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Michot Caroline - One of the best experts on this subject based on the ideXlab platform.
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LPIN1 - étude génétique d'une nouvelle cause de rhabdomyolyse héréditaire et analyses physiopathologiques à partir de myoblastes de patients
2013Co-Authors: Michot CarolineAbstract:Rhabdomyolyses correspond to the destruction of skeletal muscular fibers and are possibly life-threatening. The main genetic cause is linked to defects of fatty acid oxidation (FAO) ; nevertheless, half of the cases have no identified aetiology. In 2008, mutations of LPIN1 gene have been reported as a new cause of autosomal recessive rhabdomyolysis. Lipin1 protein has a double function : 1) a role of phosphatidate phosphatase 1 (PAP1) involved in synthesis of triacylglycerol and membrane phospholipids ; 2) a role of transcriptional co-activator which regulates, in association with the PPARs (peroxysome-proliferator activated receptor) and PGC1α (PPARγ-coactivator1α), numerous genes involved in the metabolism including some genes encoding FAO enzymes. Lipin1 has got two homologues, lipin2 and lipin3, which have a PAP1 activity and a binding site for nuclear receptors, such as the PPARs. We have shown that LPIN1 mutations account for more than 50% of the cases of severe rhabdomyolysis of early infancy, when FAO defects have been excluded. An intragenic in frame deletion has been frequently identified in Caucasians. We have shown that it probably comes from a founding effect and that this deletion is deleterious. Unlike normal lipin1, deleted lipin1 protein is unable to complement the Δpah1 yeast which is defective for the yeast LPIN1 homolog. In a series of 171 patients, we have further studied the involvement LPIN1 in less severe muscular diseases, as well as the role of the two homologues LPIN2 and LPIN3. LPIN1 mutations are involved only in severe and early rhabdomyolyses and the bouts of rhabdomyolysis always have a triggerring factor, mainly acute febrile infections. No Major Alteration of LPIN2 and LPIN3 has been identified, even in milder phenotypes. Eventually, we have cultivated myoblasts and myotubes of patients with LPIN1 mutations in order to study the mechanisms of the rhabdomyolysis. Lipin1-deficient myoblasts have a drastically decreased PAP1 activity and an accumulation of lipid droplets. The expression level of target genes of the transcription factors co-activated by lipin1 (PPARδ, PPARα, PGC1α, acyl-Coenzyme A very long chain dehydrogenase (ACADVL), carnitine palmitoyl-transferase 1B and 2 (CPT1B and CPT2)) are similar to controls, whereas the level of lipin2 is increased. Transcriptomic analysis of myotube cultures have identified in patients 19 under-expressed genes and 51 over-expressed ones, notably ACACB, which encodes Accβ (acetyl-CoA carboxylase β), key enzyme of the balance between fatty acid synthesis and FAO. ACACB invalidation by siRNA in lipin1-deficient myoblasts decreases the number of lipid droplets, comforting the link between ACACB over-expression and free fatty acid accumulation in patients. However, the level of malonyl-CoA, product of Accβ, and CPT1 activity (limitative step of FAO, inhibited by malonyl-CoA), are similar between myoblasts of patients and controls. But treatment of the cultures with an association of tumor necrosis factor α and interleukin-1 β (TNFα + IL-1β), chosen for mimicking pro-inflammatory conditions of acute infections, leads to a further increase of the level of malonyl-CoA, a decrease of CPT1 activity and an increase of lipid droplets accumulation in patients. In total, our data show that LPIN1 is an important cause of inherited rhabdomyolysis. Lipin1 deficiency leads to a disturbance of the lipidic metabolism, via ACACB over-expression, which is exacerbated in pro-inflammatory conditions. Our results suggest that the consequences of lipin1 deficiency are counterbalanced by adaptative mechanisms which are sufficient at basal state, but insufficient for the metabolic request induced by environmental stresses, such as infections, leading to the rhabdomyolyses. Next step is the study of adipose tissue and the establishment of the inflammatory signature of the patients, in order to determine if this new disease is an auto-inflammatory pathology.Les rhabdomyolyses correspondent à la destruction de fibres musculaires striées squelettiques et mettent en jeu le pronostic vital. La principale cause génétique est liée à un défaut d’oxydation des acides gras ; néanmoins, plus de la moitié des cas n’ont pas de cause identifiée. En 2008, des mutations du gène LPIN1 ont été rapportées comme une nouvelle étiologie de rhabdomyolyse de transmission autosomique récessive. La protéine lipin1 a une double fonction : un rôle de PAP1 intervenant dans la synthèse du triacylglycérol et des phospholipides membranaires ; un rôle de co-activateur