Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model
Bifidobacterium species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of Bacillus subtilis C-3102 (referred to as C-3102) stimulated the growth of Bifidobac...
Gespeichert in:
Veröffentlicht in: | Scientific reports 2020-05, Vol.10 (1), p.7591-7591, Article 7591 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 7591 |
---|---|
container_issue | 1 |
container_start_page | 7591 |
container_title | Scientific reports |
container_volume | 10 |
creator | Hatanaka, Misaki Morita, Hiroto Aoyagi, Yumi Sasaki, Kengo Sasaki, Daisuke Kondo, Akihiko Nakamura, Teppei |
description | Bifidobacterium
species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of
Bacillus subtilis
C-3102 (referred to as C-3102) stimulated the growth of
Bifidobacterium
species. In this study, we isolated and identified six bifidogenic growth factors, which were cyclo (D-Val-D-Ile), cyclo (
L
-Val-D-Ile), cyclo (D-Val-L-Ile), cyclo (L-Val-L-Ile), cyclo (D-Val-L-Leu) and cyclo (L-Val-L-Leu). These six cyclic dipeptides increased the growth of
Bifidobacterium
species and had no effect on potentially harmful gut organisms. Moreover, supplementation with a mixture of these six cyclic dipeptides significantly increased the abundance of microorganisms related to the genus
Bifidobacterium
in a human colonic microbiota model culture system, although supplementation with a single type of dipeptide had no effect. These results show that cyclic dipeptides containing Val-Leu and Val-Ile produced by C-3102 could serve as bifidogenic growth factors in the gut microbial community. |
doi_str_mv | 10.1038/s41598-020-64374-w |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7200657</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2398582198</sourcerecordid><originalsourceid>FETCH-LOGICAL-c621t-e4b6446f0bafcb70c610d3d3aff42ba7c4a62c28b7953d3cb76c4e5475f6ec633</originalsourceid><addsrcrecordid>eNp9kc9u1DAQxiNERau2L8ABWeLCxcX_4iQXJFiVUmmlXoCrZTvjXVdOvNhJV_sUvDJetpSlB3yxNfObbzzzVdVrSq4o4e37LGjdtZgwgqXgjcDbF9UZI6LGjDP28uh9Wl3mfE_KqVknaPeqOuWMN4zw5qz6ee0c2Mk_ADLe-T6uYPQWrVLcTmvktJ1iysjubIj4uw54CTPSY38UuQ2ANin2s4UemR36pK0PYc4oz2bywWe0wJwShvyIpjWg9TzoEdkY4r7R4G2KxsdJoyH2EC6qE6dDhsvH-7z69vn66-ILXt7d3C4-LrGVjE4YhJFCSEeMdtY0xEpKet5z7ZxgRjdWaMksa03T1SVcEGkF1KKpnQQrOT-vPhx0N7MZoLcwTkkHtUl-0Gmnovbq38zo12oVH1TZG5F1UwTePQqk-GOGPKnBZwsh6BHinBXjXccEpbwt6Ntn6H2c01jG21Nt3TLa7Sl2oMpCck7gnj5Didpbrg6Wq2K5-m252paiN8djPJX8MbgA_ADkkhpXkP72_o_sLzD-uZc</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2398582198</pqid></control><display><type>article</type><title>Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Hatanaka, Misaki ; Morita, Hiroto ; Aoyagi, Yumi ; Sasaki, Kengo ; Sasaki, Daisuke ; Kondo, Akihiko ; Nakamura, Teppei</creator><creatorcontrib>Hatanaka, Misaki ; Morita, Hiroto ; Aoyagi, Yumi ; Sasaki, Kengo ; Sasaki, Daisuke ; Kondo, Akihiko ; Nakamura, Teppei</creatorcontrib><description>Bifidobacterium
species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of
Bacillus subtilis
C-3102 (referred to as C-3102) stimulated the growth of
Bifidobacterium
species. In this study, we isolated and identified six bifidogenic growth factors, which were cyclo (D-Val-D-Ile), cyclo (
L
-Val-D-Ile), cyclo (D-Val-L-Ile), cyclo (L-Val-L-Ile), cyclo (D-Val-L-Leu) and cyclo (L-Val-L-Leu). These six cyclic dipeptides increased the growth of
Bifidobacterium
species and had no effect on potentially harmful gut organisms. Moreover, supplementation with a mixture of these six cyclic dipeptides significantly increased the abundance of microorganisms related to the genus
