Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia
Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present study was undertaken to investigate the eff...
Gespeichert in:
| Veröffentlicht in: | The Journal of biological chemistry 2002-10, Vol.277 (42), p.39312-39319 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 39319 |
|---|---|
| container_issue | 42 |
| container_start_page | 39312 |
| container_title | The Journal of biological chemistry |
| container_volume | 277 |
| creator | Liu, Xiaojuan Jana, Malabendu Dasgupta, Subhajit Koka, Sreenivas He, Jun Wood, Charles Pahan, Kalipada |
| description | Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion
of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present
study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia.
Expression of the tat gene as RSV- tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression
of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV- tat -induced NO production by anti-Tat antibodies suggest that RSV- tat -induced production of NO is dependent on Tat and that Tat is secreted from RSV- tat -transfected astroglia. Similar to U373MG astroglial cells, RSV- tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity
by the expression of RSV- tat suggests that RSV- tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-κB and
C/EBPβ, transcription factors responsible for the induction of iNOS. Activation of NF-κB as well as C/EBPβ by RSV- tat , stimulation of RSV- tat -induced production of NO by the wild type of p65 and C/EBPβ, and inhibition of RSV- tat -induced production of NO by Îp65, a dominant-negative mutant of p65, and ÎC/EBPβ, a dominant-negative mutant of C/EBPβ, suggest
that RSV- tat induces iNOS through the activation of NF-κB and C/EBPβ. In addition, we show that extracellular signal-regulated kinase
(ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV- tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and ÎERK2, a dominant-negative mutant
of ERK2, inhibited RSV- tat -induced production of NO through the inhibition of C/EBPβ but not that of NF-κB. This study illustrates a novel role for
HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia. |
| doi_str_mv | 10.1074/jbc.M205107200 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2041896</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>18495138</sourcerecordid><originalsourceid>FETCH-LOGICAL-c446t-3bc025240ff02a6896faa9a448720fc270fa35b818c3ef1708d587b9bc1688153</originalsourceid><addsrcrecordid>eNpVkUFv1DAQhS0EotvClSPyAaH2kMVjO4lzQaoq6K5U4MBScTOOY29cJfZiJ8D-e4x21dK5jEbzzZsZPYReAVkCqfm7u1YvP1FS5oIS8gQtgAhWsBK-P0ULQigUDS3FCTpN6Y7k4A08RydAoaoraBbox2oelcfrcZx96Ix12hmv9_jWxTnhzX5nMODz1fq2gAu8URNe-27WJuHPbopOF-GP6wz-uvdTr5LBzuOD4GWaYtgOTr1Az6waknl5zGfo28cPm6tVcfPlen11eVNozqupYK0mtKScWEuoqkRTWaUaxbnIf1lNa2IVK1sBQjNjoSaiK0XdNq2GSggo2Rl6f9Ddze1oOm38FNUgd9GNKu5lUE4-7njXy234JSnhkNdlgbdHgRh-ziZNcnRJm2FQ3oQ5SRC8KYGJDC4PoI4hpWjs_RIg8p8pMpsiH0zJA6__P-0BP7qQgTcHoHfb_reLRrYu6N6Mkta15FSyhgFlfwGQhJOU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>18495138</pqid></control><display><type>article</type><title>Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Liu, Xiaojuan ; Jana, Malabendu ; Dasgupta, Subhajit ; Koka, Sreenivas ; He, Jun ; Wood, Charles ; Pahan, Kalipada</creator><creatorcontrib>Liu, Xiaojuan ; Jana, Malabendu ; Dasgupta, Subhajit ; Koka, Sreenivas ; He, Jun ; Wood, Charles ; Pahan, Kalipada</creatorcontrib><description>Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion
of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present
study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia.
