The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory
We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C...
Gespeichert in:
| Veröffentlicht in: | The Journal of neuroscience 2019-02, Vol.39 (6), p.970-983 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 983 |
|---|---|
| container_issue | 6 |
| container_start_page | 970 |
| container_title | The Journal of neuroscience |
| container_volume | 39 |
| creator | Li, Xiang Marshall, Paul R Leighton, Laura J Zajaczkowski, Esmi L Wang, Ziqi Madugalle, Sachithrani U Yin, Jiayu Bredy, Timothy W Wei, Wei |
| description | We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation.
How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs. |
| doi_str_mv | 10.1523/JNEUROSCI.2024-18.2018 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6363930</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2157670259</sourcerecordid><originalsourceid>FETCH-LOGICAL-c442t-72a1d44766c563ec3bea03f77e36ee8a5467d1df0adca1c7f128b3e18c882c673</originalsourceid><addsrcrecordid>eNpdUstu2zAQFIoWjZv2FwICvfSilC-R8qWA4TqOizQJUudM0NTKZiCRDiml8Xf1P3LpD5XKw2h72gV2ZnZ2MVl2RPAxKSj7_O18dn118WO6OKaY8pyUqZLyVTZK03FOOSavsxGmEueCS36QvYvxBmMsMZFvswOGC16MeTHKfi83gL6eT9AVbLUN-SRGb6zuoEKXwXdgHZrrquLFw68EWfdNGkXUJdIS2q0PukFTX1m3Rr5Gi7aFaiCjmQ7NDs3BpfZ-GyBG6x36abtNEhzYlwEa266sGbo6eNc9KoUO7pF2FVrEtO62tyEZqX145Ey9i76xle4GsbTvxay9A3QCOqDv0Pqwe5-9qXUT4cNzPcyuT2bL6Wl-djFfTCdnueGcdrmkmlScSyFMIRgYtgKNWS0lMAFQ6oILWZGqxroymhhZE1quGJDSlCU1QrLD7MuT7rZfpcMNuC79Q22DbXXYKa-t-nfi7Eat_Z0STLAxw0ng07NA8Lc9xE61NhpoGu3A91FRUkghMS3GCfrxP-iN74NL5yWULAtBxpQmlHhCmeBjTI_dmyFYDblR-9yoITeKlGrITSIe_X3KnvYSFPYH4CvEig</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2178561922</pqid></control><display><type>article</type><title>The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Li, Xiang ; Marshall, Paul R ; Leighton, Laura J ; Zajaczkowski, Esmi L ; Wang, Ziqi ; Madugalle, Sachithrani U ; Yin, Jiayu ; Bredy, Timothy W ; Wei, Wei</creator><creatorcontrib>Li, Xiang ; Marshall, Paul R ; Leighton, Laura J ; Zajaczkowski, Esmi L ; Wang, Ziqi ; Madugalle, Sachithrani U ; Yin, Jiayu ; Bredy, Timothy W ; Wei, Wei</creatorcontrib><description>We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation.
How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.2024-18.2018</identifier><identifier>PMID: 30545945</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Animals ; Associative memory ; Consolidation ; Cortex (temporal) ; Cues ; Demethylation ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded ; DNA damage ; DNA Methylation ; DNA repair ; DNA Repair - genetics ; Double-strand break repair ; Epigenesis, Genetic ; Fear ; Fear - physiology ; GADD45 protein ; Gene expression ; Genes, Immediate-Early - genetics ; Information processing ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - physiology ; Learning ; Limbic System - physiology ; Male ; Memory - physiology ; Memory Consolidation - physiology ; Mental Recall - physiology ; Mice ; Mice, Inbred C57BL ; Prefrontal cortex ; Prefrontal Cortex - physiology ; Proteins ; Psychomotor Performance - physiology ; Repair ; Temporal variations</subject><ispartof>The Journal of neuroscience, 2019-02, Vol.39 (6), p.970-983</ispartof><rights>Copyright © 2019 the authors 0270-6474/19/390970-14$15.00/0.</rights><rights>Copyright Society for Neuroscience Feb 6, 2019</rights><rights>Copyright © 2019 the authors 0270-6474/19/390970-14$15.00/0 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-72a1d44766c563ec3bea03f77e36ee8a5467d1df0adca1c7f128b3e18c882c673</citedby><cites>FETCH-LOGICAL-c442t-72a1d44766c563ec3bea03f77e36ee8a5467d1df0adca1c7f128b3e18c882c673</cites><orcidid>0000-0003-3280-126X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363930/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363930/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30545945$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xiang</creatorcontrib><creatorcontrib>Marshall, Paul R</creatorcontrib><creatorcontrib>Leighton, Laura J</creatorcontrib><creatorcontrib>Zajaczkowski, Esmi L</creatorcontrib><creatorcontrib>Wang, Ziqi</creatorcontrib><creatorcontrib>Madugalle, Sachithrani U</creatorcontrib><creatorcontrib>Yin, Jiayu</creatorcontrib><creatorcontrib>Bredy, Timothy W</creatorcontrib><creatorcontrib>Wei, Wei</creatorcontrib><title>The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation.
