IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life
Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In...
Gespeichert in:
| Veröffentlicht in: | The Journal of immunology (1950) 2018-06, Vol.200 (12), p.3970-3980 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3980 |
|---|---|
| container_issue | 12 |
| container_start_page | 3970 |
| container_title | The Journal of immunology (1950) |
| container_volume | 200 |
| creator | Hsu, Peter S Lai, Catherine L Hu, Mingjing Santner-Nanan, Brigitte Dahlstrom, Jane E Lee, Cheng Hiang Ajmal, Ayesha Bullman, Amanda Arbuckle, Susan Al Saedi, Ahmed Gacis, Lou Nambiar, Reta Williams, Andrew Wong, Melanie Campbell, Dianne E Nanan, Ralph |
| description | Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant β7 integrin
Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA
) Treg cells later in life. β7 integrin
Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced β7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development. |
| doi_str_mv | 10.4049/jimmunol.1701533 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2034293457</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2049659039</sourcerecordid><originalsourceid>FETCH-LOGICAL-c369t-90e3237e1494894b10ad63a57e8115a7f2fbe379d7c60d61835419cb4cf8a8db3</originalsourceid><addsrcrecordid>eNpdkM9LwzAcxYMobk7vniTgxUvnNz-aNEcZcxsUlTHPJW3T2dEm2jTC_nsr2zx4epfPezw-CN0SmHLg6nFXt22wrpkSCSRm7AyNSRxDJASIczQGoDQiUsgRuvJ-BwACKL9EI6okBU75GK1XaUTx3H5oWxiPF6HHS9fWdovfXG9sX-sGuwovQ6stftH1t8Frsw2N7l23xxs8M03j8Vx3zR7XFqd1Za7RRaUbb26OOUHvz_PNbBmlr4vV7CmNCiZUHykwjDJpCFc8UTwnoEvBdCxNQkisZUWr3DCpSlkIKAVJWMyJKnJeVIlOypxN0MNh97NzX8H4PmtrXwx_tDUu-IwC41QxHssBvf-H7lzo7PBuoLgSsQKmBgoOVNE57ztTZZ9d3epunxHIfn1nJ9_Z0fdQuTsOh7w15V_hJJj9AKpIeoU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2049659039</pqid></control><display><type>article</type><title>IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Hsu, Peter S ; Lai, Catherine L ; Hu, Mingjing ; Santner-Nanan, Brigitte ; Dahlstrom, Jane E ; Lee, Cheng Hiang ; Ajmal, Ayesha ; Bullman, Amanda ; Arbuckle, Susan ; Al Saedi, Ahmed ; Gacis, Lou ; Nambiar, Reta ; Williams, Andrew ; Wong, Melanie ; Campbell, Dianne E ; Nanan, Ralph</creator><creatorcontrib>Hsu, Peter S ; Lai, Catherine L ; Hu, Mingjing ; Santner-Nanan, Brigitte ; Dahlstrom, Jane E ; Lee, Cheng Hiang ; Ajmal, Ayesha ; Bullman, Amanda ; Arbuckle, Susan ; Al Saedi, Ahmed ; Gacis, Lou ; Nambiar, Reta ; Williams, Andrew ; Wong, Melanie ; Campbell, Dianne E ; Nanan, Ralph</creatorcontrib><description>Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant β7 integrin
Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA
) Treg cells later in life. β7 integrin
Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced β7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.1701533</identifier><identifier>PMID: 29720424</identifier><language>eng</language><publisher>United States: American Association of Immunologists</publisher><subject>Adolescent ; Antigens - immunology ; Cells, Cultured ; Child ; Child, Preschool ; Children ; Critical period ; Environmental factors ; Environmental regulations ; Female ; Gastrointestinal Tract - immunology ; Homeostasis ; Homing ; Humans ; Immune Tolerance - immunology ; Immunological tolerance ; Immunoregulation ; Infant ; Infant, Newborn ; Integrin beta Chains - immunology ; Interleukin 2 ; Interleukin 7 ; Interleukin-2 - immunology ; Interleukin-7 - immunology ; Lymphocytes ; Lymphocytes T ; Male ; Molecular chains ; Peripheral blood ; Receptors, Lymphocyte Homing - immunology ; Skin ; Skin - immunology ; T-Lymphocytes, Regulatory - immunology ; Tropism ; Tropism - immunology ; Up-Regulation - immunology</subject><ispartof>The Journal of immunology (1950), 2018-06, Vol.200 (12), p.3970-3980</ispartof><rights>Copyright © 2018 by The American Association of Immunologists, Inc.