Expression of the tat gene as RSV- tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression
of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV- tat -induced NO production by anti-Tat antibodies suggest that RSV- tat -induced production of NO is dependent on Tat and that Tat is secreted from RSV- tat -transfected astroglia. Similar to U373MG astroglial cells, RSV- tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity
by the expression of RSV- tat suggests that RSV- tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-κB and
C/EBPβ, transcription factors responsible for the induction of iNOS. Activation of NF-κB as well as C/EBPβ by RSV- tat , stimulation of RSV- tat -induced production of NO by the wild type of p65 and C/EBPβ, and inhibition of RSV- tat -induced production of NO by Îp65, a dominant-negative mutant of p65, and ÎC/EBPβ, a dominant-negative mutant of C/EBPβ, suggest
that RSV- tat induces iNOS through the activation of NF-κB and C/EBPβ. In addition, we show that extracellular signal-regulated kinase
(ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV- tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and ÎERK2, a dominant-negative mutant
of ERK2, inhibited RSV- tat -induced production of NO through the inhibition of C/EBPβ but not that of NF-κB. This study illustrates a novel role for
HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M205107200</identifier><identifier>PMID: 12167619</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Animals ; Astrocytes - enzymology ; CCAAT-Enhancer-Binding Protein-beta - metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; eIF-2 Kinase - metabolism ; Enzyme Activation ; Enzyme Inhibitors - pharmacology ; Flavonoids - pharmacology ; Gene Products, tat - metabolism ; Genes, Dominant ; Humans ; Immunoblotting ; Luciferases - metabolism ; Mitogen-Activated Protein Kinases - metabolism ; NF-kappa B - physiology ; Nitric Oxide - metabolism ; Nitric Oxide Synthase - metabolism ; Nitric Oxide Synthase Type II ; p38 Mitogen-Activated Protein Kinases ; Promoter Regions, Genetic ; Time Factors ; Transcriptional Activation ; Transfection</subject><ispartof>The Journal of biological chemistry, 2002-10, Vol.277 (42), p.39312-39319</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-3bc025240ff02a6896faa9a448720fc270fa35b818c3ef1708d587b9bc1688153</citedby><cites>FETCH-LOGICAL-c446t-3bc025240ff02a6896faa9a448720fc270fa35b818c3ef1708d587b9bc1688153</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12167619$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Xiaojuan</creatorcontrib><creatorcontrib>Jana, Malabendu</creatorcontrib><creatorcontrib>Dasgupta, Subhajit</creatorcontrib><creatorcontrib>Koka, Sreenivas</creatorcontrib><creatorcontrib>He, Jun</creatorcontrib><creatorcontrib>Wood, Charles</creatorcontrib><creatorcontrib>Pahan, Kalipada</creatorcontrib><title>Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion
of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present
study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia.
Expression of the tat gene as RSV- tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression
of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV- tat -induced NO production by anti-Tat antibodies suggest that RSV- tat -induced production of NO is dependent on Tat and that Tat is secreted from RSV- tat -transfected astroglia. Similar to U373MG astroglial cells, RSV- tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity
by the expression of RSV- tat suggests that RSV- tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-κB and
C/EBPβ, transcription factors responsible for the induction of iNOS. Activation of NF-κB as well as C/EBPβ by RSV- tat , stimulation of RSV- tat -induced production of NO by the wild type of p65 and C/EBPβ, and inhibition of RSV- tat -induced production of NO by Îp65, a dominant-negative mutant of p65, and ÎC/EBPβ, a dominant-negative mutant of C/EBPβ, suggest
that RSV- tat induces iNOS through the activation of NF-κB and C/EBPβ. In addition, we show that extracellular signal-regulated kinase
(ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV- tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and ÎERK2, a dominant-negative mutant
of ERK2, inhibited RSV- tat -induced production of NO through the inhibition of C/EBPβ but not that of NF-κB. This study illustrates a novel role for
HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia.</description><subject>Animals</subject><subject>Astrocytes - enzymology</subject><subject>CCAAT-Enhancer-Binding Protein-beta - metabolism</subject><subject>Cells, Cultured</subject><subject>Dose-Response Relationship, Drug</subject><subject>eIF-2 Kinase - metabolism</subject><subject>Enzyme Activation</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Flavonoids - pharmacology</subject><subject>Gene Products, tat - metabolism</subject><subject>Genes, Dominant</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Luciferases - metabolism</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>NF-kappa B - physiology</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nitric Oxide Synthase Type II</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>Promoter Regions, Genetic</subject><subject>Time Factors</subject><subject>Transcriptional Activation</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFv1DAQhS0EotvClSPyAaH2kMVjO4lzQaoq6K5U4MBScTOOY29cJfZiJ8D-e4x21dK5jEbzzZsZPYReAVkCqfm7u1YvP1FS5oIS8gQtgAhWsBK-P0ULQigUDS3FCTpN6Y7k4A08RydAoaoraBbox2oelcfrcZx96Ix12hmv9_jWxTnhzX5nMODz1fq2gAu8URNe-27WJuHPbopOF-GP6wz-uvdTr5LBzuOD4GWaYtgOTr1Az6waknl5zGfo28cPm6tVcfPlen11eVNozqupYK0mtKScWEuoqkRTWaUaxbnIf1lNa2IVK1sBQjNjoSaiK0XdNq2GSggo2Rl6f9Ddze1oOm38FNUgd9GNKu5lUE4-7njXy234JSnhkNdlgbdHgRh-ziZNcnRJm2FQ3oQ5SRC8KYGJDC4PoI4hpWjs_RIg8p8pMpsiH0zJA6__P-0BP7qQgTcHoHfb_reLRrYu6N6Mkta15FSyhgFlfwGQhJOU</recordid><startdate>20021018</startdate><enddate>20021018</enddate><creator>Liu, Xiaojuan</creator><creator>Jana, Malabendu</creator><creator>Dasgupta, Subhajit</creator><creator>Koka, Sreenivas</creator><creator>He, Jun</creator><creator>Wood, Charles</creator><creator>Pahan, Kalipada</creator><general>American