Loading…
Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach
Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were in...
Saved in:
Published in: | Journal of animal science 2017-09, Vol.95 (9), p.4101-4112 |
---|---|
Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | |
---|---|
cites | |
container_end_page | 4112 |
container_issue | 9 |
container_start_page | 4101 |
container_title | Journal of animal science |
container_volume | 95 |
creator | Kirsz, K Szczesna, M Molik, E Zieba, D A |
description | Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were intravenously injected with GHRL (2.5 μg/kg of BW) and meta-Chlorophenylpiperazine (mCPP; a mixed agonist of 5-HT2B/5-HT2C receptors; 1 mg/kg BW), either combined or individually, during the short-day (SDS) and long-day (LDS) seasons. Blood samples were collected at 15-min intervals for 4 h. The second in vitro experiment examined the effect of GHRL (10 ng/mL) on MEL secretion by pineal gland (PG) explants incubated for 5 h. The expression levels and/or concentrations of tryptophan 5-hydroxylase 1 (TPH1), aralkylamine N-acetyltransferase (AA-NAT), and the phosphorylated form of AA-NAT (p31T-AA-NAT) were determined at selected time points during the SDS and LDS seasons. The experiments demonstrated that GHRL reduced MEL secretion ( < 0.01) during the SDS season. Administration of mCPP or a combination of GHRL + mCPP stimulated MEL secretion ( < 0.01) regardless of the season. Furthermore, GHRL regulated nightly MEL secretion in a TPH1-independent manner. However, during the SDS season, GHRL reduced p31T-AA-NAT expression and the AA-NAT concentration ( < 0.01) and inhibited MEL secretion ( < 0.001), whereas during the LDS season, GHRL had no effect on MEL secretion or on the expression of the examined enzymes. These findings indicate that GHRL directly and indirectly affects PG activity in sheep and that the photoperiod modulates the effects of GHRL. |
doi_str_mv | 10.2527/jas2017.1737 |
format | article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1949693341</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1946270829</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1211-9f1bfc5a161d8999ef34fb337abbf5d81a431165387b2275e394725763f105d53</originalsourceid><addsrcrecordid>eNpdkM1LxDAQxYMo7rp68ywBLx7s2kmapvG2LOsHLHjRqyVNE7dL29SkXfC_N_uhiDCQeZkfb5KH0CXEU8IIv1tLT2LgU-CUH6ExMMIiCik9_tOP0Jn36zgGwgQ7RSOSCQGhxuh9YYxWvcfW4I-V03XVYtvi1qp-cK2scaNr2ds2XHutnO6rMN2KldbdPZ7txKbqncWyLfdiE_quc1aq1Tk6MbL2-uJwTtDbw-J1_hQtXx6f57NlpIAARMJAYRSTkEIZnia0oYkpKOWyKAwrM5AJBUgZzXhBCGeaioQTxlNqIGYloxN0s_cNaz8H7fu8qbzSdS1bbQefg0hEKihNIKDX_9C13X11R6WExxkRgbrdU8pZ7502eeeqRrqvHOJ8m3t-yD3f5h7wq4PpUDS6_IV_gqbfHeV8Qg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1946270829</pqid></control><display><type>article</type><title>Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach</title><source>Oxford Journals Online</source><creator>Kirsz, K ; Szczesna, M ; Molik, E ; Zieba, D A</creator><creatorcontrib>Kirsz, K ; Szczesna, M ; Molik, E ; Zieba, D A</creatorcontrib><description>Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were intravenously injected with GHRL (2.5 μg/kg of BW) and meta-Chlorophenylpiperazine (mCPP; a mixed agonist of 5-HT2B/5-HT2C receptors; 1 mg/kg BW), either combined or individually, during the short-day (SDS) and long-day (LDS) seasons. Blood samples were collected at 15-min intervals for 4 h. The second in vitro experiment examined the effect of GHRL (10 ng/mL) on MEL secretion by pineal gland (PG) explants incubated for 5 h. The expression levels and/or concentrations of tryptophan 5-hydroxylase 1 (TPH1), aralkylamine N-acetyltransferase (AA-NAT), and the phosphorylated form of AA-NAT (p31T-AA-NAT) were determined at selected time points during the SDS and LDS seasons. The experiments demonstrated that GHRL reduced MEL secretion ( < 0.01) during the SDS season. Administration of mCPP or a combination of GHRL + mCPP stimulated MEL secretion ( < 0.01) regardless of the season. Furthermore, GHRL regulated nightly MEL secretion in a TPH1-independent manner. However, during the SDS season, GHRL reduced p31T-AA-NAT expression and the AA-NAT concentration ( < 0.01) and inhibited MEL secretion ( < 0.001), whereas during the LDS season, GHRL had no effect on MEL secretion or on the expression of the examined enzymes. These findings indicate that GHRL directly and indirectly affects PG activity in sheep and that the photoperiod modulates the effects of GHRL.