transcriptionnel en association avec les PPARs et PGC1α pour réguler de nombreux gènes impliqués dans le métabolisme, dont certains de l’OAG. Lipin1 a deux homologues, lipin2 et lipin3, qui possèdent une activité PAP1 et un site de fixation à des récepteurs nucléaires tels que les PPARs. Nous avons montré que les mutations de LPIN1 rendent compte de plus de 50% des cas de rhabdomyolyse sévère de la petite enfance, une fois écarté le diagnostic de déficit de l’OAG. Une délétion intragénique en phase a été fréquemment identifiée chez les Caucasiens. Nous avons montré qu’il s’agissait d’un probable effet fondateur et que cette délétion est délétère. En effet, à l’inverse de la forme normale de lipin1, la forme délétée est incapable de complémenter la levure pah1, déficiente pour l’homologue de LPIN1. Nous avons ensuite étudié, dans une série de 171 patients, l’implication de LPIN1 dans des pathologies musculaires moins sévères, ainsi que le rôle des deux homologues LPIN2 et LPIN3. Les mutations de LPIN1 sont impliquées dans les rhabdomyolyses sévères et précoces uniquement et les accès de rhabdomyolyse ont toujours un facteur déclenchant, le principal étant les infections aiguës fébriles. Aucune altération majeure de LPIN2 et de LPIN3 n’a été identifiée, même dans des phénotypes modérés. Enfin, nous avons cultivé des myoblastes et des myotubes de patients avec mutations de LPIN1 afin d’étudier les mécanismes de rhabdomyolyse. Les myoblastes déficients en lipin1 ont une activité PAP1 très diminuée et une accumulation de gouttelettes lipidiques. Le niveau d’expression des gènes cibles des facteurs de transcription co-activés par lipin1 (PPARδ, PPARα, PGC1α, ACADVL, CPT1B and CPT2) sont inchangés par rapport aux contrôles, alors que le niveau de lipin2 est augmenté. L’analyse transcriptomique sur cultures de myotubes a identifié chez les patients 19 gènes sous-exprimés et 51 sur-exprimés, notamment ACACB, qui code pour Accβ, enzyme clé de la balance synthèse d’acides gras/OAG. L’invalidation d’ACACB par siRNA dans des myoblastes déficients en lipin1 diminue le nombre de gouttelettes lipidiques, confirmant le lien entre la sur-expression d’ACACB et l’accumulation d’acides gras libres chez les patients. Cependant, le taux de malonyl-CoA, produit d’Accβ, et l’activité CPT1 (étape limitatrice de l’OAG, inhibée par le malonyl-CoA), sont comparables entre myoblastes de patients et de contrôles. Néanmoins, le traitement des cultures par l’association de tumor necrosis factor alpha et d’interleukine-1 β, choisis pour simuler les conditions pro-inflammatoires des infections aiguës, entraîne une augmentation encore plus poussée du taux de malonyl-CoA, une diminution de l’activité CPT1 et une augmentation de l’accumulation de gouttelettes lipidiques chez les patients. Au total, nos données placent LPIN1 comme une cause importante de rhabdomyolyse héréditaire. Le déficit en lipin1 entraine une perturbation du métabolisme lipidique, via une sur-expression d’ACACB, qui est exacerbée en conditions pro-inflammatoires. Nos résultats suggèrent que les conséquences du déficit en lipin1 sont compensées par des mécanismes d'adaptation suffisants en condition normale, mais insuffisants pour la demande métabolique induite par des stress environnementaux comme l'infection, conduisant aux rhabdomyolyses
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LPIN1 - genetic study of a new cause of inherited rhabdomyolysis and physiopathological analyses on patient myoblasts
2013Co-Authors: Michot CarolineAbstract:Les rhabdomyolyses correspondent à la destruction de fibres musculaires striées squelettiques et mettent en jeu le pronostic vital. La principale cause génétique est liée à un défaut d’oxydation des acides gras ; néanmoins, plus de la moitié des cas n’ont pas de cause identifiée. En 2008, des mutations du gène LPIN1 ont été rapportées comme une nouvelle étiologie de rhabdomyolyse de transmission autosomique récessive. La protéine lipin1 a une double fonction : un rôle de PAP1 intervenant dans la synthèse du triacylglycérol et des phospholipides membranaires ; un rôle de co-activateur transcriptionnel en association avec les PPARs et PGC1α pour réguler de nombreux gènes impliqués dans le métabolisme, dont certains de l’OAG. Lipin1 a deux homologues, lipin2 et lipin3, qui possèdent une activité PAP1 et un site de fixation à des récepteurs nucléaires tels que les PPARs. Nous avons montré que les mutations de LPIN1 rendent compte de plus de 50% des cas de rhabdomyolyse sévère de la petite enfance, une fois écarté le diagnostic de déficit de l’OAG. Une délétion intragénique en phase a été fréquemment identifiée chez les Caucasiens. Nous avons montré qu’il s’agissait d’un probable effet fondateur et que cette délétion est délétère. En effet, à l’inverse de la forme normale de lipin1, la forme délétée est incapable de complémenter la levure pah1, déficiente pour l’homologue