Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression
•Thymic regulatory T cells are resistant to glucocorticoid hormone treatment.•GC treatment enhances the Treg commitment by elevation of Foxp3 and immunosuppressive cytokine expression.•Colocalization of GR and Foxp3 in Treg suggests an interaction between these transcription factors. Despite the fac...
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| Veröffentlicht in: | Immunobiology (1979) 2018-04, Vol.223 (4-5), p.422-431 |
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| creator | Ugor, Emese Prenek, Lilla Pap, Ramóna Berta, Gergely Ernszt, Dávid Najbauer, József Németh, Péter Boldizsár, Ferenc Berki, Tímea |
| description | •Thymic regulatory T cells are resistant to glucocorticoid hormone treatment.•GC treatment enhances the Treg commitment by elevation of Foxp3 and immunosuppressive cytokine expression.•Colocalization of GR and Foxp3 in Treg suggests an interaction between these transcription factors.
Despite the fact that glucocorticoids (GC) are important therapeutic tools, their effects on regulatory T cells (Treg) are not well defined. The aim of our work was to investigate how GCs influence in vivo the thymic (tTreg) and peripheral Treg (pTreg) differentiation, survival and cytokine production.
Tregs were detected with flow cytometry in lymphatic organs of 4–6 weeks old BALB/c mice after repeated (2–4days), high-dose in vivo GC treatment using CD4/CD25 cell surface and Foxp3/IL-10/TGFβ/glucocorticoid receptor (GR) intracellular staining. Cytokine, Foxp3, and GR mRNA levels of sorted CD4+CD25high T cells were analyzed using RT-PCR. Foxp3 and GR localization in Treg cells was investigated with confocal microscopy.
GC treatment of mice resulted in increased relative tTreg frequency in the thymus, which was due to decreased total thymocyte numbers with unchanged absolute tTreg cell count. In contrast the relative pTreg cell ratio in secondary lymphatic organs decreased or showed no changes after GC treatment, while the absolute number of pTregs decreased. Elevated intracellular IL-10+ and TGFβ+ tTreg and pTreg ratios were measured in GC-treated animals, accompanied with elevated Foxp3 mRNA expression. In addition, GC treatment caused increased TGFβ and IL-35 mRNA expression in CD4+CD25high+ splenic and elevated IL-10 mRNA level in thymic tTregs. GR expression of thymic tTreg cells was lower than in pTregs. GC treatment caused an opposite change in GR levels, elevating GR in tTregs but decreasing it in pTregs. We observed a nuclear localization of GR in both tTregs and pTregs, which showed high colocalization (∼60%) with Foxp3 transcription factor. These data suggest an interaction of these two transcription factors with further increase due to GC treatment in splenic pTregs.
Our data show selective survival of tTregs and elevated production of immunosuppressive cytokines by Treg cells after GC treatment, which may contribute to the immunosuppressive effects of GCs. |
| doi_str_mv | 10.1016/j.imbio.2017.10.010 |
| format | Article |
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Despite the fact that glucocorticoids (GC) are important therapeutic tools, their effects on regulatory T cells (Treg) are not well defined. The aim of our work was to investigate how GCs influence in vivo the thymic (tTreg) and peripheral Treg (pTreg) differentiation, survival and cytokine production.
Tregs were detected with flow cytometry in lymphatic organs of 4–6 weeks old BALB/c mice after repeated (2–4days), high-dose in vivo GC treatment using CD4/CD25 cell surface and Foxp3/IL-10/TGFβ/glucocorticoid receptor (GR) intracellular staining. Cytokine, Foxp3, and GR mRNA levels of sorted CD4+CD25high T cells were analyzed using RT-PCR. Foxp3 and GR localization in Treg cells was investigated with confocal microscopy.
GC treatment of mice resulted in increased relative tTreg frequency in the thymus, which was due to decreased total thymocyte numbers with unchanged absolute tTreg cell count. In contrast the relative pTreg cell ratio in secondary lymphatic organs decreased or showed no changes after GC treatment, while the absolute number of pTregs decreased. Elevated intracellular IL-10+ and TGFβ+ tTreg and pTreg ratios were measured in GC-treated animals, accompanied with elevated Foxp3 mRNA expression. In addition, GC treatment caused increased TGFβ and IL-35 mRNA expression in CD4+CD25high+ splenic and elevated IL-10 mRNA level in thymic tTregs. GR expression of thymic tTreg cells was lower than in pTregs. GC treatment caused an opposite change in GR levels, elevating GR in tTregs but decreasing it in pTregs. We observed a nuclear localization of GR in both tTregs and pTregs, which showed high colocalization (∼60%) with Foxp3 transcription factor. These data suggest an interaction of these two transcription factors with further increase due to GC treatment in splenic pTregs.
