Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway
Resveratrol has been shown to stimulate differentiation of osteoblastic MC3T3-E1 cells in vitro ; however, the mechanisms underlying the anabolic effect of resveratrol on osteoblasts remain largely unknown. Our study was aimed to investigate the molecular mechanism of resveratrol-induced differentia...
Gespeichert in:
| Veröffentlicht in: | Biochemistry (Moscow) 2019-06, Vol.84 (6), p.686-692 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 692 |
|---|---|
| container_issue | 6 |
| container_start_page | 686 |
| container_title | Biochemistry (Moscow) |
| container_volume | 84 |
| creator | Huang, Y. Huo, J. Liu, F. Q. Liu, J. Zhang, X. J. Guo, C. H. Song, L. H. |
| description | Resveratrol has been shown to stimulate differentiation of osteoblastic MC3T3-E1 cells
in vitro
; however, the mechanisms underlying the anabolic effect of resveratrol on osteoblasts remain largely unknown. Our study was aimed to investigate the molecular mechanism of resveratrol-induced differentiation of MC3T3-E1 cells. MC3T3-E1 cells were treated for 8 days with different concentrations of resveratrol (10
−8
-10
−6
M) and 10
−6
M cyclosporine A (CsA), a specific inhibitor of the calcineurin/NFAT pathway. According to the results of pilot studies of cell proliferation and alkaline phos-phatase activity, 10
−7
M concentration of resveratrol was used in subsequent experiments. The levels of mRNA expression of the osteosis-related genes
CaN
,
NFATc1
, and
Runx2
were analyzed by real-time RT-PCR; the levels of the corresponding proteins were estimated by Western blot analysis. Resveratrol upregulated expression of the
CaN
,
NFATc1
, and
Runx2
genes at both mRNA and protein levels compared to the control group (
p
< 0.05), while CsA reduced the effects of resveratrol (
p
< 0.05). Using immunohistochemical staining, we showed that resveratrol induced NFATc1 accumulation in the cell nuclei, and treatment with CsA inhibited resveratrol-mediated induction of NFATc1, suggesting that the calcineurin/NFATc1 signaling pathway plays an important role in the regulatory effect of resveratrol on osteoblasts. |
| doi_str_mv | 10.1134/S0006297919060117 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_2261262191</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A599184564</galeid><sourcerecordid>A599184564</sourcerecordid><originalsourceid>FETCH-LOGICAL-c439t-768f9ed8a9fe1e5fce9178dc6ceec40c425cf0dd0c4ce9b3f7212b6bf8b8bf6d3</originalsourceid><addsrcrecordid>eNp1kc1u1DAUhSMEokPhAdggS2zYpPVP4tjLUdoCUqEjOqwjx7meukrsYjtFfQTeGkdTKL_ywr73fOfoWrcoXhJ8RAirji8xxpzKRhKJOSakeVSsCMeiZLjCj4vVIpeLflA8i_E6lxRL9rQ4YIQyIbhYFd8-QbyFoFLwI9oEP_kEEVmHbm1uoRNrDARwyapkvUPeoIuYwPejislq9KFlW1aeEtTCOMZsUmiTE37l0xWgVo3aOpiDdccfz9ZbTdCl3Tk1WrdDG5Wuvqq758UTo8YIL-7vw-Lz2em2fVeeX7x9367PS10xmcqGCyNhEEoaIFAbDZI0YtBcA-gK64rW2uBhyK8s9cw0lNCe90b0ojd8YIfFm33uTfBfZoipm2zUeXzlwM-xo5QTyimRJKOv_0Cv_Rzy2AvFZE1qSpsHaqdG6KwzPgWll9BuXUtJRFXzKlNH_6DyGWCy2jswNvd_M5C9QQcfYwDT3QQ7qXDXEdwt6-_-Wn_2vLofeO4nGH46fuw7A3QPxCy5HYSHH_0_9TvcBLld</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2239515227</pqid></control><display><type>article</type><title>Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway</title><source>Springer Nature - Complete Springer Journals</source><creator>Huang, Y. ; Huo, J. ; Liu, F. Q. ; Liu, J. ; Zhang, X. J. ; Guo, C. H. ; Song, L. H.</creator><creatorcontrib>Huang, Y. ; Huo, J. ; Liu, F. Q. ; Liu, J. ; Zhang, X. J. ; Guo, C. H. ; Song, L. H.</creatorcontrib><description>Resveratrol has been shown to stimulate differentiation of osteoblastic MC3T3-E1 cells
in vitro
; however, the mechanisms underlying the anabolic effect of resveratrol on osteoblasts remain largely unknown. Our study was aimed to investigate the molecular mechanism of resveratrol-induced differentiation of MC3T3-E1 cells. MC3T3-E1 cells were treated for 8 days with different concentrations of resveratrol (10