de LPIN1. Nous avons ensuite étudié, dans une série de 171 patients, l’implication de LPIN1 dans des pathologies musculaires moins sévères, ainsi que le rôle des deux homologues LPIN2 et LPIN3. Les mutations de LPIN1 sont impliquées dans les rhabdomyolyses sévères et précoces uniquement et les accès de rhabdomyolyse ont toujours un facteur déclenchant, le principal étant les infections aiguës fébriles. Aucune altération majeure de LPIN2 et de LPIN3 n’a été identifiée, même dans des phénotypes modérés. Enfin, nous avons cultivé des myoblastes et des myotubes de patients avec mutations de LPIN1 afin d’étudier les mécanismes de rhabdomyolyse. Les myoblastes déficients en lipin1 ont une activité PAP1 très diminuée et une accumulation de gouttelettes lipidiques. Le niveau d’expression des gènes cibles des facteurs de transcription co-activés par lipin1 (PPARδ, PPARα, PGC1α, ACADVL, CPT1B and CPT2) sont inchangés par rapport aux contrôles, alors que le niveau de lipin2 est augmenté. L’analyse transcriptomique sur cultures de myotubes a identifié chez les patients 19 gènes sous-exprimés et 51 sur-exprimés, notamment ACACB, qui code pour Accβ, enzyme clé de la balance synthèse d’acides gras/OAG. L’invalidation d’ACACB par siRNA dans des myoblastes déficients en lipin1 diminue le nombre de gouttelettes lipidiques, confirmant le lien entre la sur-expression d’ACACB et l’accumulation d’acides gras libres chez les patients. Cependant, le taux de malonyl-CoA, produit d’Accβ, et l’activité CPT1 (étape limitatrice de l’OAG, inhibée par le malonyl-CoA), sont comparables entre myoblastes de patients et de contrôles. Néanmoins, le traitement des cultures par l’association de tumor necrosis factor alpha et d’interleukine-1 β, choisis pour simuler les conditions pro-inflammatoires des infections aiguës, entraîne une augmentation encore plus poussée du taux de malonyl-CoA, une diminution de l’activité CPT1 et une augmentation de l’accumulation de gouttelettes lipidiques chez les patients. Au total, nos données placent LPIN1 comme une cause importante de rhabdomyolyse héréditaire. Le déficit en lipin1 entraine une perturbation du métabolisme lipidique, via une sur-expression d’ACACB, qui est exacerbée en conditions pro-inflammatoires. Nos résultats suggèrent que les conséquences du déficit en lipin1 sont compensées par des mécanismes d'adaptation suffisants en condition normale, mais insuffisants pour la demande métabolique induite par des stress environnementaux comme l'infection, conduisant aux rhabdomyolyses.Rhabdomyolyses correspond to the destruction of skeletal muscular fibers and are possibly life-threatening. The main genetic cause is linked to defects of fatty acid oxidation (FAO) ; nevertheless, half of the cases have no identified aetiology. In 2008, mutations of LPIN1 gene have been reported as a new cause of autosomal recessive rhabdomyolysis. Lipin1 protein has a double function : 1) a role of phosphatidate phosphatase 1 (PAP1) involved in synthesis of triacylglycerol and membrane phospholipids ; 2) a role of transcriptional co-activator which regulates, in association with the PPARs (peroxysome-proliferator activated receptor) and PGC1α (PPARγ-coactivator1α), numerous genes involved in the metabolism including some genes encoding FAO enzymes. Lipin1 has got two homologues, lipin2 and lipin3, which have a PAP1 activity and a binding site for nuclear receptors, such as the PPARs. We have shown that LPIN1 mutations account for more than 50% of the cases of severe rhabdomyolysis of early infancy, when FAO defects have been excluded. An intragenic in frame deletion has been frequently identified in Caucasians. We have shown that it probably comes from a founding effect and that this deletion is deleterious. Unlike normal lipin1, deleted lipin1 protein is unable to complement the Δpah1 yeast which is defective for the yeast LPIN1 homolog. In a series of 171 patients, we have further studied the involvement LPIN1 in less severe muscular diseases, as well as the role of the two homologues LPIN2 and LPIN3. LPIN1 mutations are involved only in severe and early rhabdomyolyses and the bouts of rhabdomyolysis always have a triggerring factor, mainly acute febrile infections. No Major Alteration of LPIN2 and LPIN3 has been identified, even in milder phenotypes. Eventually, we have cultivated myoblasts and myotubes of patients with LPIN1 mutations in order to study the mechanisms of the rhabdomyolysis. Lipin1-deficient myoblasts have a drastically decreased PAP1 activity and an accumulation of lipid droplets. The expression level of target genes of the transcription factors co-activated by lipin1 (PPARδ, PPARα, PGC1α, acyl-Coenzyme A very long chain dehydrogenase (ACADVL), carnitine palmitoyl-transferase 1B and 2 (CPT1B and CPT2)) are similar to controls, whereas the level of lipin2 is increased. Transcriptomic analysis of myotube cultures have identified in