Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions
- Autores
- Tóth, Gergely; Neumann, Thomas; Berthet, Amandine; Masliah, Eliezer; Spencer, Brian; Tao, Jiahui; Jobling, Michael F.; Gardai, Shyra J.; Bertoncini, Carlos Walter; Cremades, Nunilo; Bova, Michael; Ballaron, Stephen; Chen, Xiao-Hua; Mao, Wenxian; Nguyen, Phuong; Tabios, Mariano C.; Tambe, Mitali A.; Rochet, Jean Christophe; Junker, Hans Dieter; Schwizer, Daniel; Sekul, Renate; Ott, Inge; Anderson, John P.; Szoke, Balazs; Hoffman, Wherly; Christodoulou, John; Yednock, Ted; Agard, David A.; Schenk, Dale; McConlogue, Lisa
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.
Fil: Tóth, Gergely. Elan Pharmaceuticals; Estados Unidos. University of Cambridge; Estados Unidos. Hungarian Academy of Sciences; Hungría. Cantabio Pharmaceuticals; Estados Unidos
Fil: Neumann, Thomas. NovAliX; Francia
Fil: Berthet, Amandine. Gladstone Institute of Neurological Disease; Estados Unidos
Fil: Masliah, Eliezer. University of California at San Diego; Estados Unidos. National Institutes of Health; Estados Unidos
Fil: Spencer, Brian. University of California at San Diego; Estados Unidos
Fil: Tao, Jiahui. University of California; Estados Unidos
Fil: Jobling, Michael F.. Elan Pharmaceuticals; Estados Unidos
Fil: Gardai, Shyra J.. Elan Pharmaceuticals; Estados Unidos
Fil: Bertoncini, Carlos Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Cambridge; Reino Unido. Institute for Research in Biomedicine; España
Fil: Cremades, Nunilo. University of Cambridge; Reino Unido
Fil: Bova, Michael. Elan Pharmaceuticals; Estados Unidos
Fil: Ballaron, Stephen. Elan Pharmaceuticals; Estados Unidos
Fil: Chen, Xiao-Hua. Elan Pharmaceuticals; Estados Unidos
Fil: Mao, Wenxian. Elan Pharmaceuticals; Estados Unidos
Fil: Nguyen, Phuong. University of California; Estados Unidos
Fil: Tabios, Mariano C.. University of California; Estados Unidos
Fil: Tambe, Mitali A.. Purdue University; Estados Unidos
Fil: Rochet, Jean Christophe. Purdue University; Estados Unidos
Fil: Junker, Hans Dieter. Aalen University; Alemania. NovAliX; Francia
Fil: Schwizer, Daniel. NovAliX; Francia
Fil: Sekul, Renate. NovAliX; Francia
Fil: Ott, Inge. NovAliX; Francia
Fil: Anderson, John P.. Elan Pharmaceuticals; Estados Unidos
Fil: Szoke, Balazs. Elan Pharmaceuticals; Estados Unidos
Fil: Hoffman, Wherly. Elan Pharmaceuticals; Estados Unidos
Fil: Christodoulou, John. Colegio Universitario de Londres; Reino Unido
Fil: Yednock, Ted. Elan Pharmaceuticals; Estados Unidos
Fil: Agard, David A.. University of California; Estados Unidos
Fil: Schenk, Dale. Elan Pharmaceuticals; Estados Unidos
Fil: McConlogue, Lisa. Elan Pharmaceuticals; Estados Unidos. Gladstone Institute of Neurological Disease; Estados Unidos. University of California; Estados Unidos - Materia
-
PARKINSONS DISEASE
DRUG DISCOVERY
STRUCTURAL BIOLOGY
NEURODEGENERATION - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/175630
Ver los metadatos del registro completo
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Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctionsTóth, GergelyNeumann, ThomasBerthet, AmandineMasliah, EliezerSpencer, BrianTao, JiahuiJobling, Michael F.Gardai, Shyra J.Bertoncini, Carlos WalterCremades, NuniloBova, MichaelBallaron, StephenChen, Xiao-HuaMao, WenxianNguyen, PhuongTabios, Mariano C.Tambe, Mitali A.Rochet, Jean ChristopheJunker, Hans DieterSchwizer, DanielSekul, RenateOtt, IngeAnderson, John P.Szoke, BalazsHoffman, WherlyChristodoulou, JohnYednock, TedAgard, David A.Schenk, DaleMcConlogue, LisaPARKINSONS DISEASEDRUG DISCOVERYSTRUCTURAL BIOLOGYNEURODEGENERATIONhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.Fil: Tóth, Gergely. Elan Pharmaceuticals; Estados Unidos. University of Cambridge; Estados Unidos. Hungarian Academy of Sciences; Hungría. Cantabio Pharmaceuticals; Estados UnidosFil: Neumann, Thomas. NovAliX; FranciaFil: Berthet, Amandine. Gladstone Institute of Neurological Disease; Estados UnidosFil: Masliah, Eliezer. University of California at San Diego; Estados Unidos. National Institutes of Health; Estados