Loading…

Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels

Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen sa...

Full description

Saved in:
Bibliographic Details
Published in:International journal of molecular sciences 2019-01, Vol.20 (1), p.203
Main Authors: Dias, Tânia R, Samanta, Luna, Agarwal, Ashok, Pushparaj, Peter N, Panner Selvam, Manesh Kumar, Sharma, Rakesh
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3
cites cdi_FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3
container_end_page
container_issue 1
container_start_page 203
container_title International journal of molecular sciences
container_volume 20
creator Dias, Tânia R
Samanta, Luna
Agarwal, Ashok
Pushparaj, Peter N
Panner Selvam, Manesh Kumar
Sharma, Rakesh
description Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen samples from fertile men were divided into two groups: control ( = 10, ROS < 102.2 RLU/s/10⁶ sperm) and ROS+ ( = 10, ROS > 102.2 RLU/s/10⁶ sperm). Proteomic analysis of seminal plasma and spermatozoa was used to identify the differentially expressed proteins (DEPs) between the experimental groups, from which some proteins were validated by Western blot (WB). A total of 44 and 371 DEPs were identified between the study groups in the seminal plasma and spermatozoa, respectively. The identified DEPs were primarily involved in oxidoreductase, endopeptidase inhibitor, and antioxidant activities. We validated by WB the underexpression of NADH:ubiquinone oxidoreductase core subunit S1 ( = 0.01), as well as the overexpression of superoxide dismutase 1 ( = 0.03) and peroxiredoxin 4 ( = 0.04) in spermatozoa of ROS+ group. Our data suggest that fertile men with high ROS levels possess an effective antioxidant defense system that protects sperm proteins, as well as an active proteasomal system for degradation of defective proteins.
doi_str_mv 10.3390/ijms20010203
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6337289</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2179310522</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3</originalsourceid><addsrcrecordid>eNpdkU1vEzEQhi0EoqXlxhlZ4sKhaf21u_EFKWoprZSqqClny2vPJo527WB7A_0f_GAcWqrAyda8jx7PeBB6R8kp55KcufWQGCGUMMJfoEMqGJsQUjcv9-4H6E1Ka0IYZ5V8jQ44qVlNqDhEv77GkCEMzuCFW3qdxwgJ38EWdI8vXNdBBG9KyXm8yCXbhWkTfIITPPPZhZ_Oap_xBXRQilh7i_84dQpDccxMdluXH3aCS4jZ9YBvwOMfLq_wlVuu8AIG5wt5d7vA8_Jwn47Rq073Cd4-nUfo2-Xn-_Oryfz2y_X5bD4xgrI8qYWuNWmnVtiOc0tI09ryC8y2bVPVDetaK5uOV4wJaSrBpRCyallbGV4SY_gR-vTo3YztANaAz1H3ahPdoOODCtqpfxPvVmoZtqrmvGFTWQQfnwQxfB8hZTW4ZKDvtYcwJsVoIzklpYOCfvgPXYcxlrkLxTmdSiqbaaFOHikTQ0oRuudmKFG7dav9dRf8_f4Az_Df_fLftqmoNw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2331891978</pqid></control><display><type>article</type><title>Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels</title><source>PubMed (Medline)</source><source>Publicly Available Content (ProQuest)</source><creator>Dias, Tânia R ; Samanta, Luna ; Agarwal, Ashok ; Pushparaj, Peter N ; Panner Selvam, Manesh Kumar ; Sharma, Rakesh</creator><creatorcontrib>Dias, Tânia R ; Samanta, Luna ; Agarwal, Ashok ; Pushparaj, Peter N ; Panner Selvam, Manesh Kumar ; Sharma, Rakesh</creatorcontrib><description>Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen samples from fertile men were divided into two groups: control ( = 10, ROS &lt; 102.2 RLU/s/10⁶ sperm) and ROS+ ( = 10, ROS &gt; 102.2 RLU/s/10⁶ sperm). Proteomic analysis of seminal plasma and spermatozoa was used to identify the differentially expressed proteins (DEPs) between the experimental groups, from which some proteins were validated by Western blot (WB). A total of 44 and 371 DEPs were identified between the study groups in the seminal plasma and spermatozoa, respectively. The identified DEPs were primarily involved in oxidoreductase, endopeptidase inhibitor, and antioxidant activities. We validated by WB the underexpression of NADH:ubiquinone oxidoreductase core subunit S1 ( = 0.01), as well as the overexpression of superoxide dismutase 1 ( = 0.03) and peroxiredoxin 4 ( = 0.04) in spermatozoa of ROS+ group. Our data suggest that fertile men with high ROS levels possess an effective antioxidant defense system that protects sperm proteins, as well as an active proteasomal system for degradation of defective proteins.