New Approaches to the Prevention and Treatment of Viral Diseases
The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation...
Gespeichert in:
| Veröffentlicht in: | Archivum Immunologiae et Therapiae Experimentalis 2021, Vol.69 (1), p.10, Article 10 |
|---|---|
| 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 | 10 |
| container_title | Archivum Immunologiae et Therapiae Experimentalis |
| container_volume | 69 |
| creator | Pronin, Alexander V. Narovlyansky, Alexander N. Sanin, Alexander V. |
| description | The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases. |
| doi_str_mv | 10.1007/s00005-021-00613-w |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8019082</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2508229667</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-cb5ce7054e3bd008e0fed234370029c5eb5a7735164e43cbd2f0c7e3ff4c747c3</originalsourceid><addsrcrecordid>eNp9kEtPwzAQhC0EouXxBzggS5wD60fi5oKoylNCwAEQN8txNm2qNi522op_j6FQ4IIvlj2zs6OPkAMGxwxAnQSIJ02AswQgYyJZbpAuyzKWyJypTdKNskwgy186ZCeEcXyJlMlt0hGix1jKZZec3eGS9mcz74wdYaCto-0I6YPHBTZt7RpqmpI-ejTtNH5QV9Hn2psJPa8DmoBhj2xVZhJw_-veJU-XF4-D6-T2_upm0L9NrFSyTWyRWlSQShRFCdBDqLDkQgoFwHObYpEapWK9TKIUtih5BVahqCpplVRW7JLTVe5sXkyxtLFMrKFnvp4a_6adqfVfpalHeugWugcshx6PAUdfAd69zjG0euzmvomdNU-jgedZpqKLr1zWuxA8VusNDPQHdb2iriN1_UldL-PQ4e9u65FvzNEgVoYQpWaI_mf3P7HvALGOJg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2508229667</pqid></control><display><type>article</type><title>New Approaches to the Prevention and Treatment of Viral Diseases</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Pronin, Alexander V. ; Narovlyansky, Alexander N. ; Sanin, Alexander V.</creator><creatorcontrib>Pronin, Alexander V. ; Narovlyansky, Alexander N. ; Sanin, Alexander V.</creatorcontrib><description>The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.</description><identifier>ISSN: 0004-069X</identifier><identifier>EISSN: 1661-4917</identifier><identifier>DOI: 10.1007/s00005-021-00613-w</identifier><identifier>PMID: 33811524</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Clinical trials ; Clinical Trials as Topic ; Coronaviruses ; Disease Models, Animal ; Encephalitis ; Farnesol ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - immunology ; Hepatitis ; Hepatitis A ; Hepatitis C ; Herpes simplex ; High-performance liquid chromatography ; HIV ; Human immunodeficiency virus ; Humans ; Immunology ; Influenza ; Influenza A ; Interferon ; Interferons - metabolism ; Medical treatment ; Mevalonate pathway ; Mevalonic acid ; Microscopy, Electron ; NMR ; Nuclear magnetic resonance ; Pharmacology/Toxicology ; Pine needles ; Pinus - chemistry ; Polyisoprenyl Phosphates - pharmacology ; Polyisoprenyl Phosphates - therapeutic use ; Polyprenyl phosphate ; Protein Prenylation - drug effects ; Proteins ; Review ; Sterol Regulatory Element Binding Protein 2 - metabolism ; Tick-borne encephalitis ; Treatment Outcome ; Viral diseases ; Viral infections ; Viral Proteins - metabolism ; Virion - drug effects ; Virion - ultrastructure ; Virus Diseases - drug therapy ; Virus Diseases - immunology ; Virus Diseases - prevention & control ; Virus Replication - drug effects ; Virus Replication - immunology ; Viruses</subject><ispartof>Archivum Immunologiae et Therapiae Experimentalis, 2021, Vol.69 (1), p.10, Article 10</ispartof><rights>L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2021</rights><rights>L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-cb5ce7054e3bd008e0fed234370029c5eb5a7735164e43cbd2f0c7e3ff4c747c3</citedby><cites>FETCH-LOGICAL-c474t-cb5ce7054e3bd008e0fed234370029c5eb5a7735164e43cbd2f0c7e3ff4c747c3</cites><orcidid>0000-0001-5266-9783</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00005-021-00613-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00005-021-00613-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33811524$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pronin, Alexander V.</creatorcontrib><creatorcontrib>Narovlyansky, Alexander N.</creatorcontrib><creatorcontrib>Sanin, Alexander V.</creatorcontrib><title>New Approaches to the Prevention and Treatment of Viral Diseases</title><title>Archivum Immunologiae et Therapiae Experimentalis</title><addtitle>Arch. Immunol. Ther. Exp</addtitle><addtitle>Arch Immunol Ther Exp (Warsz)</addtitle><description>The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.