</description><identifier>ISSN: 1525-3163</identifier><identifier>ISSN: 0021-8812</identifier><identifier>EISSN: 1525-3163</identifier><identifier>DOI: 10.2527/jas2017.1737</identifier><identifier>PMID: 28991991</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Acyltransferases - genetics ; Acyltransferases - metabolism ; Animals ; Aralkylamine N-acetyltransferase ; Chlorophenylpiperazine ; Circadian Rhythm - drug effects ; Explants ; Female ; Ghrelin ; Ghrelin - administration & dosage ; Growth hormones ; Hydroxylase ; In vivo methods and tests ; Melatonin ; Melatonin - secretion ; Photoperiod ; Pineal gland ; Pineal Gland - drug effects ; Pineal Gland - metabolism ; Pineal Gland - secretion ; Piperazines - administration & dosage ; Receptors ; Reproduction - drug effects ; Seasons ; Secretion ; Serotonin ; Serotonin Receptor Agonists - administration & dosage ; Serotonin receptors ; Serotonin S2 receptors ; Sheep ; Sheep - physiology ; Tryptophan ; Tryptophan Hydroxylase - genetics ; Tryptophan Hydroxylase - metabolism</subject><ispartof>Journal of animal science, 2017-09, Vol.95 (9), p.4101-4112</ispartof><rights>Copyright American Society of Animal Science Sep 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28991991$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kirsz, K</creatorcontrib><creatorcontrib>Szczesna, M</creatorcontrib><creatorcontrib>Molik, E</creatorcontrib><creatorcontrib>Zieba, D A</creatorcontrib><title>Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach</title><title>Journal of animal science</title><addtitle>J Anim Sci</addtitle><description>Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were intravenously injected with GHRL (2.5 μg/kg of BW) and meta-Chlorophenylpiperazine (mCPP; a mixed agonist of 5-HT2B/5-HT2C receptors; 1 mg/kg BW), either combined or individually, during the short-day (SDS) and long-day (LDS) seasons. Blood samples were collected at 15-min intervals for 4 h. The second in vitro experiment examined the effect of GHRL (10 ng/mL) on MEL secretion by pineal gland (PG) explants incubated for 5 h. The expression levels and/or concentrations of tryptophan 5-hydroxylase 1 (TPH1), aralkylamine N-acetyltransferase (AA-NAT), and the phosphorylated form of AA-NAT (p31T-AA-NAT) were determined at selected time points during the SDS and LDS seasons. The experiments demonstrated that GHRL reduced MEL secretion ( < 0.01) during the SDS season. Administration of mCPP or a combination of GHRL + mCPP stimulated MEL secretion ( < 0.01) regardless of the season. Furthermore, GHRL regulated nightly MEL secretion in a TPH1-independent manner. However, during the SDS season, GHRL reduced p31T-AA-NAT expression and the AA-NAT concentration ( < 0.01) and inhibited MEL secretion ( < 0.001), whereas during the LDS season, GHRL had no effect on MEL secretion or on the expression of the examined enzymes. These findings indicate that GHRL directly and indirectly affects PG activity in sheep and that the photoperiod modulates the effects of GHRL.