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20010203</identifier><identifier>PMID: 30626014</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Antioxidants ; Antioxidants - metabolism ; Biological activity ; Chromatin ; Cytokines ; Deoxyribonucleic acid ; DNA ; DNA fragmentation ; Fertility ; Fragmentation ; Genetic screening ; Genetic testing ; Humans ; Infertility ; Male ; Molecular Sequence Annotation ; Oxidative Stress ; Physiology ; Proteasomes ; Protein expression ; Protein folding ; Proteins ; Proteomics - methods ; Reactive Oxygen Species - metabolism ; Regulation ; Reproductive technologies ; Semen ; Semen - metabolism ; Sperm ; Spermatozoa - metabolism ; Stress response ; Tumor necrosis factor-TNF</subject><ispartof>International journal of molecular sciences, 2019-01, Vol.20 (1), p.203</ispartof><rights>2019. This work is licensed under https://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><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3</citedby><cites>FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3</cites><orcidid>0000-0001-7574-1880 ; 0000-0002-2969-0071 ; 0000-0003-0585-1026 ; 0000-0002-2336-8006</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2331891978/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2331891978?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25728,27898,27899,36986,36987,44563,53763,53765,75093</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30626014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dias, Tânia R</creatorcontrib><creatorcontrib>Samanta, Luna</creatorcontrib><creatorcontrib>Agarwal, Ashok</creatorcontrib><creatorcontrib>Pushparaj, Peter N</creatorcontrib><creatorcontrib>Panner Selvam, Manesh Kumar</creatorcontrib><creatorcontrib>Sharma, Rakesh</creatorcontrib><title>Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen samples from fertile men were divided into two groups: control ( = 10, ROS &lt; 102.2 RLU/s/10⁶ sperm) and ROS+ ( = 10, ROS &gt; 102.2 RLU/s/10⁶ sperm). Proteomic analysis of seminal plasma and spermatozoa was used to identify the differentially expressed proteins (DEPs) between the experimental groups, from which some proteins were validated by Western blot (WB). A total of 44 and 371 DEPs were identified between the study groups in the seminal plasma and spermatozoa, respectively. The identified DEPs were primarily involved in oxidoreductase, endopeptidase inhibitor, and antioxidant activities. We validated by WB the underexpression of NADH:ubiquinone oxidoreductase core subunit S1 ( = 0.01), as well as the overexpression of superoxide dismutase 1 ( = 0.03) and peroxiredoxin 4 ( = 0.04) in spermatozoa of ROS+ group. Our data suggest that fertile men with high ROS levels possess an effective antioxidant defense system that protects sperm proteins, as well as an active proteasomal system for degradation of defective proteins.