Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1
No effective therapy is available for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Using morphology, electromyography and molecular experiments, Krieger et al. study the therapeutic efficacy of PEGylated IGF-1 in a mouse model. Stimulation of IGF-I receptor signalling correspon...
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| creator | Krieger, Frank Elflein, Nicole Saenger, Stefanie Wirthgen, Elisa Rak, Kristen Frantz, Stefan Hoeflich, Andreas Toyka, Klaus V. Metzger, Friedrich Jablonka, Sibylle |
| description | No effective therapy is available for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Using morphology, electromyography and molecular experiments, Krieger et al. study the therapeutic efficacy of PEGylated IGF-1 in a mouse model. Stimulation of IGF-I receptor signalling corresponds to delayed onset of motor function deficits in the mice.
Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd2J
) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd2J
mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd2J
mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd2J
mice. Based on these findings, polyethylene glycol-coupled IGF1 may hold promise as a candidate for fu |
| doi_str_mv | 10.1093/brain/awu059 |
| format | Article |
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Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd2J
) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd2J
mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd2J
mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd2J
mice. Based on these findings, polyethylene glycol-coupled IGF1 may hold promise as a candidate for future treatment trials in human patients with spinal muscular atrophy with respiratory distress type 1.</description><identifier>ISSN: 0006-8950</identifier><identifier>EISSN: 1460-2156</identifier><identifier>DOI: 10.1093/brain/awu059</identifier><identifier>PMID: 24681663</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Age Factors ; Animals ; Biological and medical sciences ; Cells, Cultured ; Cerebrospinal fluid. Meninges. Spinal cord ; Ciliary Neurotrophic Factor - pharmacology ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease Models, Animal ; Diseases of striated muscles. Neuromuscular diseases ; DNA-Binding Proteins - genetics ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - genetics ; Insulin-Like Growth Factor I - metabolism ; Insulin-Like Growth Factor I - pharmacology ; Insulin-Like Growth Factor I - therapeutic use ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Movement Disorders - drug therapy ; Movement Disorders - etiology ; Muscle Strength - drug effects ; Muscle Strength - genetics ; Muscle, Skeletal - drug effects ; Muscle, Skeletal - physiopathology ; Muscular Atrophy, Spinal - complications ; Muscular Atrophy, Spinal - genetics ; Muscular Atrophy, Spinal - therapy ; Myocardium - pathology ; Nervous system (semeiology, syndromes) ; Neurology ; Pneumology ; Polyethylene Glycols - therapeutic use ; Receptor, IGF Type 1 - metabolism ; Respiratory system : syndromes and miscellaneous diseases ; Time Factors ; Transcription Factors - genetics</subject><ispartof>Brain (London, England : 1878), 2014-05, Vol.137 (5), p.1374-1393</ispartof><rights>The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2014</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-ebfff2f8a69b2fbcca85e51709b0f0b7d65caf40cf0d1ebef6177dc659880ef03</citedby><cites>FETCH-LOGICAL-c424t-ebfff2f8a69b2fbcca85e51709b0f0b7d65caf40cf0d1ebef6177dc659880ef03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1584,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28440729$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24681663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Krieger, Frank</creatorcontrib><creatorcontrib>Elflein, Nicole</creatorcontrib><creatorcontrib>Saenger, Stefanie</creatorcontrib><creatorcontrib>Wirthgen, Elisa</creatorcontrib><creatorcontrib>Rak, Kristen</creatorcontrib><creatorcontrib>Frantz, Stefan</creatorcontrib><creatorcontrib>Hoeflich, Andreas</creatorcontrib><creatorcontrib>Toyka, Klaus V.</creatorcontrib><creatorcontrib>Metzger, Friedrich</creatorcontrib><creatorcontrib>Jablonka, Sibylle</creatorcontrib><title>Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1</title><title>Brain (London, England : 1878)</title><addtitle>Brain</addtitle><description>No effective therapy is available for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Using morphology, electromyography and molecular experiments, Krieger et al. study the therapeutic efficacy of PEGylated IGF-1 in a mouse model. Stimulation of IGF-I receptor signalling corresponds to delayed onset of motor function deficits in the mice.
Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd2J
) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd2J
mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd2J
mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd2J
mice. Based on these findings, polyethylene glycol-coupled IGF1 may hold promise as a candidate for future treatment trials in human patients with spinal muscular atrophy with respiratory distress type 1.</description><subject>Age Factors</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cerebrospinal fluid. Meninges. Spinal cord</subject><subject>Ciliary Neurotrophic Factor - pharmacology</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Disease Models, Animal</subject><subject>Diseases of striated muscles. Neuromuscular diseases</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - genetics</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-Like Growth Factor I - pharmacology</subject><subject>Insulin-Like Growth Factor I - therapeutic use</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Movement Disorders - drug therapy</subject><subject>Movement Disorders - etiology</subject><subject>Muscle Strength - drug effects</subject><subject>Muscle Strength - genetics</subject><subject>Muscle, Skeletal - drug effects</subject><subject>Muscle, Skeletal - physiopathology</subject><subject>Muscular Atrophy, Spinal - complications</subject><subject>Muscular Atrophy, Spinal - genetics</subject><subject>Muscular Atrophy, Spinal - therapy</subject><subject>Myocardium - pathology</subject><subject>Nervous system (semeiology, syndromes)</subject><subject>Neurology</subject><subject>Pneumology</subject><subject>Polyethylene Glycols - therapeutic use</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Respiratory system : syndromes and miscellaneous diseases</subject><subject>Time Factors</subject><subject>Transcription Factors - genetics</subject><issn>0006-8950</issn><issn>1460-2156</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFO3DAQhq2qFWwpt56RLxU9NGWcOI5zRAgoEhIc2nPkOOOuKycOtiOUZ-ClMd1te0O9jDWeT__I_gj5yOArg7Y664Oy05l6XKBu35AN4wKKktXiLdkAgChkW8MheR_jLwDGq1IckMOSC8mEqDbk6d67FdN2dTgh_elW7V2h_TI7HOjN9RWjAzq1Rjr65AM1y6ST9VO-NahTpHaiKs-WiLlmlHpD42wn5ei4RL04FahKwc_blT7atKUB8zioHLbSwcaU-0jTOiNlH8g7o1zE4_15RH5cXX6_-Fbc3l3fXJzfFpqXPBXYG2NKI5Vo-9L0WitZY80aaHsw0DeDqLUyHLSBgWGPRrCmGbSoWykBDVRH5PMudw7-YcGYutFGjc6pCfNLOlZXXJb5t8R_oKyVHKqmzeiXHaqDjzGg6eZgRxXWjkH3Yqr7barbmcr4yT556Ucc_sJ_1GTg0x5QUStngpq0jf84yTk05UvQ6Y7L0l5f-QxnbK6V</recordid><startdate>20140501</startdate><enddate>20140501</enddate><creator>Krieger, Frank</creator><creator>Elflein, Nicole</creator><creator>Saenger, Stefanie</creator><creator>Wirthgen, Elisa</creator><creator>Rak, Kristen</creator><creator>Frantz, Stefan</creator><creator>Hoeflich, Andreas</creator><creator>Toyka, Klaus V.</creator><creator>Metzger, Friedrich</creator><creator>Jablonka, Sibylle</creator><general>Oxford University Press</general><scope>IQODW</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>7X8</scope><scope>7TK</scope></search><sort><creationdate>20140501</creationdate><title>Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1</title><author>Krieger, Frank ; Elflein, Nicole ; Saenger, Stefanie ; Wirthgen, Elisa ; Rak, Kristen ; Frantz, Stefan ; Hoeflich, Andreas ; Toyka, Klaus V. ; Metzger, Friedrich ; Jablonka, Sibylle</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-ebfff2f8a69b2fbcca85e51709b0f0b7d65caf40cf0d1ebef6177dc659880ef03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Age Factors</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cerebrospinal fluid. Meninges. Spinal cord</topic><topic>Ciliary Neurotrophic Factor - pharmacology</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</topic><topic>Disease Models, Animal</topic><topic>Diseases of striated muscles. Neuromuscular diseases</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Expression Regulation - genetics</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Insulin-Like Growth Factor I - pharmacology</topic><topic>Insulin-Like Growth Factor I - therapeutic use</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Movement Disorders - drug therapy</topic><topic>Movement Disorders - etiology</topic><topic>Muscle Strength - drug effects</topic><topic>Muscle Strength - genetics</topic><topic>Muscle, Skeletal - drug effects</topic><topic>Muscle, Skeletal - physiopathology</topic><topic>Muscular Atrophy, Spinal - complications</topic><topic>Muscular Atrophy, Spinal - genetics</topic><topic>Muscular Atrophy, Spinal - therapy</topic><topic>Myocardium - pathology</topic><topic>Nervous system (semeiology, syndromes)</topic><topic>Neurology</topic><topic>Pneumology</topic><topic>Polyethylene Glycols - therapeutic use</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Respiratory system : syndromes and miscellaneous diseases</topic><topic>Time Factors</topic><topic>Transcription Factors - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Krieger, Frank</creatorcontrib><creatorcontrib>Elflein, Nicole</creatorcontrib><creatorcontrib>Saenger, Stefanie</creatorcontrib><creatorcontrib>Wirthgen, Elisa</creatorcontrib><creatorcontrib>Rak, Kristen</creatorcontrib><creatorcontrib>Frantz, Stefan</creatorcontrib><creatorcontrib>Hoeflich, Andreas</creatorcontrib><creatorcontrib>Toyka, Klaus V.</creatorcontrib><creatorcontrib>Metzger, Friedrich</creatorcontrib><creatorcontrib>Jablonka, Sibylle</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Brain (London, England : 1878)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Krieger, Frank</au><au>Elflein, Nicole</au><au>Saenger, Stefanie</au><au>Wirthgen, Elisa</au><au>Rak, Kristen</au><au>Frantz, Stefan</au><au>Hoeflich, Andreas</au><au>Toyka, Klaus V.</au><au>Metzger, Friedrich</au><au>Jablonka, Sibylle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1</atitle><jtitle>Brain (London, England : 1878)</jtitle><addtitle>Brain</addtitle><date>2014-05-01</date><risdate>2014</risdate><volume>137</volume><issue>5</issue><spage>1374</spage><epage>1393</epage><pages>1374-1393</pages><issn>0006-8950</issn><eissn>1460-2156</eissn><abstract>No effective therapy is available for spinal muscular atrophy with respiratory distress type 1 (SMARD1). Using morphology, electromyography and molecular experiments, Krieger et al. study the therapeutic efficacy of PEGylated IGF-1 in a mouse model. Stimulation of IGF-I receptor signalling corresponds to delayed onset of motor function deficits in the mice.
