Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice

Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx‐1, Msx‐2, and Dlx‐2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late fo...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of bone and mineral research 2000-03, Vol.15 (3), p.430-441
Hauptverfasser: Lézot, F., Thomas, B., Hotton, D., Forest, N., Orestes‐Cardoso, S., Robert, B., Sharpe, P., Berdal, A.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 441
container_issue 3
container_start_page 430
container_title Journal of bone and mineral research
container_volume 15
creator Lézot, F.
Thomas, B.
Hotton, D.
Forest, N.
Orestes‐Cardoso, S.
Robert, B.
Sharpe, P.
Berdal, A.
description Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx‐1, Msx‐2, and Dlx‐2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx‐2 and Dlx‐2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx‐2 and Msx‐1 were used to detect different components of the gene expression patterns with the sensitive β‐galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx‐2, with stage‐specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx‐2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx‐2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site‐specific manner as shown here for Dlx‐2.
doi_str_mv 10.1359/jbmr.2000.15.3.430
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70994876</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17564682</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4806-955b6a49c52b24e6fe5e27c87948889481738832df1646356ff42de5c7fdb2223</originalsourceid><addsrcrecordid>eNqNkctu1DAYRi0EokPhBVggLxArMvgeZ4NEh9KCZlQJBomd5SS_wVUSD3ZGvaz6CH1GngRHGQl2sPFFOt_x5UPoOSVLymX15rLu45IRkrdyyZeCkwdoQSXjhVCaPkQLorUoiOD0CD1J6TKTSir1GB1RUkoiZblA9yc-9H6AaDt_a0cfhtd47R38urvf-h5wcPiiDcMYvsPgG7yCrkvYDi1-752DCMPobYdPr3cRUsrpKTD-ALy9Cvg89BDqcI3PYICEN1--ZSud0-tpzbAf8DbaIc32jW_gKXrkbJfg2WE-Rl8_nG5X58X64uzj6t26aIQmqqikrJUVVSNZzQQoBxJY2eiyElrrPNCSa81Z66gSikvlnGAtyKZ0bc0Y48fo1ezdxfBzD2k0vU9Nfp4dIOyTKUmVLaX6J0hLmU_Qk5HNYBNDShGc2UXf23hjKDFTYWYqzEyFGSoNN7mwHHpxsO_rHtq_InNDGXh5AGxqbOfybzU-_eFYpRibbvl2xq58Bzf_cbL5dLL5LJUkVBJOFP8N-vyzYQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17564682</pqid></control><display><type>article</type><title>Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Access via Wiley Online Library</source><source>Oxford University Press Journals All Titles (1996-Current)</source><creator>Lézot, F. ; Thomas, B. ; Hotton, D. ; Forest, N. ; Orestes‐Cardoso, S. ; Robert, B. ; Sharpe, P. ; Berdal, A.</creator><creatorcontrib>Lézot, F. ; Thomas, B. ; Hotton, D. ; Forest, N. ; Orestes‐Cardoso, S. ; Robert, B. ; Sharpe, P. ; Berdal, A.</creatorcontrib><description>Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx‐1, Msx‐2, and Dlx‐2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx‐2 and Dlx‐2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx‐2 and Msx‐1 were used to detect different components of the gene expression patterns with the sensitive β‐galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx‐2, with stage‐specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx‐2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx‐2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site‐specific manner as shown here for Dlx‐2.</description><identifier>ISSN: 0884-0431</identifier><identifier>EISSN: 1523-4681</identifier><identifier>DOI: 10.1359/jbmr.2000.15.3.430</identifier><identifier>PMID: 10750557</identifier><identifier>CODEN: JBMREJ</identifier><language>eng</language><publisher>Washington, DC: John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)</publisher><subject>Animals ; beta-Galactosidase - analysis ; beta-Galactosidase - biosynthesis ; Biological and medical sciences ; Dental Enamel - metabolism ; Dentin - metabolism ; Dlx ; Dlx-2 gene ; DNA-Binding Proteins - biosynthesis ; DNA-Binding Proteins - genetics ; Epithelial Cells - metabolism ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation, Developmental ; Genes, Homeobox ; homeobox genes ; Homeodomain Proteins - biosynthesis ; Homeodomain Proteins - genetics ; Incisor - embryology ; Incisor - growth &amp; development ; Incisor - metabolism ; Lac Operon ; Mesoderm - metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; mineralization ; Minerals - metabolism ; morphogenesis ; Morphogenesis - genetics ; Mouth. Exocrine and endocrine salivary glands. Teeth. Esophagus ; Msx ; Msx1 gene ; MSX1 Transcription Factor ; Odontogenesis - genetics ; Transcription Factors ; Transgenes ; Vertebrates: digestive system</subject><ispartof>Journal of bone and mineral research, 2000-03, Vol.15 (3), p.430-441</ispartof><rights>Copyright © 2000 ASBMR</rights><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4806-955b6a49c52b24e6fe5e27c87948889481738832df1646356ff42de5c7fdb2223</citedby><cites>FETCH-LOGICAL-c4806-955b6a49c52b24e6fe5e27c87948889481738832df1646356ff42de5c7fdb2223</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1359%2Fjbmr.2000.15.3.430$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1359%2Fjbmr.2000.15.3.430$$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&amp;idt=1296226$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10750557$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lézot, F.