Our data show selective survival of tTregs and elevated production of immunosuppressive cytokines by Treg cells after GC treatment, which may contribute to the immunosuppressive effects of GCs.</description><identifier>ISSN: 0171-2985</identifier><identifier>EISSN: 1878-3279</identifier><identifier>DOI: 10.1016/j.imbio.2017.10.010</identifier><identifier>PMID: 29223294</identifier><language>eng</language><publisher>Netherlands: Elsevier GmbH</publisher><subject>Animals ; Blood Circulation ; Cell Survival ; Cells, Cultured ; Dexamethasone ; Forkhead Transcription Factors - genetics ; Forkhead Transcription Factors - metabolism ; Foxp3 ; Glucocorticoid receptor ; Glucocorticoids - therapeutic use ; IL-10 ; Immunosuppression ; Interleukin-10 - metabolism ; Interleukin-2 Receptor alpha Subunit - metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Receptors, Glucocorticoid - metabolism ; T-Lymphocytes, Regulatory - immunology ; TGFβ ; Thymus Gland - immunology ; Transforming Growth Factor beta - metabolism ; Treg ; Up-Regulation</subject><ispartof>Immunobiology (1979), 2018-04, Vol.223 (4-5), p.422-431</ispartof><rights>2017 The Authors</rights><rights>Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-30f22a87ab8c9e9baf3a7173b78abd9faa461d98bf02887364c32af88517f0293</citedby><cites>FETCH-LOGICAL-c404t-30f22a87ab8c9e9baf3a7173b78abd9faa461d98bf02887364c32af88517f0293</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.imbio.2017.10.010$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29223294$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ugor, Emese</creatorcontrib><creatorcontrib>Prenek, Lilla</creatorcontrib><creatorcontrib>Pap, Ramóna</creatorcontrib><creatorcontrib>Berta, Gergely</creatorcontrib><creatorcontrib>Ernszt, Dávid</creatorcontrib><creatorcontrib>Najbauer, József</creatorcontrib><creatorcontrib>Németh, Péter</creatorcontrib><creatorcontrib>Boldizsár, Ferenc</creatorcontrib><creatorcontrib>Berki, Tímea</creatorcontrib><title>Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression</title><title>Immunobiology (1979)</title><addtitle>Immunobiology</addtitle><description>•Thymic regulatory T cells are resistant to glucocorticoid hormone treatment.•GC treatment enhances the Treg commitment by elevation of Foxp3 and immunosuppressive cytokine expression.•Colocalization of GR and Foxp3 in Treg suggests an interaction between these transcription factors.
Despite the fact that glucocorticoids (GC) are important therapeutic tools, their effects on regulatory T cells (Treg) are not well defined. The aim of our work was to investigate how GCs influence in vivo the thymic (tTreg) and peripheral Treg (pTreg) differentiation, survival and cytokine production.
Tregs were detected with flow cytometry in lymphatic organs of 4–6 weeks old BALB/c mice after repeated (2–4days), high-dose in vivo GC treatment using CD4/CD25 cell surface and Foxp3/IL-10/TGFβ/glucocorticoid receptor (GR) intracellular staining. Cytokine, Foxp3, and GR mRNA levels of sorted CD4+CD25high T cells were analyzed using RT-PCR. Foxp3 and GR localization in Treg cells was investigated with confocal microscopy.