</rights><rights>Copyright American Association of Immunologists Jun 15, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-90e3237e1494894b10ad63a57e8115a7f2fbe379d7c60d61835419cb4cf8a8db3</citedby><cites>FETCH-LOGICAL-c369t-90e3237e1494894b10ad63a57e8115a7f2fbe379d7c60d61835419cb4cf8a8db3</cites><orcidid>0000-0002-0104-2072 ; 0000-0003-1025-6520 ; 0000-0002-4076-0464 ; 0000-0002-7493-4055 ; 0000-0002-2479-5317</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29720424$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hsu, Peter S</creatorcontrib><creatorcontrib>Lai, Catherine L</creatorcontrib><creatorcontrib>Hu, Mingjing</creatorcontrib><creatorcontrib>Santner-Nanan, Brigitte</creatorcontrib><creatorcontrib>Dahlstrom, Jane E</creatorcontrib><creatorcontrib>Lee, Cheng Hiang</creatorcontrib><creatorcontrib>Ajmal, Ayesha</creatorcontrib><creatorcontrib>Bullman, Amanda</creatorcontrib><creatorcontrib>Arbuckle, Susan</creatorcontrib><creatorcontrib>Al Saedi, Ahmed</creatorcontrib><creatorcontrib>Gacis, Lou</creatorcontrib><creatorcontrib>Nambiar, Reta</creatorcontrib><creatorcontrib>Williams, Andrew</creatorcontrib><creatorcontrib>Wong, Melanie</creatorcontrib><creatorcontrib>Campbell, Dianne E</creatorcontrib><creatorcontrib>Nanan, Ralph</creatorcontrib><title>IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant β7 integrin
Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA
) Treg cells later in life. β7 integrin
Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced β7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.</description><subject>Adolescent</subject><subject>Antigens - immunology</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Children</subject><subject>Critical period</subject><subject>Environmental factors</subject><subject>Environmental regulations</subject><subject>Female</subject><subject>Gastrointestinal Tract - immunology</subject><subject>Homeostasis</subject><subject>Homing</subject><subject>Humans</subject><subject>Immune Tolerance - immunology</subject><subject>Immunological tolerance</subject><subject>Immunoregulation</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Integrin beta Chains - immunology</subject><subject>Interleukin 2</subject><subject>Interleukin 7</subject><subject>Interleukin-2 - immunology</subject><subject>Interleukin-7 - immunology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Molecular chains</subject><subject>Peripheral blood</subject><subject>Receptors, Lymphocyte Homing - immunology</subject><subject>Skin</subject><subject>Skin - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>Tropism</subject><subject>Tropism - immunology</subject><subject>Up-Regulation - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkM9LwzAcxYMobk7vniTgxUvnNz-aNEcZcxsUlTHPJW3T2dEm2jTC_nsr2zx4epfPezw-CN0SmHLg6nFXt22wrpkSCSRm7AyNSRxDJASIczQGoDQiUsgRuvJ-BwACKL9EI6okBU75GK1XaUTx3H5oWxiPF6HHS9fWdovfXG9sX-sGuwovQ6stftH1t8Frsw2N7l23xxs8M03j8Vx3zR7XFqd1Za7RRaUbb26OOUHvz_PNbBmlr4vV7CmNCiZUHykwjDJpCFc8UTwnoEvBdCxNQkisZUWr3DCpSlkIKAVJWMyJKnJeVIlOypxN0MNh97NzX8H4PmtrXwx_tDUu-IwC41QxHssBvf-H7lzo7PBuoLgSsQKmBgoOVNE57ztTZZ9d3epunxHIfn1nJ9_Z0fdQuTsOh7w15V_hJJj9AKpIeoU</recordid><startdate>20180615</startdate><enddate>20180615</enddate><creator>Hsu, Peter S</creator><creator>Lai, Catherine L</creator><creator>Hu, Mingjing</creator><creator>Santner-Nanan, Brigitte</creator><creator>Dahlstrom, Jane E</creator><creator>Lee, Cheng Hiang</creator><creator>Ajmal, Ayesha</creator><creator>Bullman, Amanda</creator><creator>Arbuckle, Susan</creator><creator>Al Saedi, Ahmed</creator><creator>Gacis, Lou</creator><creator>Nambiar, Reta</creator><creator>Williams, Andrew</creator><creator>Wong, Melanie</creator><creator>Campbell, Dianne E</creator><creator>Nanan, Ralph</creator><general>American Association of Immunologists</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-0104-2072</orcidid><orcidid>https://orcid.org/0000-0003-1025-6520</orcidid><orcidid>https://orcid.org/0000-0002-4076-0464</orcidid><orcidid>https://orcid.org/0000-0002-7493-4055</orcidid><orcidid>https://orcid.org/0000-0002-2479-5317</orcidid></search><sort><creationdate>20180615</creationdate><title>IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life</title><author>Hsu, Peter S ; Lai, Catherine L ; Hu, Mingjing ; Santner-Nanan, Brigitte ; Dahlstrom, Jane E ; Lee, Cheng Hiang ; Ajmal, Ayesha ; Bullman, Amanda ; Arbuckle, Susan ; Al Saedi, Ahmed ; Gacis, Lou ; Nambiar, Reta ; Williams, Andrew ; Wong, Melanie ; Campbell, Dianne E ; Nanan, Ralph</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c369t-90e3237e1494894b10ad63a57e8115a7f2fbe379d7c60d61835419cb4cf8a8db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Antigens - immunology</topic><topic>Cells, Cultured</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Children</topic><topic>Critical period</topic><topic>Environmental factors</topic><topic>Environmental regulations</topic><topic>Female</topic><topic>Gastrointestinal