</creatorcontrib><creatorcontrib>Thomas, B.</creatorcontrib><creatorcontrib>Hotton, D.</creatorcontrib><creatorcontrib>Forest, N.</creatorcontrib><creatorcontrib>Orestes‐Cardoso, S.</creatorcontrib><creatorcontrib>Robert, B.</creatorcontrib><creatorcontrib>Sharpe, P.</creatorcontrib><creatorcontrib>Berdal, A.</creatorcontrib><title>Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice</title><title>Journal of bone and mineral research</title><addtitle>J Bone Miner Res</addtitle><description>Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx‐1, Msx‐2, and Dlx‐2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx‐2 and Dlx‐2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx‐2 and Msx‐1 were used to detect different components of the gene expression patterns with the sensitive β‐galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx‐2, with stage‐specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx‐2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx‐2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site‐specific manner as shown here for Dlx‐2.</description><subject>Animals</subject><subject>beta-Galactosidase - analysis</subject><subject>beta-Galactosidase - biosynthesis</subject><subject>Biological and medical sciences</subject><subject>Dental Enamel - metabolism</subject><subject>Dentin - metabolism</subject><subject>Dlx</subject><subject>Dlx-2 gene</subject><subject>DNA-Binding Proteins - biosynthesis</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Epithelial Cells - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Genes, Homeobox</subject><subject>homeobox genes</subject><subject>Homeodomain Proteins - biosynthesis</subject><subject>Homeodomain Proteins - genetics</subject><subject>Incisor - embryology</subject><subject>Incisor - growth &amp; development</subject><subject>Incisor - metabolism</subject><subject>Lac Operon</subject><subject>Mesoderm - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>mineralization</subject><subject>Minerals - metabolism</subject><subject>morphogenesis</subject><subject>Morphogenesis - genetics</subject><subject>Mouth. Exocrine and endocrine salivary glands. Teeth. Esophagus</subject><subject>Msx</subject><subject>Msx1 gene</subject><subject>MSX1 Transcription Factor</subject><subject>Odontogenesis - genetics</subject><subject>Transcription Factors</subject><subject>Transgenes</subject><subject>Vertebrates: digestive system</subject><issn>0884-0431</issn><issn>1523-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctu1DAYRi0EokPhBVggLxArMvgeZ4NEh9KCZlQJBomd5SS_wVUSD3ZGvaz6CH1GngRHGQl2sPFFOt_x5UPoOSVLymX15rLu45IRkrdyyZeCkwdoQSXjhVCaPkQLorUoiOD0CD1J6TKTSir1GB1RUkoiZblA9yc-9H6AaDt_a0cfhtd47R38urvf-h5wcPiiDcMYvsPgG7yCrkvYDi1-752DCMPobYdPr3cRUsrpKTD-ALy9Cvg89BDqcI3PYICEN1--ZSud0-tpzbAf8DbaIc32jW_gKXrkbJfg2WE-Rl8_nG5X58X64uzj6t26aIQmqqikrJUVVSNZzQQoBxJY2eiyElrrPNCSa81Z66gSikvlnGAtyKZ0bc0Y48fo1ezdxfBzD2k0vU9Nfp4dIOyTKUmVLaX6J0hLmU_Qk5HNYBNDShGc2UXf23hjKDFTYWYqzEyFGSoNN7mwHHpxsO_rHtq_InNDGXh5AGxqbOfybzU-_eFYpRibbvl2xq58Bzf_cbL5dLL5LJUkVBJOFP8N-vyzYQ</recordid><startdate>200003</startdate><enddate>200003</enddate><creator>Lézot, F.</creator><creator>Thomas, B.</creator><creator>Hotton, D.</creator><creator>Forest, N.</creator><creator>Orestes‐Cardoso, S.</creator><creator>Robert, B.</creator><creator>Sharpe, P.</creator><creator>Berdal, A.</creator><general>John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)</general><general>American Society for Bone and Mineral Research</general><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>7QP</scope><scope>7X8</scope></search><sort><creationdate>200003</creationdate><title>Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice</title><author>Lézot, F. ; Thomas, B. ; Hotton, D. ; Forest, N. ; Orestes‐Cardoso, S. ; Robert, B. ; Sharpe, P. ; Berdal, A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4806-955b6a49c52b24e6fe5e27c87948889481738832df1646356ff42de5c7fdb2223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>beta-Galactosidase - analysis</topic><topic>beta-Galactosidase - biosynthesis</topic><topic>Biological and medical sciences</topic><topic>Dental Enamel - metabolism</topic><topic>Dentin - metabolism</topic><topic>Dlx</topic><topic>Dlx-2 gene</topic><topic>DNA-Binding Proteins - biosynthesis</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Epithelial Cells - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression Regulation, Developmental</topic><topic>Genes, Homeobox</topic><topic>homeobox genes</topic><topic>Homeodomain Proteins - biosynthesis</topic><topic>Homeodomain Proteins - genetics</topic><topic>Incisor - embryology</topic><topic>Incisor - growth &amp; development</topic><topic>Incisor - metabolism</topic><topic>Lac Operon</topic><topic>Mesoderm - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>mineralization</topic><topic>Minerals - metabolism</topic><topic>morphogenesis</topic><topic>Morphogenesis - genetics</topic><topic>Mouth. Exocrine and endocrine salivary glands. Teeth. Esophagus</topic><topic>Msx</topic><topic>Msx1 gene</topic><topic>MSX1 Transcription Factor</topic><topic>Odontogenesis - genetics</topic><topic>Transcription Factors</topic><topic>Transgenes</topic><topic>Vertebrates: digestive system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lézot, F.</creatorcontrib><creatorcontrib>Thomas, B.</creatorcontrib><creatorcontrib>Hotton, D.</creatorcontrib><creatorcontrib>Forest, N.</creatorcontrib><creatorcontrib>Orestes‐Cardoso, S.</creatorcontrib><creatorcontrib>Robert, B.</creatorcontrib><creatorcontrib>Sharpe, P.</creatorcontrib><creatorcontrib>Berdal, A.</creatorcontrib><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>Calcium &amp; Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of bone and mineral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lézot, F.</au><au>Thomas, B.</au><au>Hotton, D.</au><au>Forest, N.</au><au>Orestes‐Cardoso, S.</au><au>Robert, B.</au><au>Sharpe, P.</au><au>Berdal, A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice</atitle><jtitle>Journal of bone and mineral research</jtitle><addtitle>J Bone Miner Res</addtitle><date>2000-03</date><risdate>2000</risdate><volume>15</volume><issue>3</issue><spage>430</spage><epage>441</epage><pages>430-441</pages><issn>0884-0431</issn><eissn>1523-4681</eissn><coden>JBMREJ</coden><abstract>Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx‐1, Msx‐2, and Dlx‐2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx‐2 and Dlx‐2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx‐2 and Msx‐1 were used to detect different components of the gene expression patterns with the sensitive β‐galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx‐2, with stage‐specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx‐2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx‐2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site‐specific manner as shown here for Dlx‐2.</abstract><cop>Washington, DC</cop><pub>John Wiley and Sons and The American Society for Bone and Mineral Research (ASBMR)</pub><pmid>10750557</pmid><doi>10.1359/jbmr.2000.15.3.430</doi><tpages>12</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0884-0431
ispartof Journal of bone and mineral research, 2000-03, Vol.15 (3), p.430-441
issn 0884-0431
1523-4681
language eng
recordid cdi_proquest_miscellaneous_70994876
source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via Wiley Online Library; Oxford University Press Journals All Titles (1996-Current)
subjects Animals
beta-Galactosidase - analysis
beta-Galactosidase - biosynthesis
Biological and medical sciences
Dental Enamel - metabolism
Dentin - metabolism
Dlx
Dlx-2 gene
DNA-Binding Proteins - biosynthesis
DNA-Binding Proteins - genetics
Epithelial Cells - metabolism
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Developmental
Genes, Homeobox
homeobox genes
Homeodomain Proteins - biosynthesis
Homeodomain Proteins - genetics
Incisor - embryology
Incisor - growth & development
Incisor - metabolism
Lac Operon
Mesoderm - metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
mineralization
Minerals - metabolism
morphogenesis
Morphogenesis - genetics
Mouth. Exocrine and endocrine salivary glands. Teeth. Esophagus
Msx
Msx1 gene
MSX1 Transcription Factor
Odontogenesis - genetics
Transcription Factors
Transgenes
Vertebrates: digestive system
title Biomineralization, Life‐Time of Odontogenic Cells and Differential Expression of the Two Homeobox Genes MSX‐1 and DLX‐2 in Transgenic Mice
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T02%3A08%3A31IST&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=Biomineralization,%20Life%E2%80%90Time%20of%20Odontogenic%20Cells%20and%20Differential%20Expression%20of%20the%20Two%20Homeobox%20Genes%20MSX%E2%80%901%20and%20DLX%E2%80%902%20in%20Transgenic%20Mice&rft.jtitle=Journal%20of%20bone%20and%20mineral%20research&rft.au=L%C3%A9zot,%20F.&rft.date=2000-03&rft.volume=15&rft.issue=3&rft.spage=430&rft.epage=441&rft.pages=430-441&rft.issn=0884-0431&rft.eissn=1523-4681&rft.coden=JBMREJ&rft_id=info:doi/10.1359/jbmr.2000.15.3.430&rft_dat=%3Cproquest_cross%3E17564682%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=17564682&rft_id=info:pmid/10750557&rfr_iscdi=true