patients 19 under-expressed genes and 51 over-expressed ones, notably ACACB, which encodes Accβ (acetyl-CoA carboxylase β), key enzyme of the balance between fatty acid synthesis and FAO. ACACB invalidation by siRNA in lipin1-deficient myoblasts decreases the number of lipid droplets, comforting the link between ACACB over-expression and free fatty acid accumulation in patients. However, the level of malonyl-CoA, product of Accβ, and CPT1 activity (limitative step of FAO, inhibited by malonyl-CoA), are similar between myoblasts of patients and controls. But treatment of the cultures with an association of tumor necrosis factor α and interleukin-1 β (TNFα + IL-1β), chosen for mimicking pro-inflammatory conditions of acute infections, leads to a further increase of the level of malonyl-CoA, a decrease of CPT1 activity and an increase of lipid droplets accumulation in patients. In total, our data show that LPIN1 is an important cause of inherited rhabdomyolysis. Lipin1 deficiency leads to a disturbance of the lipidic metabolism, via ACACB over-expression, which is exacerbated in pro-inflammatory conditions. Our results suggest that the consequences of lipin1 deficiency are counterbalanced by adaptative mechanisms which are sufficient at basal state, but insufficient for the metabolic request induced by environmental stresses, such as infections, leading to the rhabdomyolyses. Next step is the study of adipose tissue and the establishment of the inflammatory signature of the patients, in order to determine if this new disease is an auto-inflammatory pathology
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LPIN1 - étude génétique d'une nouvelle cause de rhabdomyolyse héréditaire et analyses physiopathologiques à partir de myoblastes de patients
2013Co-Authors: Michot Caroline, Pascale De ,lonlayAbstract:Les rhabdomyolyses correspondent à la destruction de fibres musculaires striées squelettiques et mettent en jeu le pronostic vital. La principale cause génétique est liée à un défaut d oxydation des acides gras ; néanmoins, plus de la moitié des cas n ont pas de cause identifiée. En 2008, des mutations du gène LPIN1 ont été rapportées comme une nouvelle étiologie de rhabdomyolyse de transmission autosomique récessive. La protéine lipin1 a une double fonction : un rôle de PAP1 intervenant dans la synthèse du triacylglycérol et des phospholipides membranaires ; un rôle de co-activateur transcriptionnel en association avec les PPARs et PGC1a pour réguler de nombreux gènes impliqués dans le métabolisme, dont certains de l OAG. Lipin1 a deux homologues, lipin2 et lipin3, qui possèdent une activité PAP1 et un site de fixation à des récepteurs nucléaires tels que les PPARs. Nous avons montré que les mutations de LPIN1 rendent compte de plus de 50% des cas de rhabdomyolyse sévère de la petite enfance, une fois écarté le diagnostic de déficit de l OAG. Une délétion intragénique en phase a été fréquemment identifiée chez les Caucasiens. Nous avons montré qu il s agissait d un probable effet fondateur et que cette délétion est délétère. En effet, à l inverse de la forme normale de lipin1, la forme délétée est incapable de complémenter la levure pah1, déficiente pour l homologue de LPIN1. Nous avons ensuite étudié, dans une série de 171 patients, l implication de LPIN1 dans des pathologies musculaires moins sévères, ainsi que le rôle des deux homologues LPIN2 et LPIN3. Les mutations de LPIN1 sont impliquées dans les rhabdomyolyses sévères et précoces uniquement et les accès de rhabdomyolyse ont toujours un facteur déclenchant, le principal étant les infections aiguës fébriles. Aucune altération majeure de LPIN2 et de LPIN3 n a été identifiée, même dans des phénotypes modérés. Enfin, nous avons cultivé des myoblastes et des myotubes de patients avec mutations de LPIN1 afin d étudier les mécanismes de rhabdomyolyse. Les myoblastes déficients en lipin1 ont une activité PAP1 très diminuée et une accumulation de gouttelettes lipidiques. Le niveau d expression des gènes cibles des facteurs de transcription co-activés par lipin1 (PPAR , PPARa, PGC1a, ACADVL, CPT1B and CPT2) sont inchangés par rapport aux contrôles, alors que le niveau de lipin2 est augmenté. L analyse transcriptomique sur cultures de myotubes a identifié chez les patients 19 gènes sous-exprimés et 51 sur-exprimés, notamment ACACB, qui code pour Accb, enzyme clé de la balance synthèse d acides gras/OAG. L invalidation d ACACB par siRNA dans des myoblastes déficients en lipin1 diminue le nombre de gouttelettes lipidiques, confirmant le lien entre la sur-expression d ACACB et l accumulation d acides gras libres chez les patients. Cependant, le taux de malonyl-CoA, produit d Accb, et l activité CPT1 (étape limitatrice de l OAG, inhibée par le malonyl-CoA), sont comparables entre myoblastes de patients et de contrôles. Néanmoins, le traitement des cultures par l association de tumor necrosis factor alpha