</description><subject>Animals</subject><subject>Antiviral Agents - pharmacology</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Clinical trials</subject><subject>Clinical Trials as Topic</subject><subject>Coronaviruses</subject><subject>Disease Models, Animal</subject><subject>Encephalitis</subject><subject>Farnesol</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - immunology</subject><subject>Hepatitis</subject><subject>Hepatitis A</subject><subject>Hepatitis C</subject><subject>Herpes simplex</subject><subject>High-performance liquid chromatography</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immunology</subject><subject>Influenza</subject><subject>Influenza A</subject><subject>Interferon</subject><subject>Interferons - metabolism</subject><subject>Medical treatment</subject><subject>Mevalonate pathway</subject><subject>Mevalonic acid</subject><subject>Microscopy, Electron</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Pharmacology/Toxicology</subject><subject>Pine needles</subject><subject>Pinus - chemistry</subject><subject>Polyisoprenyl Phosphates - pharmacology</subject><subject>Polyisoprenyl Phosphates - therapeutic use</subject><subject>Polyprenyl phosphate</subject><subject>Protein Prenylation - drug effects</subject><subject>Proteins</subject><subject>Review</subject><subject>Sterol Regulatory Element Binding Protein 2 - metabolism</subject><subject>Tick-borne encephalitis</subject><subject>Treatment Outcome</subject><subject>Viral diseases</subject><subject>Viral infections</subject><subject>Viral Proteins - metabolism</subject><subject>Virion - drug effects</subject><subject>Virion - ultrastructure</subject><subject>Virus Diseases - drug therapy</subject><subject>Virus Diseases - immunology</subject><subject>Virus Diseases - prevention & control</subject><subject>Virus Replication - drug effects</subject><subject>Virus Replication - immunology</subject><subject>Viruses</subject><issn>0004-069X</issn><issn>1661-4917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EouXxBzggS5wD60fi5oKoylNCwAEQN8txNm2qNi522op_j6FQ4IIvlj2zs6OPkAMGxwxAnQSIJ02AswQgYyJZbpAuyzKWyJypTdKNskwgy186ZCeEcXyJlMlt0hGix1jKZZec3eGS9mcz74wdYaCto-0I6YPHBTZt7RpqmpI-ejTtNH5QV9Hn2psJPa8DmoBhj2xVZhJw_-veJU-XF4-D6-T2_upm0L9NrFSyTWyRWlSQShRFCdBDqLDkQgoFwHObYpEapWK9TKIUtih5BVahqCpplVRW7JLTVe5sXkyxtLFMrKFnvp4a_6adqfVfpalHeugWugcshx6PAUdfAd69zjG0euzmvomdNU-jgedZpqKLr1zWuxA8VusNDPQHdb2iriN1_UldL-PQ4e9u65FvzNEgVoYQpWaI_mf3P7HvALGOJg</recordid><startdate>2021</startdate><enddate>2021</enddate><creator>Pronin, Alexander V.</creator><creator>Narovlyansky, Alexander N.</creator><creator>Sanin, Alexander V.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</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>7T5</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5266-9783</orcidid></search><sort><creationdate>2021</creationdate><title>New Approaches to the Prevention and Treatment of Viral Diseases</title><author>Pronin, Alexander V. ; Narovlyansky, Alexander N. ; Sanin, Alexander V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-cb5ce7054e3bd008e0fed234370029c5eb5a7735164e43cbd2f0c7e3ff4c747c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Antiviral Agents - pharmacology</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Clinical trials</topic><topic>Clinical Trials as Topic</topic><topic>Coronaviruses</topic><topic>Disease Models, Animal</topic><topic>Encephalitis</topic><topic>Farnesol</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Expression Regulation - immunology</topic><topic>Hepatitis</topic><topic>Hepatitis A</topic><topic>Hepatitis C</topic><topic>Herpes simplex</topic><topic>High-performance liquid chromatography</topic><topic>HIV</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Immunology</topic><topic>Influenza</topic><topic>Influenza A</topic><topic>Interferon</topic><topic>Interferons - metabolism</topic><topic>Medical treatment</topic><topic>Mevalonate pathway</topic><topic>Mevalonic acid</topic><topic>Microscopy, Electron</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Pharmacology/Toxicology</topic><topic>Pine needles</topic><topic>Pinus - chemistry</topic><topic>Polyisoprenyl Phosphates - pharmacology</topic><topic>Polyisoprenyl Phosphates - therapeutic use</topic><topic>Polyprenyl phosphate</topic><topic>Protein Prenylation - drug effects</topic><topic>Proteins</topic><topic>Review</topic><topic>Sterol Regulatory Element Binding Protein 2 - metabolism</topic><topic>Tick-borne encephalitis</topic><topic>Treatment Outcome</topic><topic>Viral diseases</topic><topic>Viral infections</topic><topic>Viral Proteins - metabolism</topic><topic>Virion - drug effects</topic><topic>Virion - ultrastructure</topic><topic>Virus Diseases - drug therapy</topic><topic>Virus Diseases - immunology</topic><topic>Virus Diseases - prevention & control</topic><topic>Virus Replication - drug effects</topic><topic>Virus Replication - immunology</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pronin, Alexander V.</creatorcontrib><creatorcontrib>Narovlyansky, Alexander N.</creatorcontrib><creatorcontrib>Sanin, Alexander V.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Archivum Immunologiae et Therapiae Experimentalis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pronin, Alexander V.