Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19
Coronavirus disease 2019 (COVID-19) is especially severe in aged populations 1 . Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility 2 . T...
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| Veröffentlicht in: | Nature (London) 2022-05, Vol.605 (7908), p.146-151 |
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| creator | Wong, Lok-Yin Roy Zheng, Jian Wilhelmsen, Kevin Li, Kun Ortiz, Miguel E. Schnicker, Nicholas J. Thurman, Andrew Pezzulo, Alejandro A. Szachowicz, Peter J. Li, Pengfei Pan, Ruangang Klumpp, Klaus Aswad, Fred Rebo, Justin Narumiya, Shuh Murakami, Makoto Zuniga, Sonia Sola, Isabel Enjuanes, Luis Meyerholz, David K. Fortney, Kristen McCray, Paul B. Perlman, Stanley |
| description | Coronavirus disease 2019 (COVID-19) is especially severe in aged populations
1
. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility
2
. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern
2
. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D
2
(PGD
2
)) and a phospholipase (phospholipase A2 group 2D (PLA
2
G2D)) contributed to poor outcomes in aged mice
3
,
4
. mRNA expression of PLA
2
G2D and prostaglandin D
2
receptor (PTGDR), and production of PGD
2
also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA
2
G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA
2
G2D–PGD
2
/PTGDR pathway is a useful target for therapeutic interventions.
A study reports the isolation and characterization of mouse-adapted SARS-CoV-2, demonstrates asapiprant to protect aged mice from its most severe effects, and identifies the PLA
2
G2D–PGD
2
/PTGDR pathway as a therapeutic target. |
| doi_str_mv | 10.1038/s41586-022-04630-3 |
| format | Article |
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1
. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility
2
. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern
2
. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D
2
(PGD
2
)) and a phospholipase (phospholipase A2 group 2D (PLA
2
G2D)) contributed to poor outcomes in aged mice
3
,
4
. mRNA expression of PLA
2
G2D and prostaglandin D
2
receptor (PTGDR), and production of PGD
2
also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA
2
G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA
2
G2D–PGD
2
/PTGDR pathway is a useful target for therapeutic interventions.
A study reports the isolation and characterization of mouse-adapted SARS-CoV-2, demonstrates asapiprant to protect aged mice from its most severe effects, and identifies the PLA
2
G2D–PGD
2
/PTGDR pathway as a therapeutic target.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-022-04630-3</identifier><identifier>PMID: 35314834</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/31 ; 13/51 ; 14/63 ; 45/22 ; 45/23 ; 45/44 ; 45/70 ; 45/77 ; 45/90 ; 631/326/421 ; 631/326/596/4130 ; 64/60 ; 82 ; 82/51 ; Adaptation ; Aging ; Amino acids ; Animals ; Artificial chromosomes ; Cloning ; Coronaviruses ; COVID-19 ; Dendritic cells ; Dopamine D2 receptors ; Eicosanoids ; Gene expression ; Genomes ; Glycoproteins ; Humanities and Social Sciences ; Infections ; Leukocytes, Mononuclear ; Lungs ; Mice ; Middle age ; Middle East respiratory syndrome ; multidisciplinary ; Organic Chemicals ; Oxazoles ; Peripheral blood mononuclear cells ; Phospholipase ; Phospholipase A2 ; Piperazines ; Polyesters ; Prostaglandin D2 ; Prostaglandins ; Proteins ; Respiratory diseases ; SARS-CoV-2 ; Science ; Science (multidisciplinary) ; Severe acute respiratory syndrome coronavirus 2 ; Signal transduction ; Spike Glycoprotein, Coronavirus ; Spike protein ; Sulfonamides ; Therapeutic applications ; Vaccine efficacy ; Vaccines ; Vectors (Biology) ; Viral diseases ; Virulence ; Viruses</subject><ispartof>Nature (London), 2022-05, Vol.605 (7908), p.146-151</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022. Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>Copyright Nature Publishing Group May 5, 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c419t-19a1a2a6e454b81188b2e6b4f3e17063e52432bae8b3384707b86c4ba6d4d04b3</citedby><cites>FETCH-LOGICAL-c419t-19a1a2a6e454b81188b2e6b4f3e17063e52432bae8b3384707b86c4ba6d4d04b3</cites><orcidid>0000-0003-1552-3253 ; 0000-0001-8062-6529 ; 0000-0003-4213-2354 ; 0000-0002-0727-8289 ; 0000-0002-5189-4943 ; 0000-0002-4067-577X ; 0000-0001-6518-6369 ; 0000-0001-7544-5109 ; 0000-0001-9062-3735 ; 0000-0003-2549-6826</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35314834$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wong, Lok-Yin Roy</creatorcontrib><creatorcontrib>Zheng, Jian</creatorcontrib><creatorcontrib>Wilhelmsen, Kevin</creatorcontrib><creatorcontrib>Li, Kun</creatorcontrib><creatorcontrib>Ortiz, Miguel E.