creationdate><title>Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates</title><author>Balaban, Nathalie Q. ; Schwarz, Ulrich S. ; Riveline, Daniel ; Goichberg, Polina ; Tzur, Gila ; Sabanay, Ilana ; Mahalu, Diana ; Safran, Sam ; Bershadsky, Alexander ; Addadi, Lia ; Geiger, Benjamin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c507t-4674f4f6dea0d3c14c6a94a8f78429bdb28ea981e72064c364ba54c671590a133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adhesion</topic><topic>Animals</topic><topic>Biology</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer Research</topic><topic>Cell Adhesion</topic><topic>Cell adhesion &amp; migration</topic><topic>Cell adhesion molecules</topic><topic>Cell Biology</topic><topic>Cells, Cultured</topic><topic>Developmental Biology</topic><topic>Diagnostic Imaging - methods</topic><topic>Elastomers - metabolism</topic><topic>Fibroblasts</topic><topic>Fibroblasts - ultrastructure</topic><topic>Fluorescence</topic><topic>Focal Adhesions - metabolism</topic><topic>Green Fluorescent Proteins</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Luminescent Proteins - metabolism</topic><topic>Microscopy</topic><topic>Microscopy, Electron</topic><topic>Microscopy, Fluorescence</topic><topic>Microscopy, Phase-Contrast</topic><topic>Morphogenesis</topic><topic>Myocardium - cytology</topic><topic>Physiological aspects</topic><topic>Rats</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Semiconductor research</topic><topic>Space life sciences</topic><topic>Stem Cells</topic><topic>Stress, Mechanical</topic><topic>Substrates</topic><topic>Time Factors</topic><topic>Vinculin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Balaban, Nathalie Q.</creatorcontrib><creatorcontrib>Schwarz, Ulrich S.</creatorcontrib><creatorcontrib>Riveline, Daniel</creatorcontrib><creatorcontrib>Goichberg, Polina</creatorcontrib><creatorcontrib>Tzur, Gila</creatorcontrib><creatorcontrib>Sabanay, Ilana</creatorcontrib><creatorcontrib>Mahalu, Diana</creatorcontrib><creatorcontrib>Safran, Sam</creatorcontrib><creatorcontrib>Bershadsky, Alexander</creatorcontrib><creatorcontrib>Addadi, Lia</creatorcontrib><creatorcontrib>Geiger, Benjamin</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: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech 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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</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 &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Balaban, Nathalie Q.</au><au>Schwarz, Ulrich S.</au><au>Riveline, Daniel</au><au>Goichberg, Polina</au><au>Tzur, Gila</au><au>Sabanay, Ilana</au><au>Mahalu, Diana</au><au>Safran, Sam</au><au>Bershadsky, Alexander</au><au>Addadi, Lia</au><au>Geiger, Benjamin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates</atitle><jtitle>Nature cell biology</jtitle><stitle>Nat Cell Biol</stitle><addtitle>Nat Cell Biol</addtitle><date>2001-05-01</date><risdate>2001</risdate><volume>3</volume><issue>5</issue><spage>466</spage><epage>472</epage><pages>466-472</pages><issn>1465-7392</issn><eissn>1476-4679</eissn><abstract>Mechanical forces play a major role in the regulation of cell adhesion and cytoskeletal organization. In order to explore the molecular mechanism underlying this regulation, we have investigated the relationship between local force applied by the cell to the substrate and the assembly of focal adhesions. A novel approach was developed for real-time, high-resolution measurements of forces applied by cells at single adhesion sites. This method combines micropatterning of elastomer substrates and fluorescence imaging of focal adhesions in live cells expressing GFP-tagged vinculin. Local forces are correlated with the orientation, total fluorescence intensity and area of the focal adhesions, indicating a constant stress of 5.5 ± 2 nNμm-2. The dynamics of the force-dependent modulation of focal adhesions were characterized by blocking actomyosin contractility and were found to be on a time scale of seconds. The results put clear constraints on the possible molecular mechanisms for the mechanosensory response of focal adhesions to applied force.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>11331874</pmid><doi>10.1038/35074532</doi><tpages>7</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1465-7392
ispartof Nature cell biology, 2001-05, Vol.3 (5), p.466-472
issn 1465-7392
1476-4679
language eng
recordid cdi_proquest_miscellaneous_70810531
source MEDLINE; SpringerLink Journals; Nature Journals Online
subjects Adhesion
Animals
Biology
Biomedical and Life Sciences
Cancer Research
Cell Adhesion
Cell adhesion & migration
Cell adhesion molecules
Cell Biology
Cells, Cultured
Developmental Biology
Diagnostic Imaging - methods
Elastomers - metabolism
Fibroblasts
Fibroblasts - ultrastructure
Fluorescence
Focal Adhesions - metabolism
Green Fluorescent Proteins
Humans
Life Sciences
Luminescent Proteins - metabolism
Microscopy
Microscopy, Electron
Microscopy, Fluorescence
Microscopy, Phase-Contrast
Morphogenesis
Myocardium - cytology
Physiological aspects
Rats
Recombinant Fusion Proteins - metabolism
Semiconductor research
Space life sciences
Stem Cells
Stress, Mechanical
Substrates
Time Factors
Vinculin - metabolism
title Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T04%3A09%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Force%20and%20focal%20adhesion%20assembly:%20a%20close%20relationship%20studied%20using%20elastic%20micropatterned%20substrates&rft.jtitle=Nature%20cell%20biology&rft.au=Balaban,%20Nathalie%20Q.&rft.date=2001-05-01&rft.volume=3&rft.issue=5&rft.spage=466&rft.epage=472&rft.pages=466-472&rft.issn=1465-7392&rft.eissn=1476-4679&rft_id=info:doi/10.1038/35074532&rft_dat=%3Cgale_proqu%3EA183279952%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=222387330&rft_id=info:pmid/11331874&rft_galeid=A183279952&rfr_iscdi=true