Bifidobacterium
in a human colonic microbiota model culture system, although supplementation with a single type of dipeptide had no effect. These results show that cyclic dipeptides containing Val-Leu and Val-Ile produced by C-3102 could serve as bifidogenic growth factors in the gut microbial community.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-64374-w</identifier><identifier>PMID: 32372037</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>140/131 ; 45/77 ; 631/326/2565/2134 ; 631/326/41 ; Bacillus subtilis ; Bacillus subtilis - drug effects ; Bacillus subtilis - metabolism ; Bifidobacterium ; Bifidobacterium - drug effects ; Bifidobacterium - growth & development ; Chromatography, Liquid ; Colon ; Cyclic dipeptides ; Fermentation ; Gastrointestinal Microbiome ; Growth factors ; Humanities and Social Sciences ; Humans ; Intestinal microflora ; Microbiota ; Microorganisms ; multidisciplinary ; Peptides, Cyclic - analysis ; Peptides, Cyclic - biosynthesis ; Peptides, Cyclic - pharmacology ; Science ; Science (multidisciplinary) ; Species ; Tandem Mass Spectrometry</subject><ispartof>Scientific reports, 2020-05, Vol.10 (1), p.7591-7591, Article 7591</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c621t-e4b6446f0bafcb70c610d3d3aff42ba7c4a62c28b7953d3cb76c4e5475f6ec633</citedby><cites>FETCH-LOGICAL-c621t-e4b6446f0bafcb70c610d3d3aff42ba7c4a62c28b7953d3cb76c4e5475f6ec633</cites><orcidid>0000-0003-1527-5288 ; 0000-0002-5764-1429</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/PMC7200657/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200657/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32372037$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hatanaka, Misaki</creatorcontrib><creatorcontrib>Morita, Hiroto</creatorcontrib><creatorcontrib>Aoyagi, Yumi</creatorcontrib><creatorcontrib>Sasaki, Kengo</creatorcontrib><creatorcontrib>Sasaki, Daisuke</creatorcontrib><creatorcontrib>Kondo, Akihiko</creatorcontrib><creatorcontrib>Nakamura, Teppei</creatorcontrib><title>Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Bifidobacterium
species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of
Bacillus subtilis
C-3102 (referred to as C-3102) stimulated the growth of
Bifidobacterium
species. In this study, we isolated and identified six bifidogenic growth factors, which were cyclo (D-Val-D-Ile), cyclo (
L
-Val-D-Ile), cyclo (D-Val-L-Ile), cyclo (L-Val-L-Ile), cyclo (D-Val-L-Leu) and cyclo (L-Val-L-Leu). These six cyclic dipeptides increased the growth of
Bifidobacterium
species and had no effect on potentially harmful gut organisms. Moreover, supplementation with a mixture of these six cyclic dipeptides significantly increased the abundance of microorganisms related to the genus
Bifidobacterium
in a human colonic microbiota model culture system, although supplementation with a single type of dipeptide had no effect. These results show that cyclic dipeptides containing Val-Leu and Val-Ile produced by C-3102 could serve as bifidogenic growth factors in the gut microbial community.