−8
-10
−6
M) and 10
−6
M cyclosporine A (CsA), a specific inhibitor of the calcineurin/NFAT pathway. According to the results of pilot studies of cell proliferation and alkaline phos-phatase activity, 10
−7
M concentration of resveratrol was used in subsequent experiments. The levels of mRNA expression of the osteosis-related genes
CaN
,
NFATc1
, and
Runx2
were analyzed by real-time RT-PCR; the levels of the corresponding proteins were estimated by Western blot analysis. Resveratrol upregulated expression of the
CaN
,
NFATc1
, and
Runx2
genes at both mRNA and protein levels compared to the control group (
p
< 0.05), while CsA reduced the effects of resveratrol (
p
< 0.05). Using immunohistochemical staining, we showed that resveratrol induced NFATc1 accumulation in the cell nuclei, and treatment with CsA inhibited resveratrol-mediated induction of NFATc1, suggesting that the calcineurin/NFATc1 signaling pathway plays an important role in the regulatory effect of resveratrol on osteoblasts.</description><identifier>ISSN: 0006-2979</identifier><identifier>EISSN: 1608-3040</identifier><identifier>DOI: 10.1134/S0006297919060117</identifier><identifier>PMID: 31238868</identifier><language>eng</language><publisher>Moscow: Pleiades Publishing</publisher><subject>Analysis ; Biochemistry ; Biocompatibility ; Biomedical and Life Sciences ; Biomedical materials ; Biomedicine ; Bioorganic Chemistry ; Calcineurin ; Cbfa-1 protein ; Cell proliferation ; Cellular signal transduction ; Comparative analysis ; Cyclosporins ; Differentiation ; Gene expression ; Genes ; Kinases ; Life Sciences ; Microbiology ; NF-AT protein ; Nuclei (cytology) ; Osteoblastogenesis ; Osteoblasts ; Osteosis ; Polymerase chain reaction ; Proteins ; Resveratrol ; Signal transduction ; Signaling</subject><ispartof>Biochemistry (Moscow), 2019-06, Vol.84 (6), p.686-692</ispartof><rights>Pleiades Publishing, Ltd. 2019</rights><rights>COPYRIGHT 2019 Springer</rights><rights>Biochemistry (Moscow) is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-768f9ed8a9fe1e5fce9178dc6ceec40c425cf0dd0c4ce9b3f7212b6bf8b8bf6d3</citedby><cites>FETCH-LOGICAL-c439t-768f9ed8a9fe1e5fce9178dc6ceec40c425cf0dd0c4ce9b3f7212b6bf8b8bf6d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1134/S0006297919060117$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1134/S0006297919060117$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31238868$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Y.</creatorcontrib><creatorcontrib>Huo, J.</creatorcontrib><creatorcontrib>Liu, F. Q.</creatorcontrib><creatorcontrib>Liu, J.</creatorcontrib><creatorcontrib>Zhang, X. J.</creatorcontrib><creatorcontrib>Guo, C. H.</creatorcontrib><creatorcontrib>Song, L. H.</creatorcontrib><title>Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway</title><title>Biochemistry (Moscow)</title><addtitle>Biochemistry Moscow</addtitle><addtitle>Biochemistry (Mosc)</addtitle><description>Resveratrol has been shown to stimulate differentiation of osteoblastic MC3T3-E1 cells
in vitro
; however, the mechanisms underlying the anabolic effect of resveratrol on osteoblasts remain largely unknown. Our study was aimed to investigate the molecular mechanism of resveratrol-induced differentiation of MC3T3-E1 cells. MC3T3-E1 cells were treated for 8 days with different concentrations of resveratrol (10
−8
-10
−6
M) and 10
−6
M cyclosporine A (CsA), a specific inhibitor of the calcineurin/NFAT pathway. According to the results of pilot studies of cell proliferation and alkaline phos-phatase activity, 10
−7
M concentration of resveratrol was used in subsequent experiments. The levels of mRNA expression of the osteosis-related genes
CaN
,
NFATc1
, and
Runx2
were analyzed by real-time RT-PCR; the levels of the corresponding proteins were estimated by Western blot analysis. Resveratrol upregulated expression of the