</description><subject>Acyltransferases - genetics</subject><subject>Acyltransferases - metabolism</subject><subject>Animals</subject><subject>Aralkylamine N-acetyltransferase</subject><subject>Chlorophenylpiperazine</subject><subject>Circadian Rhythm - drug effects</subject><subject>Explants</subject><subject>Female</subject><subject>Ghrelin</subject><subject>Ghrelin - administration & dosage</subject><subject>Growth hormones</subject><subject>Hydroxylase</subject><subject>In vivo methods and tests</subject><subject>Melatonin</subject><subject>Melatonin - secretion</subject><subject>Photoperiod</subject><subject>Pineal gland</subject><subject>Pineal Gland - drug effects</subject><subject>Pineal Gland - metabolism</subject><subject>Pineal Gland - secretion</subject><subject>Piperazines - administration & dosage</subject><subject>Receptors</subject><subject>Reproduction - drug effects</subject><subject>Seasons</subject><subject>Secretion</subject><subject>Serotonin</subject><subject>Serotonin Receptor Agonists - administration & dosage</subject><subject>Serotonin receptors</subject><subject>Serotonin S2 receptors</subject><subject>Sheep</subject><subject>Sheep - physiology</subject><subject>Tryptophan</subject><subject>Tryptophan Hydroxylase - genetics</subject><subject>Tryptophan Hydroxylase - metabolism</subject><issn>1525-3163</issn><issn>0021-8812</issn><issn>1525-3163</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpdkM1LxDAQxYMo7rp68ywBLx7s2kmapvG2LOsHLHjRqyVNE7dL29SkXfC_N_uhiDCQeZkfb5KH0CXEU8IIv1tLT2LgU-CUH6ExMMIiCik9_tOP0Jn36zgGwgQ7RSOSCQGhxuh9YYxWvcfW4I-V03XVYtvi1qp-cK2scaNr2ds2XHutnO6rMN2KldbdPZ7txKbqncWyLfdiE_quc1aq1Tk6MbL2-uJwTtDbw-J1_hQtXx6f57NlpIAARMJAYRSTkEIZnia0oYkpKOWyKAwrM5AJBUgZzXhBCGeaioQTxlNqIGYloxN0s_cNaz8H7fu8qbzSdS1bbQefg0hEKihNIKDX_9C13X11R6WExxkRgbrdU8pZ7502eeeqRrqvHOJ8m3t-yD3f5h7wq4PpUDS6_IV_gqbfHeV8Qg</recordid><startdate>201709</startdate><enddate>201709</enddate><creator>Kirsz, K</creator><creator>Szczesna, M</creator><creator>Molik, E</creator><creator>Zieba, D A</creator><general>Oxford University Press</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>3V.</scope><scope>7RQ</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>S0X</scope><scope>U9A</scope><scope>7X8</scope></search><sort><creationdate>201709</creationdate><title>Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach</title><author>Kirsz, K ; Szczesna, M ; Molik, E ; Zieba, D A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1211-9f1bfc5a161d8999ef34fb337abbf5d81a431165387b2275e394725763f105d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acyltransferases - genetics</topic><topic>Acyltransferases - metabolism</topic><topic>Animals</topic><topic>Aralkylamine N-acetyltransferase</topic><topic>Chlorophenylpiperazine</topic><topic>Circadian Rhythm - drug effects</topic><topic>Explants</topic><topic>Female</topic><topic>Ghrelin</topic><topic>Ghrelin - administration & dosage</topic><topic>Growth hormones</topic><topic>Hydroxylase</topic><topic>In vivo methods and tests</topic><topic>Melatonin</topic><topic>Melatonin - secretion</topic><topic>Photoperiod</topic><topic>Pineal gland</topic><topic>Pineal Gland - drug effects</topic><topic>Pineal Gland - metabolism</topic><topic>Pineal Gland - secretion</topic><topic>Piperazines - administration & dosage</topic><topic>Receptors</topic><topic>Reproduction - drug effects</topic><topic>Seasons</topic><topic>Secretion</topic><topic>Serotonin</topic><topic>Serotonin Receptor Agonists - administration & dosage</topic><topic>Serotonin receptors</topic><topic>Serotonin S2 receptors</topic><topic>Sheep</topic><topic>Sheep - physiology</topic><topic>Tryptophan</topic><topic>Tryptophan Hydroxylase - genetics</topic><topic>Tryptophan Hydroxylase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kirsz, K</creatorcontrib><creatorcontrib>Szczesna, M</creatorcontrib><creatorcontrib>Molik, E</creatorcontrib><creatorcontrib>Zieba, D A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Career & Technical Education Database</collection><collection>Agricultural Science Collection</collection><collection>ProQuest 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>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Research Library (Alumni Edition)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest research library</collection><collection>ProQuest Science Journals</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Environmental 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 China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of animal