</creatorcontrib><creatorcontrib>Schnicker, Nicholas J.</creatorcontrib><creatorcontrib>Thurman, Andrew</creatorcontrib><creatorcontrib>Pezzulo, Alejandro A.</creatorcontrib><creatorcontrib>Szachowicz, Peter J.</creatorcontrib><creatorcontrib>Li, Pengfei</creatorcontrib><creatorcontrib>Pan, Ruangang</creatorcontrib><creatorcontrib>Klumpp, Klaus</creatorcontrib><creatorcontrib>Aswad, Fred</creatorcontrib><creatorcontrib>Rebo, Justin</creatorcontrib><creatorcontrib>Narumiya, Shuh</creatorcontrib><creatorcontrib>Murakami, Makoto</creatorcontrib><creatorcontrib>Zuniga, Sonia</creatorcontrib><creatorcontrib>Sola, Isabel</creatorcontrib><creatorcontrib>Enjuanes, Luis</creatorcontrib><creatorcontrib>Meyerholz, David K.</creatorcontrib><creatorcontrib>Fortney, Kristen</creatorcontrib><creatorcontrib>McCray, Paul B.</creatorcontrib><creatorcontrib>Perlman, Stanley</creatorcontrib><title>Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Coronavirus disease 2019 (COVID-19) is especially severe in aged populations
1
. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility
2
. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern
2
. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D
2
(PGD
2
)) and a phospholipase (phospholipase A2 group 2D (PLA
2
G2D)) contributed to poor outcomes in aged mice
3
,
4
. mRNA expression of PLA
2
G2D and prostaglandin D
2
receptor (PTGDR), and production of PGD
2
also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA
2
G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA
2
G2D–PGD
2
/PTGDR pathway is a useful target for therapeutic interventions.
A study reports the isolation and characterization of mouse-adapted SARS-CoV-2, demonstrates asapiprant to protect aged mice from its most severe effects, and identifies the PLA
2
G2D–PGD
2
/PTGDR pathway as a therapeutic target.</description><subject>13/1</subject><subject>13/106</subject><subject>13/31</subject><subject>13/51</subject><subject>14/63</subject><subject>45/22</subject><subject>45/23</subject><subject>45/44</subject><subject>45/70</subject><subject>45/77</subject><subject>45/90</subject><subject>631/326/421</subject><subject>631/326/596/4130</subject><subject>64/60</subject><subject>82</subject><subject>82/51</subject><subject>Adaptation</subject><subject>Aging</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Artificial chromosomes</subject><subject>Cloning</subject><subject>Coronaviruses</subject><subject>COVID-19</subject><subject>Dendritic cells</subject><subject>Dopamine D2 receptors</subject><subject>Eicosanoids</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Glycoproteins</subject><subject>Humanities and Social Sciences</subject><subject>Infections</subject><subject>Leukocytes, Mononuclear</subject><subject>Lungs</subject><subject>Mice</subject><subject>Middle age</subject><subject>Middle East respiratory syndrome</subject><subject>multidisciplinary</subject><subject>Organic Chemicals</subject><subject>Oxazoles</subject><subject>Peripheral blood mononuclear cells</subject><subject>Phospholipase</subject><subject>Phospholipase A2</subject><subject>Piperazines</subject><subject>Polyesters</subject><subject>Prostaglandin D2</subject><subject>Prostaglandins</subject><subject>Proteins</subject><subject>Respiratory diseases</subject><subject>SARS-CoV-2</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Signal transduction</subject><subject>Spike Glycoprotein, Coronavirus</subject><subject>Spike protein</subject><subject>Sulfonamides</subject><subject>Therapeutic applications</subject><subject>Vaccine efficacy</subject><subject>Vaccines</subject><subject>Vectors 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diseases</subject><subject>Virulence</subject><subject>Viruses</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kMtKAzEUhoMotlZfwIUMuHETTXLOZNKl1FtBcaNuQzJzWqbOpSat4NsbrRdw4eoEzvf_ST7GDqU4lQLMWUSZG82FUlygBsFhiw0lFpqjNsU2GwqhDBcG9IDtxbgQQuSywF02gBwkGsAhu7usyz66rq-rLNbzzjVN3c0z3_Tls6soW4Z-ReUqZm1dVQ1xN6cqnUvKZqFvs0ivFCib3D9NL7gc77OdmWsiHXzNEXu8unyY3PDb--vp5PyWlyjHqwQ66ZTThDl6I6UxXpH2OAOShdBAuUJQ3pHxAAYLUXijS_ROV1gJ9DBiJ5ve9LyXNcWVbetYUtO4jvp1tEqjNBqMLhJ6_Add9OuQ_vlBaZmPQSmZKLWhytDHGGhml6FuXXizUtgP2XYj2ybZ9lO2hRQ6-qpe-5aqn8i33QTABohp1c0p_N79T-07dryHqg</recordid><startdate>20220505</startdate><enddate>20220505</enddate><creator>Wong, 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signalling blockade protects middle-aged mice from severe COVID-19</title><author>Wong, Lok-Yin Roy ; Zheng, Jian ; Wilhelmsen, Kevin ; Li, Kun ; Ortiz, Miguel E. ; Schnicker, Nicholas J. ; Thurman, Andrew ; Pezzulo, Alejandro A. ; Szachowicz, Peter J. ; Li, Pengfei ; Pan, Ruangang ; Klumpp, Klaus ; Aswad, Fred ; Rebo, Justin ; Narumiya, Shuh ; Murakami, Makoto ; Zuniga, Sonia ; Sola, Isabel ; Enjuanes, Luis ; Meyerholz, David K. ; Fortney, Kristen ; McCray, Paul B. ; Perlman, 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Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</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 One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wong, Lok-Yin Roy</au><au>Zheng, Jian</au><au>Wilhelmsen, Kevin</au><au>Li, Kun</au><au>Ortiz, Miguel E.