</description><subject>140/131</subject><subject>45/77</subject><subject>631/326/2565/2134</subject><subject>631/326/41</subject><subject>Bacillus subtilis</subject><subject>Bacillus subtilis - drug effects</subject><subject>Bacillus subtilis - metabolism</subject><subject>Bifidobacterium</subject><subject>Bifidobacterium - drug effects</subject><subject>Bifidobacterium - growth & development</subject><subject>Chromatography, Liquid</subject><subject>Colon</subject><subject>Cyclic dipeptides</subject><subject>Fermentation</subject><subject>Gastrointestinal Microbiome</subject><subject>Growth factors</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Intestinal microflora</subject><subject>Microbiota</subject><subject>Microorganisms</subject><subject>multidisciplinary</subject><subject>Peptides, Cyclic - analysis</subject><subject>Peptides, Cyclic - biosynthesis</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Species</subject><subject>Tandem Mass Spectrometry</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc9u1DAQxiNERau2L8ABWeLCxcX_4iQXJFiVUmmlXoCrZTvjXVdOvNhJV_sUvDJetpSlB3yxNfObbzzzVdVrSq4o4e37LGjdtZgwgqXgjcDbF9UZI6LGjDP28uh9Wl3mfE_KqVknaPeqOuWMN4zw5qz6ee0c2Mk_ADLe-T6uYPQWrVLcTmvktJ1iysjubIj4uw54CTPSY38UuQ2ANin2s4UemR36pK0PYc4oz2bywWe0wJwShvyIpjWg9TzoEdkY4r7R4G2KxsdJoyH2EC6qE6dDhsvH-7z69vn66-ILXt7d3C4-LrGVjE4YhJFCSEeMdtY0xEpKet5z7ZxgRjdWaMksa03T1SVcEGkF1KKpnQQrOT-vPhx0N7MZoLcwTkkHtUl-0Gmnovbq38zo12oVH1TZG5F1UwTePQqk-GOGPKnBZwsh6BHinBXjXccEpbwt6Ntn6H2c01jG21Nt3TLa7Sl2oMpCck7gnj5Didpbrg6Wq2K5-m252paiN8djPJX8MbgA_ADkkhpXkP72_o_sLzD-uZc</recordid><startdate>20200505</startdate><enddate>20200505</enddate><creator>Hatanaka, Misaki</creator><creator>Morita, Hiroto</creator><creator>Aoyagi, Yumi</creator><creator>Sasaki, Kengo</creator><creator>Sasaki, Daisuke</creator><creator>Kondo, Akihiko</creator><creator>Nakamura, Teppei</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1527-5288</orcidid><orcidid>https://orcid.org/0000-0002-5764-1429</orcidid></search><sort><creationdate>20200505</creationdate><title>Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model</title><author>Hatanaka, Misaki ; Morita, Hiroto ; Aoyagi, Yumi ; Sasaki, Kengo ; Sasaki, Daisuke ; Kondo, Akihiko ; Nakamura, Teppei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c621t-e4b6446f0bafcb70c610d3d3aff42ba7c4a62c28b7953d3cb76c4e5475f6ec633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>140/131</topic><topic>45/77</topic><topic>631/326/2565/2134</topic><topic>631/326/41</topic><topic>Bacillus subtilis</topic><topic>Bacillus subtilis - drug effects</topic><topic>Bacillus subtilis - metabolism</topic><topic>Bifidobacterium</topic><topic>Bifidobacterium - drug effects</topic><topic>Bifidobacterium - growth & development</topic><topic>Chromatography, Liquid</topic><topic>Colon</topic><topic>Cyclic dipeptides</topic><topic>Fermentation</topic><topic>Gastrointestinal Microbiome</topic><topic>Growth factors</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Intestinal microflora</topic><topic>Microbiota</topic><topic>Microorganisms</topic><topic>multidisciplinary</topic><topic>Peptides, Cyclic - analysis</topic><topic>Peptides, Cyclic - biosynthesis</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Species</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hatanaka, Misaki</creatorcontrib><creatorcontrib>Morita, Hiroto</creatorcontrib><creatorcontrib>Aoyagi, Yumi</creatorcontrib><creatorcontrib>Sasaki, Kengo</creatorcontrib><creatorcontrib>Sasaki, Daisuke</creatorcontrib><creatorcontrib>Kondo, Akihiko</creatorcontrib><creatorcontrib>Nakamura, Teppei</creatorcontrib><collection>Springer Nature OA Free Journals</collection><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>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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 Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</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>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>Biological