Tract - immunology</topic><topic>Homeostasis</topic><topic>Homing</topic><topic>Humans</topic><topic>Immune Tolerance - immunology</topic><topic>Immunological tolerance</topic><topic>Immunoregulation</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Integrin beta Chains - immunology</topic><topic>Interleukin 2</topic><topic>Interleukin 7</topic><topic>Interleukin-2 - immunology</topic><topic>Interleukin-7 - immunology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Molecular chains</topic><topic>Peripheral blood</topic><topic>Receptors, Lymphocyte Homing - immunology</topic><topic>Skin</topic><topic>Skin - immunology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>Tropism</topic><topic>Tropism - immunology</topic><topic>Up-Regulation - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hsu, Peter S</creatorcontrib><creatorcontrib>Lai, Catherine L</creatorcontrib><creatorcontrib>Hu, Mingjing</creatorcontrib><creatorcontrib>Santner-Nanan, Brigitte</creatorcontrib><creatorcontrib>Dahlstrom, Jane E</creatorcontrib><creatorcontrib>Lee, Cheng Hiang</creatorcontrib><creatorcontrib>Ajmal, Ayesha</creatorcontrib><creatorcontrib>Bullman, Amanda</creatorcontrib><creatorcontrib>Arbuckle, Susan</creatorcontrib><creatorcontrib>Al Saedi, Ahmed</creatorcontrib><creatorcontrib>Gacis, Lou</creatorcontrib><creatorcontrib>Nambiar, Reta</creatorcontrib><creatorcontrib>Williams, Andrew</creatorcontrib><creatorcontrib>Wong, Melanie</creatorcontrib><creatorcontrib>Campbell, Dianne E</creatorcontrib><creatorcontrib>Nanan, Ralph</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hsu, Peter S</au><au>Lai, Catherine L</au><au>Hu, Mingjing</au><au>Santner-Nanan, Brigitte</au><au>Dahlstrom, Jane E</au><au>Lee, Cheng Hiang</au><au>Ajmal, Ayesha</au><au>Bullman, Amanda</au><au>Arbuckle, Susan</au><au>Al Saedi, Ahmed</au><au>Gacis, Lou</au><au>Nambiar, Reta</au><au>Williams, Andrew</au><au>Wong, Melanie</au><au>Campbell, Dianne E</au><au>Nanan, Ralph</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2018-06-15</date><risdate>2018</risdate><volume>200</volume><issue>12</issue><spage>3970</spage><epage>3980</epage><pages>3970-3980</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant β7 integrin
Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA
) Treg cells later in life. β7 integrin
Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced β7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.</abstract><cop>United States</cop><pub>American Association of Immunologists</pub><pmid>29720424</pmid><doi>10.4049/jimmunol.1701533</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-0104-2072</orcidid><orcidid>https://orcid.org/0000-0003-1025-6520</orcidid><orcidid>https://orcid.org/0000-0002-4076-0464</orcidid><orcidid>https://orcid.org/0000-0002-7493-4055</orcidid><orcidid>https://orcid.org/0000-0002-2479-5317</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-1767 |
| ispartof | The Journal of immunology (1950), 2018-06, Vol.200 (12), p.3970-3980 |
| issn | 0022-1767 1550-6606 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2034293457 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent Antigens - immunology Cells, Cultured Child Child, Preschool Children Critical period Environmental factors Environmental regulations Female Gastrointestinal Tract - immunology Homeostasis Homing Humans Immune Tolerance - immunology Immunological tolerance Immunoregulation Infant Infant, Newborn Integrin beta Chains - immunology Interleukin 2 Interleukin 7 Interleukin-2 - immunology Interleukin-7 - immunology Lymphocytes Lymphocytes T Male Molecular chains Peripheral blood Receptors, Lymphocyte Homing - immunology Skin Skin - immunology T-Lymphocytes, Regulatory - immunology Tropism Tropism - immunology Up-Regulation - immunology |
| title | IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-16T00%3A48%3A29IST&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=IL-2%20Enhances%20Gut%20Homing%20Potential%20of%20Human%20Naive%20Regulatory%20T%20Cells%20Early%20in%20Life&rft.jtitle=The%20Journal%20of%20immunology%20(1950)&rft.au=Hsu,%20Peter%20S&rft.date=2018-06-15&rft.volume=200&rft.issue=12&rft.spage=3970&rft.epage=3980&rft.pages=3970-3980&rft.issn=0022-1767&rft.eissn=1550-6606&rft_id=info:doi/10.4049/jimmunol.1701533&rft_dat=%3Cproquest_cross%3E2049659039%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=2049659039&rft_id=info:pmid/29720424&rfr_iscdi=true |