UnidosFil: Spencer, Brian. University of California at San Diego; Estados UnidosFil: Tao, Jiahui. University of California; Estados UnidosFil: Jobling, Michael F.. Elan Pharmaceuticals; Estados UnidosFil: Gardai, Shyra J.. Elan Pharmaceuticals; Estados UnidosFil: Bertoncini, Carlos Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Cambridge; Reino Unido. Institute for Research in Biomedicine; EspañaFil: Cremades, Nunilo. University of Cambridge; Reino UnidoFil: Bova, Michael. Elan Pharmaceuticals; Estados UnidosFil: Ballaron, Stephen. Elan Pharmaceuticals; Estados UnidosFil: Chen, Xiao-Hua. Elan Pharmaceuticals; Estados UnidosFil: Mao, Wenxian. Elan Pharmaceuticals; Estados UnidosFil: Nguyen, Phuong. University of California; Estados UnidosFil: Tabios, Mariano C.. University of California; Estados UnidosFil: Tambe, Mitali A.. Purdue University; Estados UnidosFil: Rochet, Jean Christophe. Purdue University; Estados UnidosFil: Junker, Hans Dieter. Aalen University; Alemania. NovAliX; FranciaFil: Schwizer, Daniel. NovAliX; FranciaFil: Sekul, Renate. NovAliX; FranciaFil: Ott, Inge. NovAliX; FranciaFil: Anderson, John P.. Elan Pharmaceuticals; Estados UnidosFil: Szoke, Balazs. Elan Pharmaceuticals; Estados UnidosFil: Hoffman, Wherly. Elan Pharmaceuticals; Estados UnidosFil: Christodoulou, John. Colegio Universitario de Londres; Reino UnidoFil: Yednock, Ted. Elan Pharmaceuticals; Estados UnidosFil: Agard, David A.. University of California; Estados UnidosFil: Schenk, Dale. Elan Pharmaceuticals; Estados UnidosFil: McConlogue, Lisa. Elan Pharmaceuticals; Estados Unidos. Gladstone Institute of Neurological Disease; Estados Unidos. University of California; Estados UnidosNature Publishing Group2019-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/175630Tóth, Gergely; Neumann, Thomas; Berthet, Amandine; Masliah, Eliezer; Spencer, Brian; et al.; Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions; Nature Publishing Group; Scientific Reports; 9; 1; 11-2019; 1-142045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-52598-4info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-52598-4info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:42:00Zoai:ri.conicet.gov.ar:11336/175630instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:42:00.772CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| title |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| spellingShingle |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions Tóth, Gergely PARKINSONS DISEASE DRUG DISCOVERY STRUCTURAL BIOLOGY NEURODEGENERATION |
| title_short |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| title_full |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| title_fullStr |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| title_full_unstemmed |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| title_sort |
Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions |
| dc.creator.none.fl_str_mv |
Tóth, Gergely Neumann, Thomas Berthet, Amandine Masliah, Eliezer Spencer, Brian Tao, Jiahui Jobling, Michael F. Gardai, Shyra J. Bertoncini, Carlos Walter Cremades, Nunilo Bova, Michael Ballaron, Stephen Chen, Xiao-Hua Mao, Wenxian Nguyen, Phuong Tabios, Mariano C. Tambe, Mitali A. Rochet, Jean Christophe Junker, Hans Dieter Schwizer, Daniel Sekul, Renate Ott, Inge Anderson, John P. Szoke, Balazs Hoffman, Wherly Christodoulou, John Yednock, Ted Agard, David A. Schenk, Dale McConlogue, Lisa |
| author |
Tóth, Gergely |
| author_facet |
Tóth, Gergely Neumann, Thomas Berthet, Amandine Masliah, Eliezer Spencer, Brian Tao, Jiahui Jobling, Michael F. Gardai, Shyra J. Bertoncini, Carlos Walter Cremades, Nunilo Bova, Michael Ballaron, Stephen Chen, Xiao-Hua Mao, Wenxian Nguyen, Phuong Tabios, Mariano C. Tambe, Mitali A. Rochet, Jean Christophe Junker, Hans Dieter Schwizer, Daniel Sekul, Renate Ott, Inge Anderson, John P. Szoke, Balazs Hoffman, Wherly Christodoulou, John Yednock, Ted Agard, David A. Schenk, Dale McConlogue, Lisa |
| author_role |
author |
| author2 |