CaN
,
NFATc1
, and
Runx2
genes at both mRNA and protein levels compared to the control group (
p
< 0.05), while CsA reduced the effects of resveratrol (
p
< 0.05). Using immunohistochemical staining, we showed that resveratrol induced NFATc1 accumulation in the cell nuclei, and treatment with CsA inhibited resveratrol-mediated induction of NFATc1, suggesting that the calcineurin/NFATc1 signaling pathway plays an important role in the regulatory effect of resveratrol on osteoblasts.</description><subject>Analysis</subject><subject>Biochemistry</subject><subject>Biocompatibility</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical materials</subject><subject>Biomedicine</subject><subject>Bioorganic Chemistry</subject><subject>Calcineurin</subject><subject>Cbfa-1 protein</subject><subject>Cell proliferation</subject><subject>Cellular signal transduction</subject><subject>Comparative analysis</subject><subject>Cyclosporins</subject><subject>Differentiation</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Microbiology</subject><subject>NF-AT protein</subject><subject>Nuclei (cytology)</subject><subject>Osteoblastogenesis</subject><subject>Osteoblasts</subject><subject>Osteosis</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Resveratrol</subject><subject>Signal transduction</subject><subject>Signaling</subject><issn>0006-2979</issn><issn>1608-3040</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kc1u1DAUhSMEokPhAdggS2zYpPVP4tjLUdoCUqEjOqwjx7meukrsYjtFfQTeGkdTKL_ywr73fOfoWrcoXhJ8RAirji8xxpzKRhKJOSakeVSsCMeiZLjCj4vVIpeLflA8i_E6lxRL9rQ4YIQyIbhYFd8-QbyFoFLwI9oEP_kEEVmHbm1uoRNrDARwyapkvUPeoIuYwPejislq9KFlW1aeEtTCOMZsUmiTE37l0xWgVo3aOpiDdccfz9ZbTdCl3Tk1WrdDG5Wuvqq758UTo8YIL-7vw-Lz2em2fVeeX7x9367PS10xmcqGCyNhEEoaIFAbDZI0YtBcA-gK64rW2uBhyK8s9cw0lNCe90b0ojd8YIfFm33uTfBfZoipm2zUeXzlwM-xo5QTyimRJKOv_0Cv_Rzy2AvFZE1qSpsHaqdG6KwzPgWll9BuXUtJRFXzKlNH_6DyGWCy2jswNvd_M5C9QQcfYwDT3QQ7qXDXEdwt6-_-Wn_2vLofeO4nGH46fuw7A3QPxCy5HYSHH_0_9TvcBLld</recordid><startdate>20190601</startdate><enddate>20190601</enddate><creator>Huang, Y.</creator><creator>Huo, J.</creator><creator>Liu, F. Q.</creator><creator>Liu, J.</creator><creator>Zhang, X. J.</creator><creator>Guo, C. H.</creator><creator>Song, L. H.</creator><general>Pleiades Publishing</general><general>Springer</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8C1</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>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>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20190601</creationdate><title>Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway</title><author>Huang, Y. ; Huo, J. ; Liu, F. Q. ; Liu, J. ; Zhang, X. J. ; Guo, C. H. ; Song, L. H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-768f9ed8a9fe1e5fce9178dc6ceec40c425cf0dd0c4ce9b3f7212b6bf8b8bf6d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Analysis</topic><topic>Biochemistry</topic><topic>Biocompatibility</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical materials</topic><topic>Biomedicine</topic><topic>Bioorganic Chemistry</topic><topic>Calcineurin</topic><topic>Cbfa-1 protein</topic><topic>Cell proliferation</topic><topic>Cellular signal transduction</topic><topic>Comparative analysis</topic><topic>Cyclosporins</topic><topic>Differentiation</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Microbiology</topic><topic>NF-AT protein</topic><topic>Nuclei (cytology)</topic><topic>Osteoblastogenesis</topic><topic>Osteoblasts</topic><topic>Osteosis</topic><topic>Polymerase chain reaction</topic><topic>Proteins</topic><topic>Resveratrol</topic><topic>Signal transduction</topic><topic>Signaling</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Y.</creatorcontrib><creatorcontrib>Huo, J.</creatorcontrib><creatorcontrib>Liu, F. Q.</creatorcontrib><creatorcontrib>Liu, J.</creatorcontrib><creatorcontrib>Zhang, X. J.</creatorcontrib><creatorcontrib>Guo, C. H.