</description><subject>Antioxidants</subject><subject>Antioxidants - metabolism</subject><subject>Biological activity</subject><subject>Chromatin</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA fragmentation</subject><subject>Fertility</subject><subject>Fragmentation</subject><subject>Genetic screening</subject><subject>Genetic testing</subject><subject>Humans</subject><subject>Infertility</subject><subject>Male</subject><subject>Molecular Sequence Annotation</subject><subject>Oxidative Stress</subject><subject>Physiology</subject><subject>Proteasomes</subject><subject>Protein expression</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Proteomics - methods</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Regulation</subject><subject>Reproductive technologies</subject><subject>Semen</subject><subject>Semen - metabolism</subject><subject>Sperm</subject><subject>Spermatozoa - metabolism</subject><subject>Stress response</subject><subject>Tumor necrosis factor-TNF</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>PIMPY</sourceid><recordid>eNpdkU1vEzEQhi0EoqXlxhlZ4sKhaf21u_EFKWoprZSqqClny2vPJo527WB7A_0f_GAcWqrAyda8jx7PeBB6R8kp55KcufWQGCGUMMJfoEMqGJsQUjcv9-4H6E1Ka0IYZ5V8jQ44qVlNqDhEv77GkCEMzuCFW3qdxwgJ38EWdI8vXNdBBG9KyXm8yCXbhWkTfIITPPPZhZ_Oap_xBXRQilh7i_84dQpDccxMdluXH3aCS4jZ9YBvwOMfLq_wlVuu8AIG5wt5d7vA8_Jwn47Rq073Cd4-nUfo2-Xn-_Oryfz2y_X5bD4xgrI8qYWuNWmnVtiOc0tI09ryC8y2bVPVDetaK5uOV4wJaSrBpRCyallbGV4SY_gR-vTo3YztANaAz1H3ahPdoOODCtqpfxPvVmoZtqrmvGFTWQQfnwQxfB8hZTW4ZKDvtYcwJsVoIzklpYOCfvgPXYcxlrkLxTmdSiqbaaFOHikTQ0oRuudmKFG7dav9dRf8_f4Az_Df_fLftqmoNw</recordid><startdate>20190108</startdate><enddate>20190108</enddate><creator>Dias, Tânia R</creator><creator>Samanta, Luna</creator><creator>Agarwal, Ashok</creator><creator>Pushparaj, Peter N</creator><creator>Panner Selvam, Manesh Kumar</creator><creator>Sharma, Rakesh</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>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</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/0000-0001-7574-1880</orcidid><orcidid>https://orcid.org/0000-0002-2969-0071</orcidid><orcidid>https://orcid.org/0000-0003-0585-1026</orcidid><orcidid>https://orcid.org/0000-0002-2336-8006</orcidid></search><sort><creationdate>20190108</creationdate><title>Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels</title><author>Dias, Tânia R ; Samanta, Luna ; Agarwal, Ashok ; Pushparaj, Peter N ; Panner Selvam, Manesh Kumar ; Sharma, Rakesh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Antioxidants</topic><topic>Antioxidants - metabolism</topic><topic>Biological activity</topic><topic>Chromatin</topic><topic>Cytokines</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA fragmentation</topic><topic>Fertility</topic><topic>Fragmentation</topic><topic>Genetic screening</topic><topic>Genetic testing</topic><topic>Humans</topic><topic>Infertility</topic><topic>Male</topic><topic>Molecular Sequence Annotation</topic><topic>Oxidative Stress</topic><topic>Physiology</topic><topic>Proteasomes</topic><topic>Protein expression</topic><topic>Protein folding</topic><topic>Proteins</topic><topic>Proteomics - methods</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Regulation</topic><topic>Reproductive technologies</topic><topic>Semen</topic><topic>Semen - metabolism</topic><topic>Sperm</topic><topic>Spermatozoa - metabolism</topic><topic>Stress response</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dias, Tânia R</creatorcontrib><creatorcontrib>Samanta, Luna</creatorcontrib><creatorcontrib>Agarwal, Ashok</creatorcontrib><creatorcontrib>Pushparaj, Peter N</creatorcontrib><creatorcontrib>Panner Selvam, Manesh Kumar</creatorcontrib><creatorcontrib>Sharma, Rakesh</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 &amp; 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)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest research library</collection><collection>Research Library (Corporate)</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest Health &amp; Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health &amp; Nursing</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>Dias, Tânia