et d interleukine-1 b, choisis pour simuler les conditions pro-inflammatoires des infections aiguës, entraîne une augmentation encore plus poussée du taux de malonyl-CoA, une diminution de l activité CPT1 et une augmentation de l accumulation de gouttelettes lipidiques chez les patients. Au total, nos données placent LPIN1 comme une cause importante de rhabdomyolyse héréditaire. Le déficit en lipin1 entraine une perturbation du métabolisme lipidique, via une sur-expression d ACACB, qui est exacerbée en conditions pro-inflammatoires. Nos résultats suggèrent que les conséquences du déficit en lipin1 sont compensées par des mécanismes d'adaptation suffisants en condition normale, mais insuffisants pour la demande métabolique induite par des stress environnementaux comme l'infection, conduisant aux rhabdomyolyses.Rhabdomyolyses correspond to the destruction of skeletal muscular fibers and are possibly life-threatening. The main genetic cause is linked to defects of fatty acid oxidation (FAO) ; nevertheless, half of the cases have no identified aetiology. In 2008, mutations of LPIN1 gene have been reported as a new cause of autosomal recessive rhabdomyolysis. Lipin1 protein has a double function : 1) a role of phosphatidate phosphatase 1 (PAP1) involved in synthesis of triacylglycerol and membrane phospholipids ; 2) a role of transcriptional co-activator which regulates, in association with the PPARs (peroxysome-proliferator activated receptor) and PGC1a (PPARg-coactivator1a), numerous genes involved in the metabolism including some genes encoding FAO enzymes. Lipin1 has got two homologues, lipin2 and lipin3, which have a PAP1 activity and a binding site for nuclear receptors, such as the PPARs. We have shown that LPIN1 mutations account for more than 50% of the cases of severe rhabdomyolysis of early infancy, when FAO defects have been excluded. An intragenic in frame deletion has been frequently identified in Caucasians. We have shown that it probably comes from a founding effect and that this deletion is deleterious. Unlike normal lipin1, deleted lipin1 protein is unable to complement the pah1 yeast which is defective for the yeast LPIN1 homolog. In a series of 171 patients, we have further studied the involvement LPIN1 in less severe muscular diseases, as well as the role of the two homologues LPIN2 and LPIN3. LPIN1 mutations are involved only in severe and early rhabdomyolyses and the bouts of rhabdomyolysis always have a triggerring factor, mainly acute febrile infections. No Major Alteration of LPIN2 and LPIN3 has been identified, even in milder phenotypes. Eventually, we have cultivated myoblasts and myotubes of patients with LPIN1 mutations in order to study the mechanisms of the rhabdomyolysis. Lipin1-deficient myoblasts have a drastically decreased PAP1 activity and an accumulation of lipid droplets. The expression level of target genes of the transcription factors co-activated by lipin1 (PPAR , PPARa, PGC1a, acyl-Coenzyme A very long chain dehydrogenase (ACADVL), carnitine palmitoyl-transferase 1B and 2 (CPT1B and CPT2)) are similar to controls, whereas the level of lipin2 is increased. Transcriptomic analysis of myotube cultures have identified in patients 19 under-expressed genes and 51 over-expressed ones, notably ACACB, which encodes Accb (acetyl-CoA carboxylase b), key enzyme of the balance between fatty acid synthesis and FAO. ACACB invalidation by siRNA in lipin1-deficient myoblasts decreases the number of lipid droplets, comforting the link between ACACB over-expression and free fatty acid accumulation in patients. However, the level of malonyl-CoA, product of Accb, and CPT1 activity (limitative step of FAO, inhibited by malonyl-CoA), are similar between myoblasts of patients and controls. But treatment of the cultures with an association of tumor necrosis factor a and interleukin-1 b (TNFa + IL-1b), chosen for mimicking pro-inflammatory conditions of acute infections, leads to a further increase of the level of malonyl-CoA, a decrease of CPT1 activity and an increase of lipid droplets accumulation in patients. In total, our data show that LPIN1 is an important cause of inherited rhabdomyolysis. Lipin1 deficiency leads to a disturbance of the lipidic metabolism, via ACACB over-expression, which is exacerbated in pro-inflammatory conditions. Our results suggest that the consequences of lipin1 deficiency are counterbalanced by adaptative mechanisms which are sufficient at basal state, but insufficient for the metabolic request induced by environmental stresses, such as infections, leading to the rhabdomyolyses. Next step is the study of adipose tissue and the establishment of the inflammatory signature of the patients, in order to determine if this new disease is an auto-inflammatory pathology.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF
Il Millar - One of the best experts on this subject based on the ideXlab platform.