GC treatment of mice resulted in increased relative tTreg frequency in the thymus, which was due to decreased total thymocyte numbers with unchanged absolute tTreg cell count. In contrast the relative pTreg cell ratio in secondary lymphatic organs decreased or showed no changes after GC treatment, while the absolute number of pTregs decreased. Elevated intracellular IL-10+ and TGFβ+ tTreg and pTreg ratios were measured in GC-treated animals, accompanied with elevated Foxp3 mRNA expression. In addition, GC treatment caused increased TGFβ and IL-35 mRNA expression in CD4+CD25high+ splenic and elevated IL-10 mRNA level in thymic tTregs. GR expression of thymic tTreg cells was lower than in pTregs. GC treatment caused an opposite change in GR levels, elevating GR in tTregs but decreasing it in pTregs. We observed a nuclear localization of GR in both tTregs and pTregs, which showed high colocalization (∼60%) with Foxp3 transcription factor. These data suggest an interaction of these two transcription factors with further increase due to GC treatment in splenic pTregs.
Our data show selective survival of tTregs and elevated production of immunosuppressive cytokines by Treg cells after GC treatment, which may contribute to the immunosuppressive effects of GCs.</description><subject>Animals</subject><subject>Blood Circulation</subject><subject>Cell Survival</subject><subject>Cells, Cultured</subject><subject>Dexamethasone</subject><subject>Forkhead Transcription Factors - genetics</subject><subject>Forkhead Transcription Factors - metabolism</subject><subject>Foxp3</subject><subject>Glucocorticoid receptor</subject><subject>Glucocorticoids - therapeutic use</subject><subject>IL-10</subject><subject>Immunosuppression</subject><subject>Interleukin-10 - metabolism</subject><subject>Interleukin-2 Receptor alpha Subunit - metabolism</subject><subject>Lymphocyte Activation</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>TGFβ</subject><subject>Thymus Gland - immunology</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Treg</subject><subject>Up-Regulation</subject><issn>0171-2985</issn><issn>1878-3279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EgvL4AiTkJZsUP9LaXrBAiJeExAbWluNMqEsSF9tBVPw8Di0sWVk6c8czcxA6pWRKCZ1fLKeuq5yfMkJFJlNCyQ6aUClkwZlQu2iSC7RgSs4O0GGMS0KoYkLuowOmGONMlRP0ddcO1lsfkrPe1XjhQ-d7wCmASR30CUO_ML2FiNMCsF0n_-ZyfRV8PdjkfI99gwO8Dq1JPqzxM7bQthFXazystnybuvWfK47hM-MYMztGe41pI5xs3yP0cnvzfH1fPD7dPVxfPRa2JGUqOGkYM1KYSloFqjINN4IKXglpqlo1xpRzWitZNYRJKfi8tJyZRsoZFRkpfoTON__mpd8HiEl3Lo5bmh78EDVVYjZTJVNjlG-iNvgYAzR6FVxnwlpTokfreql_rOvR-giz9dx1th0wVB3Ufz2_mnPgchOAfOaHg6CjdZCt1i6ATbr27t8B3wjml0I</recordid><startdate>201804</startdate><enddate>201804</enddate><creator>Ugor, Emese</creator><creator>Prenek, Lilla</creator><creator>Pap, Ramóna</creator><creator>Berta, Gergely</creator><creator>Ernszt, Dávid</creator><creator>Najbauer, József</creator><creator>Németh, Péter</creator><creator>Boldizsár, Ferenc</creator><creator>Berki, Tímea</creator><general>Elsevier GmbH</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope></search><sort><creationdate>201804</creationdate><title>Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression</title><author>Ugor, Emese ; Prenek, Lilla ; Pap, Ramóna ; Berta, Gergely ; Ernszt, Dávid ; Najbauer, József ; Németh, Péter ; Boldizsár, Ferenc ; Berki, Tímea</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-30f22a87ab8c9e9baf3a7173b78abd9faa461d98bf02887364c32af88517f0293</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Blood Circulation</topic><topic>Cell Survival</topic><topic>Cells, Cultured</topic><topic>Dexamethasone</topic><topic>Forkhead Transcription Factors - genetics</topic><topic>Forkhead Transcription Factors - metabolism</topic><topic>Foxp3</topic><topic>Glucocorticoid receptor</topic><topic>Glucocorticoids - therapeutic use</topic><topic>IL-10</topic><topic>Immunosuppression</topic><topic>Interleukin-10 - metabolism</topic><topic>Interleukin-2 Receptor alpha Subunit - metabolism</topic><topic>Lymphocyte Activation</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>TGFβ</topic><topic>Thymus Gland - immunology</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Treg</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ugor, Emese</creatorcontrib><creatorcontrib>Prenek, Lilla</creatorcontrib><creatorcontrib>Pap, Ramóna</creatorcontrib><creatorcontrib>Berta, Gergely</creatorcontrib><creatorcontrib>Ernszt, Dávid</creatorcontrib><creatorcontrib>Najbauer, József</creatorcontrib><creatorcontrib>Németh, Péter</creatorcontrib><creatorcontrib>Boldizsár, Ferenc</creatorcontrib><creatorcontrib>Berki, Tímea</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Immunobiology (1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ugor, Emese</au><au>Prenek, Lilla</au><au>Pap, Ramóna</au><au>Berta, Gergely</au><au>Ernszt, Dávid</au><au>Najbauer, József</au><au>Németh, Péter</au><au>Boldizsár, Ferenc</au><au>Berki, Tímea</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression</atitle><jtitle>Immunobiology (1979)</jtitle><addtitle>Immunobiology</addtitle><date>2018-04</date><risdate>2018</risdate><volume>223</volume><issue>4-5</issue><spage>422</spage><epage>431</epage><pages>422-431</pages><issn>0171-2985</issn><eissn>1878-3279</eissn><abstract>•Thymic regulatory T cells are resistant to glucocorticoid hormone treatment.•GC treatment enhances the Treg commitment by elevation of Foxp3 and immunosuppressive cytokine expression.•Colocalization of GR and Foxp3 in Treg suggests an interaction between these transcription factors.
Despite the fact that glucocorticoids (GC) are important therapeutic tools, their effects on regulatory T cells (Treg) are not well defined. The aim of our work was to investigate how GCs influence in vivo the thymic (tTreg) and peripheral Treg (pTreg) differentiation, survival and cytokine production.
Tregs were detected with flow cytometry in lymphatic organs of 4–6 weeks old BALB/c mice after repeated (2–4days), high-dose in vivo GC treatment using CD4/CD25 cell surface and Foxp3/IL-10/TGFβ/glucocorticoid receptor (GR) intracellular staining. Cytokine, Foxp3, and GR mRNA levels of sorted CD4+CD25high T cells were analyzed using RT-PCR. Foxp3 and GR localization in Treg cells was investigated with confocal microscopy.
GC treatment of mice resulted in increased relative tTreg frequency in the thymus, which was due to decreased total thymocyte numbers with unchanged absolute tTreg cell count. In contrast the relative pTreg cell ratio in secondary lymphatic organs decreased or showed no changes after GC treatment, while the absolute number of pTregs decreased. Elevated intracellular IL-10+ and TGFβ+ tTreg and pTreg ratios were measured in GC-treated animals, accompanied with elevated Foxp3 mRNA expression. In addition, GC treatment caused increased TGFβ and IL-35 mRNA expression in CD4+CD25high+ splenic and elevated IL-10 mRNA level in thymic tTregs. GR expression of thymic tTreg cells was lower than in pTregs. GC treatment caused an opposite change in GR levels, elevating GR in tTregs but decreasing it in pTregs. We observed a nuclear localization of GR in both tTregs and pTregs, which showed high colocalization (∼60%) with Foxp3 transcription factor. These data suggest an interaction of these two transcription factors with further increase due to GC treatment in splenic pTregs.
Our data show selective survival of tTregs and elevated production of immunosuppressive cytokines by Treg cells after GC treatment, which may contribute to the immunosuppressive effects of GCs.</abstract><cop>Netherlands</cop><pub>Elsevier GmbH</pub><pmid>29223294</pmid><doi>10.1016/j.imbio.2017.10.010</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blood Circulation Cell Survival Cells, Cultured Dexamethasone Forkhead Transcription Factors - genetics Forkhead Transcription Factors - metabolism Foxp3 Glucocorticoid receptor Glucocorticoids - therapeutic use IL-10 Immunosuppression Interleukin-10 - metabolism Interleukin-2 Receptor alpha Subunit - metabolism Lymphocyte Activation Mice Mice, Inbred BALB C Receptors, Glucocorticoid - metabolism T-Lymphocytes, Regulatory - immunology TGFβ Thymus Gland - immunology Transforming Growth Factor beta - metabolism Treg Up-Regulation |
| title | Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression |
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