Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity
β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (...
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| Veröffentlicht in: | The Journal of neuroscience 2024-04, Vol.44 (14), p.e1666232024 |
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| creator | Rizwan, Mohammed Z Kamstra, Kaj Pretz, Dominik Shepherd, Peter R Tups, Alexander Grattan, David R |
| description | β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female β-catenin
mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (
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| doi_str_mv | 10.1523/JNEUROSCI.1666-23.2024 |
| format | Article |
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mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (
< 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-β-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.</description><identifier>ISSN: 0270-6474</identifier><identifier>ISSN: 1529-2401</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.1666-23.2024</identifier><identifier>PMID: 38395612</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Animals ; Arcuate nucleus ; beta Catenin - genetics ; beta Catenin - metabolism ; Body weight ; Body Weight - genetics ; Calories ; Cytoskeleton ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - pathology ; Diet ; Diet, High-Fat - adverse effects ; Energy expenditure ; Energy Metabolism - genetics ; Female ; Females ; Gene expression ; Genetic diversity ; Genetic variation ; Glucose ; Glucose - metabolism ; High fat diet ; Homeostasis ; Hypothalamus ; Hypothalamus - metabolism ; Insulin ; Leptin ; Leptin - metabolism ; Low fat diet ; Male ; Males ; Metabolic disorders ; Metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neuroendocrine system ; Neurotransmitters ; Obesity ; Obesity - genetics ; Obesity - metabolism ; Pathogenesis ; Proteins ; Transcription ; Wnt protein ; β-Catenin</subject><ispartof>The Journal of neuroscience, 2024-04, Vol.44 (14), p.e1666232024</ispartof><rights>Copyright © 2024 the authors.</rights><rights>Copyright Society for Neuroscience Apr 3, 2024</rights><rights>Copyright © 2024 the authors 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c390t-a4eb878ea9a39b7db8d2ba31ccb51c44fa06aa8f2e314c5c86b9dc160cf525163</cites><orcidid>0000-0001-5606-2559</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/PMC10993030/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10993030/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38395612$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rizwan, Mohammed Z</creatorcontrib><creatorcontrib>Kamstra, Kaj</creatorcontrib><creatorcontrib>Pretz, Dominik</creatorcontrib><creatorcontrib>Shepherd, Peter R</creatorcontrib><creatorcontrib>Tups, Alexander</creatorcontrib><creatorcontrib>Grattan, David R</creatorcontrib><title>Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female β-catenin
mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (
< 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-β-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.</description><subject>Animals</subject><subject>Arcuate nucleus</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Body weight</subject><subject>Body Weight - genetics</subject><subject>Calories</subject><subject>Cytoskeleton</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 2 - pathology</subject><subject>Diet</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Energy expenditure</subject><subject>Energy Metabolism - genetics</subject><subject>Female</subject><subject>Females</subject><subject>Gene expression</subject><subject>Genetic diversity</subject><subject>Genetic variation</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>High fat diet</subject><subject>Homeostasis</subject><subject>Hypothalamus</subject><subject>Hypothalamus - metabolism</subject><subject>Insulin</subject><subject>Leptin</subject><subject>Leptin - metabolism</subject><subject>Low fat diet</subject><subject>Male</subject><subject>Males</subject><subject>Metabolic disorders</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Neuroendocrine system</subject><subject>Neurotransmitters</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Obesity - metabolism</subject><subject>Pathogenesis</subject><subject>Proteins</subject><subject>Transcription</subject><subject>Wnt protein</subject><subject>β-Catenin</subject><issn>0270-6474</issn><issn>1529-2401</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdksGO0zAQhi0EYpfCK6wsceGSYseJk5zQqtulRQuVFvZsTZxJ61Vqh9hZ0SfizoPwTDhsqQDZkkcz3_y2NT8hF5zNeZ6Ktx8-Le9uN58X6zmXUiapmKcszZ6Q81itkjRj_Ck5Z2nBEpkV2Rl54f09Y6xgvHhOzkQpqlzy9Jx8XzjbmGCchY5eYYdTSF1Lf_5IFhDQGkvjDjukH7ExrgYfwdWhd2EHHexHT9f7Hszg6WUDfTAPSJcWh-2BLr_1OGmPA04St-h7Zz3S4OjKbHfJNQR6ZTBQsE2EQeNQxxv972Syts2osaGbGr0Jh5fkWQudx1fHc0burpdfFqvkZvN-vbi8SbSoWEggw7osSoQKRFUXTV02aQ2Ca13nXGdZC0wClG2Kgmc616Wsq0ZzyXSbpzmXYkbePer2Y73HRqMNA3SqH8wehoNyYNS_FWt2auseFGdVJVhcM_LmqDC4ryP6oPbGa-w6sOhGryIiGJM8zmBGXv-H3rtxiJM4UpUUvIiUfKT04LwfsD29hjM1mUGdzKAmM6iYmcwQGy_-_sup7c_0xS9C8rWE</recordid><startdate>20240403</startdate><enddate>20240403</enddate><creator>Rizwan, Mohammed Z</creator><creator>Kamstra, Kaj</creator><creator>Pretz, Dominik</creator><creator>Shepherd, Peter R</creator><creator>Tups, Alexander</creator><creator>Grattan, David