</au><au>Narovlyansky, Alexander N.</au><au>Sanin, Alexander V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Approaches to the Prevention and Treatment of Viral Diseases</atitle><jtitle>Archivum Immunologiae et Therapiae Experimentalis</jtitle><stitle>Arch. Immunol. Ther. Exp</stitle><addtitle>Arch Immunol Ther Exp (Warsz)</addtitle><date>2021</date><risdate>2021</risdate><volume>69</volume><issue>1</issue><spage>10</spage><pages>10-</pages><artnum>10</artnum><issn>0004-069X</issn><eissn>1661-4917</eissn><abstract>The review discusses a new approach to the prevention and treatment of viral infections based on the use of pine needles polyprenyl phosphate (PPP) and associated with the infringement of prenylation process—the attachment of farnesol or geranyl geraniol to the viral protein. Currently, prenylation has been detected in type 1 adenovirus, hepatitis C virus, several herpes viruses, influenza virus, HIV. However, this list is far from complete, given that prenylated proteins play an extremely important role in the activity of the virus. We assume that the interferon produced in response to PPP may suppress expression of the SREBP2 transcription factor. As a result, the mevalonic acid pathway is violated and, as a result, the formation of early polyprenols precursors (geraniol, geranyl geraniol, farnesol), which are necessary for the prenylation of viral proteins, is blocked and the formation of mature, virulent virus particles is broken. As a consequence, the maturation of viral particles is inhibited, and defective particles are formed. Polyprenol was extracted from greenery (pine, fir and spruce needles, mulberry leaves, etc.), purified by chromatography, phosphorylated and identified by HPLC and NMR. Obtained PPP was used as antiviral in some experimental models in vitro and in vivo. During numerous studies, it was found that PPP manifested versatile antiviral effects, both in vitro and in vivo. The maximum effect was observed with viruses in which the presence of prenylated proteins was established, namely influenza A virus, HIV-1, tick-borne encephalitis virus, hepatitis A and C viruses, herpes simplex viruses type 1 and 2, some coronavirus. The available data obtained both in the experimental conditions and during clinical trials allow us to regard PPPs as safe and effective medicine for prevention and treatment of viral diseases.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>33811524</pmid><doi>10.1007/s00005-021-00613-w</doi><orcidid>https://orcid.org/0000-0001-5266-9783</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0004-069X |
| ispartof | Archivum Immunologiae et Therapiae Experimentalis, 2021, Vol.69 (1), p.10, Article 10 |
| issn | 0004-069X 1661-4917 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8019082 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Animals Antiviral Agents - pharmacology Antiviral Agents - therapeutic use Biomedical and Life Sciences Biomedicine Clinical trials Clinical Trials as Topic Coronaviruses Disease Models, Animal Encephalitis Farnesol Gene Expression Regulation - drug effects Gene Expression Regulation - immunology Hepatitis Hepatitis A Hepatitis C Herpes simplex High-performance liquid chromatography HIV Human immunodeficiency virus Humans Immunology Influenza Influenza A Interferon Interferons - metabolism Medical treatment Mevalonate pathway Mevalonic acid Microscopy, Electron NMR Nuclear magnetic resonance Pharmacology/Toxicology Pine needles Pinus - chemistry Polyisoprenyl Phosphates - pharmacology Polyisoprenyl Phosphates - therapeutic use Polyprenyl phosphate Protein Prenylation - drug effects Proteins Review Sterol Regulatory Element Binding Protein 2 - metabolism Tick-borne encephalitis Treatment Outcome Viral diseases Viral infections Viral Proteins - metabolism Virion - drug effects Virion - ultrastructure Virus Diseases - drug therapy Virus Diseases - immunology Virus Diseases - prevention & control Virus Replication - drug effects Virus Replication - immunology Viruses |
| title | New Approaches to the Prevention and Treatment of Viral Diseases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T01%3A51%3A34IST&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=New%20Approaches%20to%20the%20Prevention%20and%20Treatment%20of%20Viral%20Diseases&rft.jtitle=Archivum%20Immunologiae%20et%20Therapiae%20Experimentalis&rft.au=Pronin,%20Alexander%20V.&rft.date=2021&rft.volume=69&rft.issue=1&rft.spage=10&rft.pages=10-&rft.artnum=10&rft.issn=0004-069X&rft.eissn=1661-4917&rft_id=info:doi/10.1007/s00005-021-00613-w&rft_dat=%3Cproquest_pubme%3E2508229667%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=2508229667&rft_id=info:pmid/33811524&rfr_iscdi=true |