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The Anatomy of an Alkalic Porphyry Cu-Au System: Geology and Alteration at Northparkes Mines, New South Wales, Australia
2020Co-Authors: Pacey A, Jj Wilkinson, Owens J, Priest D, Cooke Dr, Il MillarAbstract:The Late Ordovician-early Silurian (~455–435 Ma) Northparkes system is a group of silica-saturated, alkalic porphyry deposits and prospects that developed within the Macquarie island arc. The system is host to a spectacular and diverse range of rocks and Alteration-mineralization textures that facilitate a detailed understanding of its evolution, in particular the nature and controls of porphyry-related propylitic Alteration. The first intrusive phase at Northparkes is a pre- to early-mineralization pluton that underlies all the deposits and varies in composition from a biotite quartz monzonite to alkali feldspar granite. Prior to total crystallization, this pluton was intruded by a more primitive quartz monzonite that marks the onset of a fertile fractionation series. Toward its upper levels, the quartz monzonite is porphyritic and locally rich in Cu sulfides. Subsequently, a complex series of synmineralization quartz monzonite porphyries was emplaced. The quartz monzonite porphyry intrusions have a distinct pipe-like morphology and are ubiquitously K-feldspar–altered with a crystal-crowded porphyritic texture. The textures of the quartz monzonite porphyries and common occurrence of porphyry-cemented contact breccias indicate they were forcibly emplaced and of relatively low viscosity. The quartz monzonite porphyries are therefore interpreted as crystal-bearing, silicate melt-aqueous fluid slurries that represent the conduits through which deep-seated magmatic-derived ore fluid was discharged into the shallow crust (1–2 km depth). Each deposit is centered on a multiphase cluster of quartz monzonite porphyry intrusions that drove discrete hydrothermal systems. Initial fluid evolution was similar in all the deposits, with three Major Alteration facies developed as largely concentric zones around the quartz monzonite porphyry complexes. The innermost zone is host to Cu sulfide ore and dominated by K-feldspar Alteration. This transitions outward through a shell of magnetite ± biotite Alteration, with pyrite and minor chalcopyrite, to an outer halo of propylitic Alteration. Generally, epidote, chlorite, and pyrite are abundant in the most deposit-proximal propylitic zone, with a decrease in the abundance of pyrite, and then epidote, with increasing distance away from deposit centers. Propylitic Alteration, particularly within relatively low permeability rocks, is fracture-controlled and a hierarchy of veins is observed. Veins of chlorite-quartz-pyrite ± calcite ± hematite ± epidote ± chalcopyrite (P1) appear to represent the principal fluid conduits. They are surrounded by pervasive and intense Alteration halos with a distinct mineralogical zonation from vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite, through hematite-sericite-chlorite ± epidote, ultimately to a vein-distal hematite-albite ± chlorite ± epidote assemblage. These P1 veins are surrounded by regions in which smaller epidote-chlorite ± calcite ± quartz ± pyrite veins (P2) are abundant, again with zoned Alteration envelopes: vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite grades out into an epidote-rich zone, which in turn transitions into vein-distal albite-hematite ± chlorite ± epidote. Areas of weakest propylitic Alteration, distant from both P1 and P2 veins, are characterized by small epidote-only veinlets (P3) with albite-hematite halos. Mineralogical transitions across the propylitic zone are therefore repeated in the evolution from P1 to P3 veins, as well as in the halos around these veins. It is the overall vein abundance and overlap of associated Alteration halos that controls the intensity and appearance of propylitic Alteration in most rocks. Such scale invariance and spatial relationships strongly suggest the transition from P1 to P3 veins reflects a broadly decreasing outward flux of (magmatic-derived?) fluid that passed through the fracture network and progressively reacted with country rocks. Further support for this hypothesis comes from crosscutting relationships and Rb-Sr dating of epidote (returning an age of 450 ± 11 Ma), which demonstrate the bulk of propylitic Alteration was coeval with mineralization and potassic Alteration. Late-stage fluid evolution at each deposit was unique. Much of the E48 orebody, and locally the GRP314 deposit, was overprinted by texturally destructive, white sericite-albite-quartz-alunite ± chlorite Alteration. In the E26 deposit and in regions of the GRP314 deposit a series of quartz-anhydrite ± pyrite ± Cu sulfide veins with distinctive, vein-proximal, sericite-dominant Alteration halos cuts the primary, deposit-concentric Alteration facies. The vein-distal mineralogy of these Alteration halos is controlled by their distance from deposit centers, changing from K-feldspar ± biotite in deposit-proximal veins to chlorite ± epidote-albite in depositdistal veins. Late-mineralization quartz monzonite porphyries at E26 and GRP314 also appear to be related to the generation of anhydrite-quartz ± sphalerite veins and a set of quartz-calcite-pyrite-sphalerite ± chalcopyrite ± galena veins. Postmineralization magmatic activity produced relatively primitive and barren monzonite porphyries and younger alkali basalt dikes.The attached document is the author(’s’) final accepted/submitted version of the journal article. You are advised to consult the publisher’s version if you wish to cite from it