R</creator><general>Society for Neuroscience</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>7QG</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5606-2559</orcidid></search><sort><creationdate>20240403</creationdate><title>Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity</title><author>Rizwan, Mohammed Z ; Kamstra, Kaj ; Pretz, Dominik ; Shepherd, Peter R ; Tups, Alexander ; Grattan, David R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-a4eb878ea9a39b7db8d2ba31ccb51c44fa06aa8f2e314c5c86b9dc160cf525163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Arcuate nucleus</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Body weight</topic><topic>Body Weight - genetics</topic><topic>Calories</topic><topic>Cytoskeleton</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 2 - pathology</topic><topic>Diet</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Energy expenditure</topic><topic>Energy Metabolism - genetics</topic><topic>Female</topic><topic>Females</topic><topic>Gene expression</topic><topic>Genetic diversity</topic><topic>Genetic variation</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>High fat diet</topic><topic>Homeostasis</topic><topic>Hypothalamus</topic><topic>Hypothalamus - metabolism</topic><topic>Insulin</topic><topic>Leptin</topic><topic>Leptin - metabolism</topic><topic>Low fat diet</topic><topic>Male</topic><topic>Males</topic><topic>Metabolic disorders</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Neuroendocrine system</topic><topic>Neurotransmitters</topic><topic>Obesity</topic><topic>Obesity - genetics</topic><topic>Obesity - metabolism</topic><topic>Pathogenesis</topic><topic>Proteins</topic><topic>Transcription</topic><topic>Wnt protein</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rizwan, Mohammed Z</creatorcontrib><creatorcontrib>Kamstra, Kaj</creatorcontrib><creatorcontrib>Pretz, Dominik</creatorcontrib><creatorcontrib>Shepherd, Peter R</creatorcontrib><creatorcontrib>Tups, Alexander</creatorcontrib><creatorcontrib>Grattan, David R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rizwan, Mohammed Z</au><au>Kamstra, Kaj</au><au>Pretz, Dominik</au><au>Shepherd, Peter R</au><au>Tups, Alexander</au><au>Grattan, David R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2024-04-03</date><risdate>2024</risdate><volume>44</volume><issue>14</issue><spage>e1666232024</spage><pages>e1666232024-</pages><issn>0270-6474</issn><issn>1529-2401</issn><eissn>1529-2401</eissn><abstract>β-Catenin is a bifunctional molecule that is an effector of the wingless-related integration site (Wnt) signaling to control gene expression and contributes to the regulation of cytoskeleton and neurotransmitter vesicle trafficking. In its former role, β-catenin binds transcription factor 7-like 2 (TCF7L2), which shows strong genetic associations with the pathogenesis of obesity and type-2 diabetes. Here, we sought to determine whether β-catenin plays a role in the neuroendocrine regulation of body weight and glucose homeostasis. Bilateral injections of adeno-associated virus type-2 (AAV2)-mCherry-Cre were placed into the arcuate nucleus of adult male and female β-catenin
mice, to specifically delete β-catenin expression in the mediobasal hypothalamus (MBH-β-cat KO). Metabolic parameters were then monitored under conditions of low-fat (LFD) and high-fat diet (HFD). On LFD, MBH-β-cat KO mice showed minimal metabolic disturbances, but on HFD, despite having only a small difference in weekly caloric intake, the MBH-β-cat KO mice were significantly heavier than the control mice in both sexes (
< 0.05). This deficit seemed to be due to a failure to show an adaptive increase in energy expenditure seen in controls, which served to offset the increased calories by HFD. Both male and female MBH-β-cat KO mice were highly glucose intolerant when on HFD and displayed a significant reduction in both leptin and insulin sensitivity compared with controls. This study highlights a critical role for β-catenin in the hypothalamic circuits regulating body weight and glucose homeostasis and reveals potential mechanisms by which genetic variation in this pathway could impact on development of metabolic disease.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>38395612</pmid><doi>10.1523/JNEUROSCI.1666-23.2024</doi><orcidid>https://orcid.org/0000-0001-5606-2559</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Arcuate nucleus beta Catenin - genetics beta Catenin - metabolism Body weight Body Weight - genetics Calories Cytoskeleton Diabetes mellitus Diabetes Mellitus, Type 2 - pathology Diet Diet, High-Fat - adverse effects Energy expenditure Energy Metabolism - genetics Female Females Gene expression Genetic diversity Genetic variation Glucose Glucose - metabolism High fat diet Homeostasis Hypothalamus Hypothalamus - metabolism Insulin Leptin Leptin - metabolism Low fat diet Male Males Metabolic disorders Metabolism Mice Mice, Inbred C57BL Mice, Knockout Neuroendocrine system Neurotransmitters Obesity Obesity - genetics Obesity - metabolism Pathogenesis Proteins Transcription Wnt protein β-Catenin |
| title | Conditional Deletion of β-Catenin in the Mediobasal Hypothalamus Impairs Adaptive Energy Expenditure in Response to High-Fat Diet and Exacerbates Diet-Induced Obesity |
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