Spinal muscular atrophy with respiratory distress type 1 is a neuromuscular disorder characterized by progressive weakness and atrophy of the diaphragm and skeletal muscles, leading to death in childhood. No effective treatment is available. The neuromuscular degeneration (Nmd2J
) mouse shares a crucial mutation in the immunoglobulin mu-binding protein 2 gene (Ighmbp2) with spinal muscular atrophy with respiratory distress type 1 patients and also displays some basic features of the human disease. This model serves as a promising tool in understanding the complex mechanisms of the disease and in exploring novel treatment modalities such as insulin-like growth factor 1 (IGF1) which supports myogenic and neurogenic survival and stimulates differentiation during development. Here we investigated the treatment effects with polyethylene glycol-coupled IGF1 and its mechanisms of action in neurons and muscles. Polyethylene glycol-coupled IGF1 was applied subcutaneously every second day from post-natal Day 14 to post-natal Day 42 and the outcome was assessed by morphology, electromyography, and molecular studies. We found reduced IGF1 serum levels in Nmd2J
mice 2 weeks after birth, which was normalized by polyethylene glycol-coupled IGF1 treatment. Nmd2J
mice showed marked neurogenic muscle fibre atrophy in the gastrocnemius muscle and polyethylene glycol-coupled IGF1 treatment resulted in muscle fibre hypertrophy and slowed fibre degeneration along with significantly higher numbers of functionally active axonal sprouts. In the diaphragm with predominant myogenic changes a profound protection from muscle fibre degeneration was observed under treatment. No effects of polyethylene glycol-coupled IGF1 were monitored at the level of motor neuron survival. The beneficial effects of polyethylene glycol-coupled IGF1 corresponded to a marked activation of the IGF1 receptor, resulting in enhanced phosphorylation of Akt (protein kinase B) and the ribosomal protein S6 kinase in striated muscles and spinal cord from Nmd2J
mice. Based on these findings, polyethylene glycol-coupled IGF1 may hold promise as a candidate for future treatment trials in human patients with spinal muscular atrophy with respiratory distress type 1.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>24681663</pmid><doi>10.1093/brain/awu059</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Brain (London, England : 1878), 2014-05, Vol.137 (5), p.1374-1393 |
| issn | 0006-8950 1460-2156 |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Age Factors Animals Biological and medical sciences Cells, Cultured Cerebrospinal fluid. Meninges. Spinal cord Ciliary Neurotrophic Factor - pharmacology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Diseases of striated muscles. Neuromuscular diseases DNA-Binding Proteins - genetics Gene Expression Regulation - drug effects Gene Expression Regulation - genetics Insulin-Like Growth Factor I - metabolism Insulin-Like Growth Factor I - pharmacology Insulin-Like Growth Factor I - therapeutic use Medical sciences Mice Mice, Inbred C57BL Mice, Transgenic Movement Disorders - drug therapy Movement Disorders - etiology Muscle Strength - drug effects Muscle Strength - genetics Muscle, Skeletal - drug effects Muscle, Skeletal - physiopathology Muscular Atrophy, Spinal - complications Muscular Atrophy, Spinal - genetics Muscular Atrophy, Spinal - therapy Myocardium - pathology Nervous system (semeiology, syndromes) Neurology Pneumology Polyethylene Glycols - therapeutic use Receptor, IGF Type 1 - metabolism Respiratory system : syndromes and miscellaneous diseases Time Factors Transcription Factors - genetics |
| title | Polyethylene glycol-coupled IGF1 delays motor function defects in a mouse model of spinal muscular atrophy with respiratory distress type 1 |
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