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The Anatomy of an Alkalic Porphyry Cu-‐Au System: Geology and Alteration at Northparkes Mines, NSW, Australia
2019Co-Authors: Pacey A, Jj Wilkinson, Owens J, Priest D, Cooke Dr, Il MillarAbstract:The Late Ordovician-Early Silurian (~455-435 Ma) Northparkes system is a group of silica-saturated, alkalic porphyry deposits and prospects which developed within the Macquarie Island Arc. The system is host to a spectacular and diverse range of rocks and Alteration-mineralization textures that facilitate a detailed understanding of its evolution, in particular into the nature and controls of porphyry-related propylitic Alteration. The first intrusive phase at Northparkes is a pre- to early-mineralization pluton that underlies all the deposits and varies in composition from a biotite quartz monzonite (BQM) to alkali feldspar granite (AFG). Prior to total crystallization, this pluton was intruded by a more primitive quartz monzonite (QMZ) that marks the onset of a fertile fractionation series. Towards its upper levels, the QMZ is porphyritic and locally rich in Cu sulfides. Subsequently, a complex series of syn-mineralization quartz monzonite porphyries (QMP) were emplaced. The QMP intrusions have a distinct pipe-like morphology and are ubiquitously K-feldspar altered with a crystal-crowded porphyritic texture. The textures of the QMPs and common occurrence of porphyry-cemented contact breccias indicate they were forcibly emplaced and of relatively low viscosity. The QMPs are therefore interpreted as crystal-bearing, silicate melt-aqueous fluid slurries that represent the conduits through which deep-seated magmatic-derived ore fluid was discharged into the shallow crust (1-2 km depth). Each deposit is centred on a multiphase cluster of QMP intrusions that drove discrete hydrothermal systems. Initial fluid evolution was similar in all the deposits, with three Major Alteration facies developed as largely concentric zones around the QMP complexes. The innermost zone is host to Cu sulfide ore and dominated by K-feldspar Alteration. This transitions outwards through a shell of magnetite ± biotite Alteration, with pyrite and minor chalcopyrite, to an outer halo of propylitic Alteration. Generally, epidote, chlorite and pyrite are abundant in the most deposit-proximal propylitic zone, with a decrease in the abundance of pyrite, and then epidote, with increasing distance away from deposit centers. Propylitic Alteration, particularly within relatively low permeability rocks, is fracture-controlled and a hierarchy of veins is observed. Veins of chlorite-quartz-pyrite ± calcite ± hematite ± epidote ± chalcopyrite (P1) appear to represent the principal fluid conduits. They are surrounded by pervasive and intense Alteration halos with a distinct mineralogical zonation from vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite, through hematite-sericite-chlorite ± epidote, ultimately to a vein-distal hematite-albite ± chlorite ± epidote assemblage. These P1 veins are surrounded by regions in which smaller epidote-chlorite ± calcite ± quartz ± pyrite veins (P2) are abundant, again with zoned Alteration envelopes: vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite grades out into an epidote-rich zone, which in turn transitions into vein-distal albite-hematite ± chlorite ± epidote. Areas of weakest propylitic Alteration, distant from both P1 and P2 veins, are characterised by small epidote-only veinlets (P3) with albite-hematite halos. Mineralogical transitions across the propylitic zone are therefore repeated in the evolution from P1 to P3 veins, as well as in the halos around these veins. It is the overall vein abundance and overlap of associated Alteration halos which controls the intensity and appearance of propylitic Alteration in most rocks. Such scale-invariance and spatial relationships strongly suggests the transition from P1 to P3 veins reflects a broadly decreasing outward flux of (magmatic-derived?) fluid that passed through the fracture network and progressively reacted with country rocks. Further support for this hypothesis comes from cross cutting relationships and Rb-Sr dating of epidote (returning an age of 450 ± 11 Ma), which demonstrate the bulk of propylitic Alteration was coeval with mineralization and potassic Alteration. Late-stage fluid evolution at each deposit was unique. Much of the E48 orebody and locally the GRP314 