</au><au>Schnicker, Nicholas J.</au><au>Thurman, Andrew</au><au>Pezzulo, Alejandro A.</au><au>Szachowicz, Peter J.</au><au>Li, Pengfei</au><au>Pan, Ruangang</au><au>Klumpp, Klaus</au><au>Aswad, Fred</au><au>Rebo, Justin</au><au>Narumiya, Shuh</au><au>Murakami, Makoto</au><au>Zuniga, Sonia</au><au>Sola, Isabel</au><au>Enjuanes, Luis</au><au>Meyerholz, David K.</au><au>Fortney, Kristen</au><au>McCray, Paul B.</au><au>Perlman, Stanley</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2022-05-05</date><risdate>2022</risdate><volume>605</volume><issue>7908</issue><spage>146</spage><epage>151</epage><pages>146-151</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Coronavirus disease 2019 (COVID-19) is especially severe in aged populations
1
. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility
2
. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern
2
. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D
2
(PGD
2
)) and a phospholipase (phospholipase A2 group 2D (PLA
2
G2D)) contributed to poor outcomes in aged mice
3
,
4
. mRNA expression of PLA
2
G2D and prostaglandin D
2
receptor (PTGDR), and production of PGD
2
also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA
2
G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA
2
G2D–PGD
2
/PTGDR pathway is a useful target for therapeutic interventions.
A study reports the isolation and characterization of mouse-adapted SARS-CoV-2, demonstrates asapiprant to protect aged mice from its most severe effects, and identifies the PLA
2
G2D–PGD
2
/PTGDR pathway as a therapeutic target.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35314834</pmid><doi>10.1038/s41586-022-04630-3</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-1552-3253</orcidid><orcidid>https://orcid.org/0000-0001-8062-6529</orcidid><orcidid>https://orcid.org/0000-0003-4213-2354</orcidid><orcidid>https://orcid.org/0000-0002-0727-8289</orcidid><orcidid>https://orcid.org/0000-0002-5189-4943</orcidid><orcidid>https://orcid.org/0000-0002-4067-577X</orcidid><orcidid>https://orcid.org/0000-0001-6518-6369</orcidid><orcidid>https://orcid.org/0000-0001-7544-5109</orcidid><orcidid>https://orcid.org/0000-0001-9062-3735</orcidid><orcidid>https://orcid.org/0000-0003-2549-6826</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2022-05, Vol.605 (7908), p.146-151 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2641863867 |
| source | MEDLINE; Nature Journals Online; Alma/SFX Local Collection |
| subjects | 13/1 13/106 13/31 13/51 14/63 45/22 45/23 45/44 45/70 45/77 45/90 631/326/421 631/326/596/4130 64/60 82 82/51 Adaptation Aging Amino acids Animals Artificial chromosomes Cloning Coronaviruses COVID-19 Dendritic cells Dopamine D2 receptors Eicosanoids Gene expression Genomes Glycoproteins Humanities and Social Sciences Infections Leukocytes, Mononuclear Lungs Mice Middle age Middle East respiratory syndrome multidisciplinary Organic Chemicals Oxazoles Peripheral blood mononuclear cells Phospholipase Phospholipase A2 Piperazines Polyesters Prostaglandin D2 Prostaglandins Proteins Respiratory diseases SARS-CoV-2 Science Science (multidisciplinary) Severe acute respiratory syndrome coronavirus 2 Signal transduction Spike Glycoprotein, Coronavirus Spike protein Sulfonamides Therapeutic applications Vaccine efficacy Vaccines Vectors (Biology) Viral diseases Virulence Viruses |
| title | Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-12T18%3A16%3A25IST&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=Eicosanoid%20signalling%20blockade%20protects%20middle-aged%20mice%20from%20severe%20COVID-19&rft.jtitle=Nature%20(London)&rft.au=Wong,%20Lok-Yin%20Roy&rft.date=2022-05-05&rft.volume=605&rft.issue=7908&rft.spage=146&rft.epage=151&rft.pages=146-151&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-022-04630-3&rft_dat=%3Cproquest_cross%3E2641863867%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2661593221&rft_id=info:pmid/35314834&rfr_iscdi=true |