</creatorcontrib><creatorcontrib>Song, L. H.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health 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>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 & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Moscow)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Y.</au><au>Huo, J.</au><au>Liu, F. Q.</au><au>Liu, J.</au><au>Zhang, X. J.</au><au>Guo, C. H.</au><au>Song, L. H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway</atitle><jtitle>Biochemistry (Moscow)</jtitle><stitle>Biochemistry Moscow</stitle><addtitle>Biochemistry (Mosc)</addtitle><date>2019-06-01</date><risdate>2019</risdate><volume>84</volume><issue>6</issue><spage>686</spage><epage>692</epage><pages>686-692</pages><issn>0006-2979</issn><eissn>1608-3040</eissn><abstract>Resveratrol has been shown to stimulate differentiation of osteoblastic MC3T3-E1 cells
in vitro
; however, the mechanisms underlying the anabolic effect of resveratrol on osteoblasts remain largely unknown. Our study was aimed to investigate the molecular mechanism of resveratrol-induced differentiation of MC3T3-E1 cells. MC3T3-E1 cells were treated for 8 days with different concentrations of resveratrol (10
−8
-10
−6
M) and 10
−6
M cyclosporine A (CsA), a specific inhibitor of the calcineurin/NFAT pathway. According to the results of pilot studies of cell proliferation and alkaline phos-phatase activity, 10
−7
M concentration of resveratrol was used in subsequent experiments. The levels of mRNA expression of the osteosis-related genes
CaN
,
NFATc1
, and
Runx2
were analyzed by real-time RT-PCR; the levels of the corresponding proteins were estimated by Western blot analysis. Resveratrol upregulated expression of the
CaN
,
NFATc1
, and
Runx2
genes at both mRNA and protein levels compared to the control group (
p
< 0.05), while CsA reduced the effects of resveratrol (
p
< 0.05). Using immunohistochemical staining, we showed that resveratrol induced NFATc1 accumulation in the cell nuclei, and treatment with CsA inhibited resveratrol-mediated induction of NFATc1, suggesting that the calcineurin/NFATc1 signaling pathway plays an important role in the regulatory effect of resveratrol on osteoblasts.</abstract><cop>Moscow</cop><pub>Pleiades Publishing</pub><pmid>31238868</pmid><doi>10.1134/S0006297919060117</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0006-2979 |
| ispartof | Biochemistry (Moscow), 2019-06, Vol.84 (6), p.686-692 |
| issn | 0006-2979 1608-3040 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2261262191 |
| source | Springer Nature - Complete Springer Journals |
| subjects | Analysis Biochemistry Biocompatibility Biomedical and Life Sciences Biomedical materials Biomedicine Bioorganic Chemistry Calcineurin Cbfa-1 protein Cell proliferation Cellular signal transduction Comparative analysis Cyclosporins Differentiation Gene expression Genes Kinases Life Sciences Microbiology NF-AT protein Nuclei (cytology) Osteoblastogenesis Osteoblasts Osteosis Polymerase chain reaction Proteins Resveratrol Signal transduction Signaling |
| title | Resveratrol Promotes in vitro Differentiation of Osteoblastic MC3T3-E1 Cells via Potentiation of the Calcineurin/NFATc1 Signaling Pathway |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T02%3A35%3A22IST&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=Resveratrol%20Promotes%20in%20vitro%20Differentiation%20of%20Osteoblastic%20MC3T3-E1%20Cells%20via%20Potentiation%20of%20the%20Calcineurin/NFATc1%20Signaling%20Pathway&rft.jtitle=Biochemistry%20(Moscow)&rft.au=Huang,%20Y.&rft.date=2019-06-01&rft.volume=84&rft.issue=6&rft.spage=686&rft.epage=692&rft.pages=686-692&rft.issn=0006-2979&rft.eissn=1608-3040&rft_id=info:doi/10.1134/S0006297919060117&rft_dat=%3Cgale_proqu%3EA599184564%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=2239515227&rft_id=info:pmid/31238868&rft_galeid=A599184564&rfr_iscdi=true |