Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide
Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement...
Gespeichert in:
Veröffentlicht in: | International journal of molecular sciences 2019-12, Vol.21 (1), p.229 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
container_issue | 1 |
container_start_page | 229 |
container_title | International journal of molecular sciences |
container_volume | 21 |
creator | Asai, Tomoko T Oikawa, Fumi Yoshikawa, Kazunobu Inoue, Naoki Sato, Kenji |
description | Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70-80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts. |
doi_str_mv | 10.3390/ijms21010229 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6982277</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2548638812</sourcerecordid><originalsourceid>FETCH-LOGICAL-c327t-bddb1800cf4795f389372970cb718902572be8e2b703c752764e4f676e5de06a3</originalsourceid><addsrcrecordid>eNpdksFu1DAQhiMEoqVw44wscWmlDTjjJE4uSLBttkhFVCo9W04y2fXi2MFOlu6L8jx42bbacrJn5tM_89sTRW8T-oGxkn5U695DQhMKUD6LjpMUIKY0588P7kfRK-_XlAKDrHwZHbGkpBmn2XH0p7K2jc_RqQ22ZG61lks05BqHUbXoZ-TaWb3V8eW2dfZuO4RIGSSnIR1yw9mMSNOSg2pgF3rb_IMCsAvOyIVZSdMgWTj7e1wR2wVZ1Uu3JfNJj5MLrb_ZySO5-akMqVTtbK2lH8mtV2ZJKhylJl_sZqd6g27qSeUQSeds_7T3w-Cvoxed1B7f3J8n0W118WN-GV99X3ydf76KGwZ8jOu2rZOC0qZLeZl1rCgZh5LTpuZJUVLIONRYINScsoZnwPMU0y7nOWYt0lyyk-jTXneY6h7bBs3opBbD3p2wUomnFaNWYmk3Ii8LAM6DwOm9gLO_JvSj6JVvMHyDwfAiAhhLdyDQgL7_D13byZlgT0CWFjkrigQCNdtTjbPeO-weh0mo2C2MOFyYgL87NPAIP2wI-wuDMb_L</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2548638812</pqid></control><display><type>article</type><title>Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide</title><source>MEDLINE</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Asai, Tomoko T ; Oikawa, Fumi ; Yoshikawa, Kazunobu ; Inoue, Naoki ; Sato, Kenji</creator><creatorcontrib>Asai, Tomoko T ; Oikawa, Fumi ; Yoshikawa, Kazunobu ; Inoue, Naoki ; Sato, Kenji</creatorcontrib><description>Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70-80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21010229</identifier><identifier>PMID: 31905705</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Amino acids ; Animals ; Cattle ; Cell Proliferation ; Cells, Cultured ; Chromatography ; Collagen ; Collagen - pharmacology ; Dipeptides - pharmacology ; Fetal calf serum ; Fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - physiology ; Glycine ; Hydrolysates ; Hydroxyproline ; Ingestion ; Laboratories ; Low molecular weights ; Male ; Mice ; Mice, Inbred BALB C ; Molecular weight ; Peptides ; Proteins ; Serum - chemistry ; Size exclusion chromatography ; Skin ; Skin - cytology</subject><ispartof>International journal of molecular sciences, 2019-12, Vol.21 (1), p.229</ispartof><rights>2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c327t-bddb1800cf4795f389372970cb718902572be8e2b703c752764e4f676e5de06a3</cites><orcidid>0000-0002-8348-6274</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/PMC6982277/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982277/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31905705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Asai, Tomoko T</creatorcontrib><creatorcontrib>Oikawa, Fumi</creatorcontrib><creatorcontrib>Yoshikawa, Kazunobu</creatorcontrib><creatorcontrib>Inoue, Naoki</creatorcontrib><creatorcontrib>Sato, Kenji</creatorcontrib><title>Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70-80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Cattle</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Chromatography</subject><subject>Collagen</subject><subject>Collagen - pharmacology</subject><subject>Dipeptides - pharmacology</subject><subject>Fetal calf serum</subject><subject>Fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - physiology</subject><subject>Glycine</subject><subject>Hydrolysates</subject><subject>Hydroxyproline</subject><subject>Ingestion</subject><subject>Laboratories</subject><subject>Low molecular weights</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular weight</subject><subject>Peptides</subject><subject>Proteins</subject><subject>Serum - chemistry</subject><subject>Size exclusion chromatography</subject><subject>Skin</subject><subject>Skin - cytology</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdksFu1DAQhiMEoqVw44wscWmlDTjjJE4uSLBttkhFVCo9W04y2fXi2MFOlu6L8jx42bbacrJn5tM_89sTRW8T-oGxkn5U695DQhMKUD6LjpMUIKY0588P7kfRK-_XlAKDrHwZHbGkpBmn2XH0p7K2jc_RqQ22ZG61lks05BqHUbXoZ-TaWb3V8eW2dfZuO4RIGSSnIR1yw9mMSNOSg2pgF3rb_IMCsAvOyIVZSdMgWTj7e1wR2wVZ1Uu3JfNJj5MLrb_ZySO5-akMqVTtbK2lH8mtV2ZJKhylJl_sZqd6g27qSeUQSeds_7T3w-Cvoxed1B7f3J8n0W118WN-GV99X3ydf76KGwZ8jOu2rZOC0qZLeZl1rCgZh5LTpuZJUVLIONRYINScsoZnwPMU0y7nOWYt0lyyk-jTXneY6h7bBs3opBbD3p2wUomnFaNWYmk3Ii8LAM6DwOm9gLO_JvSj6JVvMHyDwfAiAhhLdyDQgL7_D13byZlgT0CWFjkrigQCNdtTjbPeO-weh0mo2C2MOFyYgL87NPAIP2wI-wuDMb_L</recordid><startdate>20191228</startdate><enddate>20191228</enddate><creator>Asai, Tomoko T</creator><creator>Oikawa, Fumi</creator><creator>Yoshikawa, Kazunobu</creator><creator>Inoue, Naoki</creator><creator>Sato, Kenji</creator><general>MDPI AG</general><general>MDPI</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8348-6274</orcidid></search><sort><creationdate>20191228</creationdate><title>Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide</title><author>Asai, Tomoko T ; Oikawa, Fumi ; Yoshikawa, Kazunobu ; Inoue, Naoki ; Sato, Kenji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c327t-bddb1800cf4795f389372970cb718902572be8e2b703c752764e4f676e5de06a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amino acids</topic><topic>Animals</topic><topic>Cattle</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Chromatography</topic><topic>Collagen</topic><topic>Collagen - pharmacology</topic><topic>Dipeptides - pharmacology</topic><topic>Fetal calf serum</topic><topic>Fibroblasts</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - physiology</topic><topic>Glycine</topic><topic>Hydrolysates</topic><topic>Hydroxyproline</topic><topic>Ingestion</topic><topic>Laboratories</topic><topic>Low molecular weights</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular weight</topic><topic>Peptides</topic><topic>Proteins</topic><topic>Serum - chemistry</topic><topic>Size exclusion chromatography</topic><topic>Skin</topic><topic>Skin - cytology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Asai, Tomoko T</creatorcontrib><creatorcontrib>Oikawa, Fumi</creatorcontrib><creatorcontrib>Yoshikawa, Kazunobu</creatorcontrib><creatorcontrib>Inoue, Naoki</creatorcontrib><creatorcontrib>Sato, Kenji</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content 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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Asai, Tomoko T</au><au>Oikawa, Fumi</au><au>Yoshikawa, Kazunobu</au><au>Inoue, Naoki</au><au>Sato, Kenji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-12-28</date><risdate>2019</risdate><volume>21</volume><issue>1</issue><spage>229</spage><pages>229-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70-80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31905705</pmid><doi>10.3390/ijms21010229</doi><orcidid>https://orcid.org/0000-0002-8348-6274</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1422-0067 |
ispartof | International journal of molecular sciences, 2019-12, Vol.21 (1), p.229 |
issn | 1422-0067 1661-6596 1422-0067 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6982277 |
source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
subjects | Amino acids Animals Cattle Cell Proliferation Cells, Cultured Chromatography Collagen Collagen - pharmacology Dipeptides - pharmacology Fetal calf serum Fibroblasts Fibroblasts - drug effects Fibroblasts - physiology Glycine Hydrolysates Hydroxyproline Ingestion Laboratories Low molecular weights Male Mice Mice, Inbred BALB C Molecular weight Peptides Proteins Serum - chemistry Size exclusion chromatography Skin Skin - cytology |
title | Food-Derived Collagen Peptides, Prolyl-Hydroxyproline (Pro-Hyp), and Hydroxyprolyl-Glycine (Hyp-Gly) Enhance Growth of Primary Cultured Mouse Skin Fibroblast Using Fetal Bovine Serum Free from Hydroxyprolyl Peptide |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T05%3A57%3A28IST&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=Food-Derived%20Collagen%20Peptides,%20Prolyl-Hydroxyproline%20(Pro-Hyp),%20and%20Hydroxyprolyl-Glycine%20(Hyp-Gly)%20Enhance%20Growth%20of%20Primary%20Cultured%20Mouse%20Skin%20Fibroblast%20Using%20Fetal%20Bovine%20Serum%20Free%20from%20Hydroxyprolyl%20Peptide&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Asai,%20Tomoko%20T&rft.date=2019-12-28&rft.volume=21&rft.issue=1&rft.spage=229&rft.pages=229-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms21010229&rft_dat=%3Cproquest_pubme%3E2548638812%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=2548638812&rft_id=info:pmid/31905705&rfr_iscdi=true |