R</au><au>Samanta, Luna</au><au>Agarwal, Ashok</au><au>Pushparaj, Peter N</au><au>Panner Selvam, Manesh Kumar</au><au>Sharma, Rakesh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-01-08</date><risdate>2019</risdate><volume>20</volume><issue>1</issue><spage>203</spage><pages>203-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Elevated levels of reactive oxygen species (ROS) are a major cause of male infertility. However, some men with high seminal ROS levels are still fertile. The main objective of this study was to understand the molecular mechanism(s) responsible for the preservation of fertility in those men. Semen samples from fertile men were divided into two groups: control ( = 10, ROS &lt; 102.2 RLU/s/10⁶ sperm) and ROS+ ( = 10, ROS &gt; 102.2 RLU/s/10⁶ sperm). Proteomic analysis of seminal plasma and spermatozoa was used to identify the differentially expressed proteins (DEPs) between the experimental groups, from which some proteins were validated by Western blot (WB). A total of 44 and 371 DEPs were identified between the study groups in the seminal plasma and spermatozoa, respectively. The identified DEPs were primarily involved in oxidoreductase, endopeptidase inhibitor, and antioxidant activities. We validated by WB the underexpression of NADH:ubiquinone oxidoreductase core subunit S1 ( = 0.01), as well as the overexpression of superoxide dismutase 1 ( = 0.03) and peroxiredoxin 4 ( = 0.04) in spermatozoa of ROS+ group. Our data suggest that fertile men with high ROS levels possess an effective antioxidant defense system that protects sperm proteins, as well as an active proteasomal system for degradation of defective proteins.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>30626014</pmid><doi>10.3390/ijms20010203</doi><orcidid>https://orcid.org/0000-0001-7574-1880</orcidid><orcidid>https://orcid.org/0000-0002-2969-0071</orcidid><orcidid>https://orcid.org/0000-0003-0585-1026</orcidid><orcidid>https://orcid.org/0000-0002-2336-8006</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1422-0067
ispartof International journal of molecular sciences, 2019-01, Vol.20 (1), p.203
issn 1422-0067
1661-6596
1422-0067
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6337289
source PubMed (Medline); Publicly Available Content (ProQuest)
subjects Antioxidants
Antioxidants - metabolism
Biological activity
Chromatin
Cytokines
Deoxyribonucleic acid
DNA
DNA fragmentation
Fertility
Fragmentation
Genetic screening
Genetic testing
Humans
Infertility
Male
Molecular Sequence Annotation
Oxidative Stress
Physiology
Proteasomes
Protein expression
Protein folding
Proteins
Proteomics - methods
Reactive Oxygen Species - metabolism
Regulation
Reproductive technologies
Semen
Semen - metabolism
Sperm
Spermatozoa - metabolism
Stress response
Tumor necrosis factor-TNF
title Proteomic Signatures Reveal Differences in Stress Response, Antioxidant Defense and Proteasomal Activity in Fertile Men with High Seminal ROS Levels
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-27T05%3A37%3A04IST&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=Proteomic%20Signatures%20Reveal%20Differences%20in%20Stress%20Response,%20Antioxidant%20Defense%20and%20Proteasomal%20Activity%20in%20Fertile%20Men%20with%20High%20Seminal%20ROS%20Levels&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Dias,%20T%C3%A2nia%20R&rft.date=2019-01-08&rft.volume=20&rft.issue=1&rft.spage=203&rft.pages=203-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms20010203&rft_dat=%3Cproquest_pubme%3E2179310522%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c412t-64a6a0b8d4df33d007bd0202dbb75672fbd97f352249c54394495b2b5c3bd9cc3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2331891978&rft_id=info:pmid/30626014&rfr_iscdi=true