How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.</description><subject>Animals</subject><subject>Associative memory</subject><subject>Consolidation</subject><subject>Cortex (temporal)</subject><subject>Cues</subject><subject>Demethylation</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA damage</subject><subject>DNA Methylation</subject><subject>DNA repair</subject><subject>DNA Repair - genetics</subject><subject>Double-strand break repair</subject><subject>Epigenesis, Genetic</subject><subject>Fear</subject><subject>Fear - physiology</subject><subject>GADD45 protein</subject><subject>Gene expression</subject><subject>Genes, Immediate-Early - genetics</subject><subject>Information processing</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - physiology</subject><subject>Learning</subject><subject>Limbic System - physiology</subject><subject>Male</subject><subject>Memory - physiology</subject><subject>Memory Consolidation - physiology</subject><subject>Mental Recall - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - physiology</subject><subject>Proteins</subject><subject>Psychomotor Performance - physiology</subject><subject>Repair</subject><subject>Temporal variations</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUstu2zAQFIoWjZv2FwICvfSilC-R8qWA4TqOizQJUudM0NTKZiCRDiml8Xf1P3LpD5XKw2h72gV2ZnZ2MVl2RPAxKSj7_O18dn118WO6OKaY8pyUqZLyVTZK03FOOSavsxGmEueCS36QvYvxBmMsMZFvswOGC16MeTHKfi83gL6eT9AVbLUN-SRGb6zuoEKXwXdgHZrrquLFw68EWfdNGkXUJdIS2q0PukFTX1m3Rr5Gi7aFaiCjmQ7NDs3BpfZ-GyBG6x36abtNEhzYlwEa266sGbo6eNc9KoUO7pF2FVrEtO62tyEZqX145Ey9i76xle4GsbTvxay9A3QCOqDv0Pqwe5-9qXUT4cNzPcyuT2bL6Wl-djFfTCdnueGcdrmkmlScSyFMIRgYtgKNWS0lMAFQ6oILWZGqxroymhhZE1quGJDSlCU1QrLD7MuT7rZfpcMNuC79Q22DbXXYKa-t-nfi7Eat_Z0STLAxw0ng07NA8Lc9xE61NhpoGu3A91FRUkghMS3GCfrxP-iN74NL5yWULAtBxpQmlHhCmeBjTI_dmyFYDblR-9yoITeKlGrITSIe_X3KnvYSFPYH4CvEig</recordid><startdate>20190206</startdate><enddate>20190206</enddate><creator>Li, Xiang</creator><creator>Marshall, Paul R</creator><creator>Leighton, Laura J</creator><creator>Zajaczkowski, Esmi L</creator><creator>Wang, Ziqi</creator><creator>Madugalle, Sachithrani U</creator><creator>Yin, Jiayu</creator><creator>Bredy, Timothy W</creator><creator>Wei, Wei</creator><general>Society for Neuroscience</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>7QG</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3280-126X</orcidid></search><sort><creationdate>20190206</creationdate><title>The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory</title><author>Li, Xiang ; Marshall, Paul R ; Leighton, Laura J ; Zajaczkowski, Esmi L ; Wang, Ziqi ; Madugalle, Sachithrani U ; Yin, Jiayu ; Bredy, Timothy W ; Wei, Wei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-72a1d44766c563ec3bea03f77e36ee8a5467d1df0adca1c7f128b3e18c882c673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Associative memory</topic><topic>Consolidation</topic><topic>Cortex (temporal)</topic><topic>Cues</topic><topic>Demethylation</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA damage</topic><topic>DNA Methylation</topic><topic>DNA repair</topic><topic>DNA Repair - genetics</topic><topic>Double-strand break repair</topic><topic>Epigenesis, Genetic</topic><topic>Fear</topic><topic>Fear - physiology</topic><topic>GADD45 protein</topic><topic>Gene expression</topic><topic>Genes, Immediate-Early - genetics</topic><topic>Information