science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kirsz, K</au><au>Szczesna, M</au><au>Molik, E</au><au>Zieba, D A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach</atitle><jtitle>Journal of animal science</jtitle><addtitle>J Anim Sci</addtitle><date>2017-09</date><risdate>2017</risdate><volume>95</volume><issue>9</issue><spage>4101</spage><epage>4112</epage><pages>4101-4112</pages><issn>1525-3163</issn><issn>0021-8812</issn><eissn>1525-3163</eissn><abstract>Recent studies confirmed that pineal melatonin (MEL) secretion is regulated by ghrelin (GHRL) in seasonally reproductive sheep. The first in vivo experiment investigated whether the effect of GHRL on nocturnal secretion of MEL in sheep is mediated by type 2 serotonin receptors. Sheep ( = 16) were intravenously injected with GHRL (2.5 μg/kg of BW) and meta-Chlorophenylpiperazine (mCPP; a mixed agonist of 5-HT2B/5-HT2C receptors; 1 mg/kg BW), either combined or individually, during the short-day (SDS) and long-day (LDS) seasons. Blood samples were collected at 15-min intervals for 4 h. The second in vitro experiment examined the effect of GHRL (10 ng/mL) on MEL secretion by pineal gland (PG) explants incubated for 5 h. The expression levels and/or concentrations of tryptophan 5-hydroxylase 1 (TPH1), aralkylamine N-acetyltransferase (AA-NAT), and the phosphorylated form of AA-NAT (p31T-AA-NAT) were determined at selected time points during the SDS and LDS seasons. The experiments demonstrated that GHRL reduced MEL secretion ( < 0.01) during the SDS season. Administration of mCPP or a combination of GHRL + mCPP stimulated MEL secretion ( < 0.01) regardless of the season. Furthermore, GHRL regulated nightly MEL secretion in a TPH1-independent manner. However, during the SDS season, GHRL reduced p31T-AA-NAT expression and the AA-NAT concentration ( < 0.01) and inhibited MEL secretion ( < 0.001), whereas during the LDS season, GHRL had no effect on MEL secretion or on the expression of the examined enzymes. These findings indicate that GHRL directly and indirectly affects PG activity in sheep and that the photoperiod modulates the effects of GHRL.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>28991991</pmid><doi>10.2527/jas2017.1737</doi><tpages>12</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1525-3163 |
ispartof | Journal of animal science, 2017-09, Vol.95 (9), p.4101-4112 |
issn | 1525-3163 0021-8812 1525-3163 |
language | eng |
recordid | cdi_proquest_miscellaneous_1949693341 |
source | Oxford Journals Online |
subjects | Acyltransferases - genetics Acyltransferases - metabolism Animals Aralkylamine N-acetyltransferase Chlorophenylpiperazine Circadian Rhythm - drug effects Explants Female Ghrelin Ghrelin - administration & dosage Growth hormones Hydroxylase In vivo methods and tests Melatonin Melatonin - secretion Photoperiod Pineal gland Pineal Gland - drug effects Pineal Gland - metabolism Pineal Gland - secretion Piperazines - administration & dosage Receptors Reproduction - drug effects Seasons Secretion Serotonin Serotonin Receptor Agonists - administration & dosage Serotonin receptors Serotonin S2 receptors Sheep Sheep - physiology Tryptophan Tryptophan Hydroxylase - genetics Tryptophan Hydroxylase - metabolism |
title | Effects of ghrelin on nocturnal melatonin secretion in sheep: An in vitro and in vivo approach |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-31T23%3A55%3A04IST&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=Effects%20of%20ghrelin%20on%20nocturnal%20melatonin%20secretion%20in%20sheep:%20An%20in%20vitro%20and%20in%20vivo%20approach&rft.jtitle=Journal%20of%20animal%20science&rft.au=Kirsz,%20K&rft.date=2017-09&rft.volume=95&rft.issue=9&rft.spage=4101&rft.epage=4112&rft.pages=4101-4112&rft.issn=1525-3163&rft.eissn=1525-3163&rft_id=info:doi/10.2527/jas2017.1737&rft_dat=%3Cproquest_cross%3E1946270829%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c1211-9f1bfc5a161d8999ef34fb337abbf5d81a431165387b2275e394725763f105d53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1946270829&rft_id=info:pmid/28991991&rfr_iscdi=true |