Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice
- Autores
- Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; Alaniz, Laura Daniela; Garcia, Mariana Gabriela; Piccioni, Flavia Valeria; Fiore, Esteban Juan; Bayo, Juan; Bataller, Ramón; Guruceaga, Elizabeth; Corrales, Fernando; Podhajcer, Osvaldo Luis; Mazzolini Rizzo, Guillermo Daniel
- Año de publicación
- 2013
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.
Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina
Fil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados Unidos
Fil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; España
Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina - Materia
-
SPARC
Collagen
TGFB1
Inflammation
Liver chirrosis
Microarray - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/4039
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Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in MiceAtorrasagasti, Maria CatalinaPeixoto, EstanislaoAquino, Jorge BenjaminKippes, Néstor FabiánMalvicini, MarianaAlaniz, Laura DanielaGarcia, Mariana GabrielaPiccioni, Flavia ValeriaFiore, Esteban JuanBayo, JuanBataller, RamónGuruceaga, ElizabethCorrales, FernandoPodhajcer, Osvaldo LuisMazzolini Rizzo, Guillermo DanielSPARCCollagenTGFB1InflammationLiver chirrosisMicroarrayhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment.Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; ArgentinaFil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados UnidosFil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; EspañaFil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; EspañaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaPublic Library of Science2013-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4039Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e549621932-6203enginfo:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054962info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1371%2Fjournal.pone.0054962info:eu-repo/semantics/altIdentifier/doi/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:55:36Zoai:ri.conicet.gov.ar:11336/4039instacron: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 09:55:37.033CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
title |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
spellingShingle |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice Atorrasagasti, Maria Catalina SPARC Collagen TGFB1 Inflammation Liver chirrosis Microarray |
title_short |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
title_full |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
title_fullStr |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
title_full_unstemmed |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
title_sort |
Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice |
dc.creator.none.fl_str_mv |
Atorrasagasti, Maria Catalina Peixoto, Estanislao Aquino, Jorge Benjamin Kippes, Néstor Fabián Malvicini, Mariana Alaniz, Laura Daniela Garcia, Mariana Gabriela Piccioni, Flavia Valeria Fiore, Esteban Juan Bayo, Juan Bataller, Ramón Guruceaga, Elizabeth Corrales, Fernando Podhajcer, Osvaldo Luis Mazzolini Rizzo, Guillermo Daniel |
author |
Atorrasagasti, Maria Catalina |
author_facet |
Atorrasagasti, Maria Catalina Peixoto, Estanislao Aquino, Jorge Benjamin Kippes, Néstor Fabián Malvicini, Mariana Alaniz, Laura Daniela Garcia, Mariana Gabriela Piccioni, Flavia Valeria Fiore, Esteban Juan Bayo, Juan Bataller, Ramón Guruceaga, Elizabeth Corrales, Fernando Podhajcer, Osvaldo Luis Mazzolini Rizzo, Guillermo Daniel |
author_role |
author |
author2 |
Peixoto, Estanislao Aquino, Jorge Benjamin Kippes, Néstor Fabián Malvicini, Mariana Alaniz, Laura Daniela Garcia, Mariana Gabriela Piccioni, Flavia Valeria Fiore, Esteban Juan Bayo, Juan Bataller, Ramón Guruceaga, Elizabeth Corrales, Fernando Podhajcer, Osvaldo Luis Mazzolini Rizzo, Guillermo Daniel |
author2_role |
author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
SPARC Collagen TGFB1 Inflammation Liver chirrosis Microarray |
topic |
SPARC Collagen TGFB1 Inflammation Liver chirrosis Microarray |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment. Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Peixoto, Estanislao. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Kippes, Néstor Fabián. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Piccioni, Flavia Valeria. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Bayo, Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina Fil: Bataller, Ramón. University of North Carolina. Department of Medicine and Nutrition; Estados Unidos Fil: Guruceaga, Elizabeth. Universidad de Navarra. Centro de Investigación Médica Aplicada; España Fil: Corrales, Fernando. Universidad de Navarra. Centro de Investigación Médica Aplicada; España Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina |
description |
Introduction Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in many biological processes and found over-expressed in cirrhotic livers. By mean of a genetic approach we herein provide evidence from different in vivo liver disease models suggesting a profibrogenic role for SPARC. Methods Two in vivo models of liver fibrosis, based on TAA administration and bile duct ligation, were developed on SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice. Hepatic SPARC expression was analyzed by qPCR. Fibrosis was assessed by Sirius Red staining, and the maturation state of collagen fibers was analyzed using polarized light. Necroinflammatory activity was evaluated by applying the Knodell score and liver inflammatory infiltration was characterized by immunohistochemistry. Hepatic stellate cell activation was assessed by α-SMA immunohistochemistry. In addition, pro-fibrogenic genes and inflammatory cytokines were measured by qPCR and/or ELISA. Liver gene expression profile was analyzed in SPARC−/− and SPARC+/+ mice using Affymetrix Mouse Gene ST 1.0 array. Results SPARC expression was found induced in fibrotic livers of mouse and human. SPARC−/− mice showed a reduction in the degree of inflammation, mainly CD4+ cells, and fibrosis. Consistently, collagen deposits and mRNA expression levels were decreased in SPARC−/− mice when compared to SPARC+/+ mice; in addition, MMP-2 expression was increased in SPARC−/− mice. A reduction in the number of activated myofibroblasts was observed. Moreover, TGF-β1 expression levels were down-regulated in the liver as well as in the serum of TAA-treated knock-out animals. Ingenuity Pathway Analysis (IPA) analysis suggested several gene networks which might involve protective mechanisms of SPARC deficiency against liver fibrogenesis and a better established machinery to repair DNA and detoxify from external chemical stimuli. Conclusions Overall our data suggest that SPARC plays a significant role in liver fibrogenesis. Interventions to inhibit SPARC expression are suggested as promising approaches for liver fibrosis treatment. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013-02 |
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/11336/4039 Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e54962 1932-6203 |
url |
http://hdl.handle.net/11336/4039 |
identifier_str_mv |
Atorrasagasti, Maria Catalina; Peixoto, Estanislao; Aquino, Jorge Benjamin; Kippes, Néstor Fabián; Malvicini, Mariana; et al.; Lack of the Matricellular Protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) Attenuates Liver Fibrogenesis in Mice; Public Library of Science; Plos One; 8; 2; 2-2013; e54962-e54962 1932-6203 |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054962 info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.1371%2Fjournal.pone.0054962 info:eu-repo/semantics/altIdentifier/doi/ |
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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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Public Library of Science |
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Public Library of Science |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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