processing</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - physiology</topic><topic>Learning</topic><topic>Limbic System - physiology</topic><topic>Male</topic><topic>Memory - physiology</topic><topic>Memory Consolidation - physiology</topic><topic>Mental Recall - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Prefrontal cortex</topic><topic>Prefrontal Cortex - physiology</topic><topic>Proteins</topic><topic>Psychomotor Performance - physiology</topic><topic>Repair</topic><topic>Temporal variations</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Xiang</creatorcontrib><creatorcontrib>Marshall, Paul R</creatorcontrib><creatorcontrib>Leighton, Laura J</creatorcontrib><creatorcontrib>Zajaczkowski, Esmi L</creatorcontrib><creatorcontrib>Wang, Ziqi</creatorcontrib><creatorcontrib>Madugalle, Sachithrani U</creatorcontrib><creatorcontrib>Yin, Jiayu</creatorcontrib><creatorcontrib>Bredy, Timothy W</creatorcontrib><creatorcontrib>Wei, Wei</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xiang</au><au>Marshall, Paul R</au><au>Leighton, Laura J</au><au>Zajaczkowski, Esmi L</au><au>Wang, Ziqi</au><au>Madugalle, Sachithrani U</au><au>Yin, Jiayu</au><au>Bredy, Timothy W</au><au>Wei, Wei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2019-02-06</date><risdate>2019</risdate><volume>39</volume><issue>6</issue><spage>970</spage><epage>983</epage><pages>970-983</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation.
How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>30545945</pmid><doi>10.1523/JNEUROSCI.2024-18.2018</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-3280-126X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0270-6474 |
| ispartof | The Journal of neuroscience, 2019-02, Vol.39 (6), p.970-983 |
| issn | 0270-6474 1529-2401 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6363930 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals Associative memory Consolidation Cortex (temporal) Cues Demethylation Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA damage DNA Methylation DNA repair DNA Repair - genetics Double-strand break repair Epigenesis, Genetic Fear Fear - physiology GADD45 protein Gene expression Genes, Immediate-Early - genetics Information processing Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - physiology Learning Limbic System - physiology Male Memory - physiology Memory Consolidation - physiology Mental Recall - physiology Mice Mice, Inbred C57BL Prefrontal cortex Prefrontal Cortex - physiology Proteins Psychomotor Performance - physiology Repair Temporal variations |
| title | The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T14%3A46%3A01IST&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=The%20DNA%20Repair-Associated%20Protein%20Gadd45%CE%B3%20Regulates%20the%20Temporal%20Coding%20of%20Immediate%20Early%20Gene%20Expression%20within%20the%20Prelimbic%20Prefrontal%20Cortex%20and%20Is%20Required%20for%20the%20Consolidation%20of%20Associative%20Fear%20Memory&rft.jtitle=The%20Journal%20of%20neuroscience&rft.au=Li,%20Xiang&rft.date=2019-02-06&rft.volume=39&rft.issue=6&rft.spage=970&rft.epage=983&rft.pages=970-983&rft.issn=0270-6474&rft.eissn=1529-2401&rft_id=info:doi/10.1523/JNEUROSCI.2024-18.2018&rft_dat=%3Cproquest_pubme%3E2157670259%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=2178561922&rft_id=info:pmid/30545945&rfr_iscdi=true |