Neumann, Thomas Berthet, Amandine Masliah, Eliezer Spencer, Brian Tao, Jiahui Jobling, Michael F. Gardai, Shyra J. Bertoncini, Carlos Walter Cremades, Nunilo Bova, Michael Ballaron, Stephen Chen, Xiao-Hua Mao, Wenxian Nguyen, Phuong Tabios, Mariano C. Tambe, Mitali A. Rochet, Jean Christophe Junker, Hans Dieter Schwizer, Daniel Sekul, Renate Ott, Inge Anderson, John P. Szoke, Balazs Hoffman, Wherly Christodoulou, John Yednock, Ted Agard, David A. Schenk, Dale McConlogue, Lisa |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
PARKINSONS DISEASE DRUG DISCOVERY STRUCTURAL BIOLOGY NEURODEGENERATION |
| topic |
PARKINSONS DISEASE DRUG DISCOVERY STRUCTURAL BIOLOGY NEURODEGENERATION |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease. Fil: Tóth, Gergely. Elan Pharmaceuticals; Estados Unidos. University of Cambridge; Estados Unidos. Hungarian Academy of Sciences; Hungría. Cantabio Pharmaceuticals; Estados Unidos Fil: Neumann, Thomas. NovAliX; Francia Fil: Berthet, Amandine. Gladstone Institute of Neurological Disease; Estados Unidos Fil: Masliah, Eliezer. University of California at San Diego; Estados Unidos. National Institutes of Health; Estados Unidos Fil: Spencer, Brian. University of California at San Diego; Estados Unidos Fil: Tao, Jiahui. University of California; Estados Unidos Fil: Jobling, Michael F.. Elan Pharmaceuticals; Estados Unidos Fil: Gardai, Shyra J.. Elan Pharmaceuticals; Estados Unidos Fil: Bertoncini, Carlos Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina. University of Cambridge; Reino Unido. Institute for Research in Biomedicine; España Fil: Cremades, Nunilo. University of Cambridge; Reino Unido Fil: Bova, Michael. Elan Pharmaceuticals; Estados Unidos Fil: Ballaron, Stephen. Elan Pharmaceuticals; Estados Unidos Fil: Chen, Xiao-Hua. Elan Pharmaceuticals; Estados Unidos Fil: Mao, Wenxian. Elan Pharmaceuticals; Estados Unidos Fil: Nguyen, Phuong. University of California; Estados Unidos Fil: Tabios, Mariano C.. University of California; Estados Unidos Fil: Tambe, Mitali A.. Purdue University; Estados Unidos Fil: Rochet, Jean Christophe. Purdue University; Estados Unidos Fil: Junker, Hans Dieter. Aalen University; Alemania. NovAliX; Francia Fil: Schwizer, Daniel. NovAliX; Francia Fil: Sekul, Renate. NovAliX; Francia Fil: Ott, Inge. NovAliX; Francia Fil: Anderson, John P.. Elan Pharmaceuticals; Estados Unidos Fil: Szoke, Balazs. Elan Pharmaceuticals; Estados Unidos Fil: Hoffman, Wherly. Elan Pharmaceuticals; Estados Unidos Fil: Christodoulou, John. Colegio Universitario de Londres; Reino Unido Fil: Yednock, Ted. Elan Pharmaceuticals; Estados Unidos Fil: Agard, David A.. University of California; Estados Unidos Fil: Schenk, Dale. Elan Pharmaceuticals; Estados Unidos Fil: McConlogue, Lisa. Elan Pharmaceuticals; Estados Unidos. Gladstone Institute of Neurological Disease; Estados Unidos. University of California; Estados Unidos |
| description |
The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019-11 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/175630 Tóth, Gergely; Neumann, Thomas; Berthet, Amandine; Masliah, Eliezer; Spencer, Brian; et al.; Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions; Nature Publishing Group; Scientific Reports; 9; 1; 11-2019; 1-14 2045-2322 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/175630 |
| identifier_str_mv |
Tóth, Gergely; Neumann, Thomas; Berthet, Amandine; Masliah, Eliezer; Spencer, Brian; et al.; Novel small molecules targeting the intrinsically disordered structural ensemble of α-Synuclein protect against diverse α-Synuclein mediated dysfunctions; Nature Publishing Group; Scientific Reports; 9; 1; 11-2019; 1-14 2045-2322 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-52598-4 info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-52598-4 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by/2.5/ar/ |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Nature Publishing Group |
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Nature Publishing Group |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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