Science Database</collection><collection>Access via ProQuest (Open Access)</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hatanaka, Misaki</au><au>Morita, Hiroto</au><au>Aoyagi, Yumi</au><au>Sasaki, Kengo</au><au>Sasaki, Daisuke</au><au>Kondo, Akihiko</au><au>Nakamura, Teppei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-05-05</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>7591</spage><epage>7591</epage><pages>7591-7591</pages><artnum>7591</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Bifidobacterium
species are known to fulfill important functions within the human colon. Thus, stimulating the activity of bifidobacteria is important to maintain host health. We revealed that culture supernatants of
Bacillus subtilis
C-3102 (referred to as C-3102) stimulated the growth of
Bifidobacterium
species. In this study, we isolated and identified six bifidogenic growth factors, which were cyclo (D-Val-D-Ile), cyclo (
L
-Val-D-Ile), cyclo (D-Val-L-Ile), cyclo (L-Val-L-Ile), cyclo (D-Val-L-Leu) and cyclo (L-Val-L-Leu). These six cyclic dipeptides increased the growth of
Bifidobacterium
species and had no effect on potentially harmful gut organisms. Moreover, supplementation with a mixture of these six cyclic dipeptides significantly increased the abundance of microorganisms related to the genus
Bifidobacterium
in a human colonic microbiota model culture system, although supplementation with a single type of dipeptide had no effect. These results show that cyclic dipeptides containing Val-Leu and Val-Ile produced by C-3102 could serve as bifidogenic growth factors in the gut microbial community.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32372037</pmid><doi>10.1038/s41598-020-64374-w</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-1527-5288</orcidid><orcidid>https://orcid.org/0000-0002-5764-1429</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2045-2322 |
ispartof | Scientific reports, 2020-05, Vol.10 (1), p.7591-7591, Article 7591 |
issn | 2045-2322 2045-2322 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7200657 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | 140/131 45/77 631/326/2565/2134 631/326/41 Bacillus subtilis Bacillus subtilis - drug effects Bacillus subtilis - metabolism Bifidobacterium Bifidobacterium - drug effects Bifidobacterium - growth & development Chromatography, Liquid Colon Cyclic dipeptides Fermentation Gastrointestinal Microbiome Growth factors Humanities and Social Sciences Humans Intestinal microflora Microbiota Microorganisms multidisciplinary Peptides, Cyclic - analysis Peptides, Cyclic - biosynthesis Peptides, Cyclic - pharmacology Science Science (multidisciplinary) Species Tandem Mass Spectrometry |
title | Effective bifidogenic growth factors cyclo-Val-Leu and cyclo-Val-Ile produced by Bacillus subtilis C-3102 in the human colonic microbiota model |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T23%3A48%3A43IST&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=Effective%20bifidogenic%20growth%20factors%20cyclo-Val-Leu%20and%20cyclo-Val-Ile%20produced%20by%20Bacillus%20subtilis%20C-3102%20in%20the%20human%20colonic%20microbiota%20model&rft.jtitle=Scientific%20reports&rft.au=Hatanaka,%20Misaki&rft.date=2020-05-05&rft.volume=10&rft.issue=1&rft.spage=7591&rft.epage=7591&rft.pages=7591-7591&rft.artnum=7591&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-020-64374-w&rft_dat=%3Cproquest_pubme%3E2398582198%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=2398582198&rft_id=info:pmid/32372037&rfr_iscdi=true |