Society for Biochemistry and Molecular Biology</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>7U9</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20021018</creationdate><title>Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia</title><author>Liu, Xiaojuan ; Jana, Malabendu ; Dasgupta, Subhajit ; Koka, Sreenivas ; He, Jun ; Wood, Charles ; Pahan, Kalipada</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-3bc025240ff02a6896faa9a448720fc270fa35b818c3ef1708d587b9bc1688153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Astrocytes - enzymology</topic><topic>CCAAT-Enhancer-Binding Protein-beta - metabolism</topic><topic>Cells, Cultured</topic><topic>Dose-Response Relationship, Drug</topic><topic>eIF-2 Kinase - metabolism</topic><topic>Enzyme Activation</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Flavonoids - pharmacology</topic><topic>Gene Products, tat - metabolism</topic><topic>Genes, Dominant</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Luciferases - metabolism</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>NF-kappa B - physiology</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - metabolism</topic><topic>Nitric Oxide Synthase Type II</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>Promoter Regions, Genetic</topic><topic>Time Factors</topic><topic>Transcriptional Activation</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Xiaojuan</creatorcontrib><creatorcontrib>Jana, Malabendu</creatorcontrib><creatorcontrib>Dasgupta, Subhajit</creatorcontrib><creatorcontrib>Koka, Sreenivas</creatorcontrib><creatorcontrib>He, Jun</creatorcontrib><creatorcontrib>Wood, Charles</creatorcontrib><creatorcontrib>Pahan, Kalipada</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>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Xiaojuan</au><au>Jana, Malabendu</au><au>Dasgupta, Subhajit</au><au>Koka, Sreenivas</au><au>He, Jun</au><au>Wood, Charles</au><au>Pahan, Kalipada</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-10-18</date><risdate>2002</risdate><volume>277</volume><issue>42</issue><spage>39312</spage><epage>39319</epage><pages>39312-39319</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion
of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present
study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia.
Expression of the tat gene as RSV- tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the induction of NO production and the expression
of iNOS protein and mRNA. Induction of NO production by recombinant HIV-1 Tat protein and inhibition of RSV- tat -induced NO production by anti-Tat antibodies suggest that RSV- tat -induced production of NO is dependent on Tat and that Tat is secreted from RSV- tat -transfected astroglia. Similar to U373MG astroglial cells, RSV- tat also induced the production of NO in human primary astroglia. The induction of human iNOS promoter-derived luciferase activity
by the expression of RSV- tat suggests that RSV- tat induces the transcription of iNOS. To understand the mechanism of induction of iNOS, we investigated the role of NF-κB and
C/EBPβ, transcription factors responsible for the induction of iNOS. Activation of NF-κB as well as C/EBPβ by RSV- tat , stimulation of RSV- tat -induced production of NO by the wild type of p65 and C/EBPβ, and inhibition of RSV- tat -induced production of NO by Îp65, a dominant-negative mutant of p65, and ÎC/EBPβ, a dominant-negative mutant of C/EBPβ, suggest
that RSV- tat induces iNOS through the activation of NF-κB and C/EBPβ. In addition, we show that extracellular signal-regulated kinase
(ERK) but not that p38 mitogen-activated protein kinase (MAPK) is involved in RSV- tat induced production of NO. Interestingly, PD98059, an inhibitor of the ERK pathway, and ÎERK2, a dominant-negative mutant
of ERK2, inhibited RSV- tat -induced production of NO through the inhibition of C/EBPβ but not that of NF-κB. This study illustrates a novel role for
HIV-1 tat in inducing the expression of iNOS in human astrocytes that may participate in the pathogenesis of HIV-associated dementia.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12167619</pmid><doi>10.1074/jbc.M205107200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-9258 |
| ispartof | The Journal of biological chemistry, 2002-10, Vol.277 (42), p.39312-39319 |
| issn | 0021-9258 1083-351X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2041896 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Astrocytes - enzymology CCAAT-Enhancer-Binding Protein-beta - metabolism Cells, Cultured Dose-Response Relationship, Drug eIF-2 Kinase - metabolism Enzyme Activation Enzyme Inhibitors - pharmacology Flavonoids - pharmacology Gene Products, tat - metabolism Genes, Dominant Humans Immunoblotting Luciferases - metabolism Mitogen-Activated Protein Kinases - metabolism NF-kappa B - physiology Nitric Oxide - metabolism Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type II p38 Mitogen-Activated Protein Kinases Promoter Regions, Genetic Time Factors Transcriptional Activation Transfection |
| title | Human Immunodeficiency Virus Type 1 (HIV-1) Tat Induces Nitric-oxide Synthase in Human Astroglia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-16T17%3A01%3A28IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Human%20Immunodeficiency%20Virus%20Type%201%20(HIV-1)%20Tat%20Induces%20Nitric-oxide%20Synthase%20in%20Human%20Astroglia&rft.jtitle=The%20Journal%20of%20biological%20chemistry&rft.au=Liu,%20Xiaojuan&rft.date=2002-10-18&rft.volume=277&rft.issue=42&rft.spage=39312&rft.epage=39319&rft.pages=39312-39319&rft.issn=0021-9258&rft.eissn=1083-351X&rft_id=info:doi/10.1074/jbc.M205107200&rft_dat=%3Cproquest_pubme%3E18495138%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=18495138&rft_id=info:pmid/12167619&rfr_iscdi=true |