deposit was overprinted by texturally-destructive, white sericite-albite-quartz-alunite ± chlorite Alteration. In the E26 deposit, and in regions of the GRP314 deposit, a series of quartz-anhydrite ± pyrite ± Cu sulfide veins with distinctive, vein-proximal, sericite-dominant Alteration halos cut the primary, deposit-concentric Alteration facies. The vein-distal mineralogy of these Alteration halos is controlled by their distance from deposit centers, changing from K-feldspar ± biotite in deposit-proximal veins to chlorite ± epidote-albite in deposit-distal veins. Late-mineralization QMPs at E26 and GRP314 also appear to be related to the generation of anhydrite-quartz ± sphalerite veins and a set of quartz-calcite-pyrite-sphalerite ± chalcopyrite ± galena veins. Post-mineralization magmatic activity produced relatively primitive and barren monzonite porphyries and younger alkali basalt dikes.© 2019 Economic Geology This document is the author’s final accepted version of the journal article. You are advised to consult the published version if you wish to cite from it
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The anatomy of an alkalic porphyry Cu-Au system: geology and Alteration at Northparkes Mines, New South Wales, Australia
2019Co-Authors: Pacey P, Jj Wilkinson, Owens J, Priest D, Cooke Dr, Il MillarAbstract:The Late Ordovician-early Silurian (∼455–435 Ma) Northparkes system is a group of silica-saturated, alkalic porphyry deposits and prospects that developed within the Macquarie island arc. The system is host to a spectacular and diverse range of rocks and Alteration-mineralization textures that facilitate a detailed understanding of its evolution, in particular the nature and controls of porphyry-related propylitic Alteration.The first intrusive phase at Northparkes is a pre- to early-mineralization pluton that underlies all the deposits and varies in composition from a biotite quartz monzonite to alkali feldspar granite. Prior to total crystallization, this pluton was intruded by a more primitive quartz monzonite that marks the onset of a fertile fractionation series. Toward its upper levels, the quartz monzonite is porphyritic and locally rich in Cu sulfides. Subsequently, a complex series of synmineralization quartz monzonite porphyries was emplaced. The quartz monzonite porphyry intrusions have a distinct pipe-like morphology and are ubiquitously K-feldspar–altered with a crystal-crowded porphyritic texture. The textures of the quartz monzonite porphyries and common occurrence of porphyry-cemented contact breccias indicate they were forcibly emplaced and of relatively low viscosity. The quartz monzonite porphyries are therefore interpreted as crystal-bearing, silicate melt-aqueous fluid slurries that represent the conduits through which deep-seated magmatic-derived ore fluid was discharged into the shallow crust (1–2 km depth).Each deposit is centered on a multiphase cluster of quartz monzonite porphyry intrusions that drove discrete hydrothermal systems. Initial fluid evolution was similar in all the deposits, with three Major Alteration facies developed as largely concentric zones around the quartz monzonite porphyry complexes. The innermost zone is host to Cu sulfide ore and dominated by K-feldspar Alteration. This transitions outward through a shell of magnetite ± biotite Alteration, with pyrite and minor chalcopyrite, to an outer halo of propylitic Alteration. Generally, epidote, chlorite, and pyrite are abundant in the most deposit-proximal propylitic zone, with a decrease in the abundance of pyrite, and then epidote, with increasing distance away from deposit centers.Propylitic Alteration, particularly within relatively low permeability rocks, is fracture-controlled and a hierarchy of veins is observed. Veins of chlorite-quartz-pyrite ± calcite ± hematite ± epidote ± chalcopyrite (P1) appear to represent the principal fluid conduits. They are surrounded by pervasive and intense Alteration halos with a distinct mineralogical zonation from vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite, through hematite-sericite-chlorite ± epidote, ultimately to a vein-distal hematite-albite ± chlorite ± epidote assemblage. These P1 veins are surrounded by regions in which smaller epidote-chlorite ± calcite ± quartz ± pyrite veins (P2) are abundant, again with zoned Alteration envelopes: vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite grades out into an epidote-rich zone, which in turn transitions into vein-distal albite-hematite ± chlorite ± epidote. Areas of weakest propylitic Alteration, distant from both P1 and P2 veins, are characterized by small epidote-only veinlets (P3) with albite-hematite halos. Mineralogical transitions across the propylitic zone are therefore repeated in the evolution from P1 to P3 veins, as well as in the halos around these veins. It is the overall vein abundance and overlap of associated Alteration halos that controls the intensity and appearance of propylitic Alteration in most rocks. Such scale invariance and spatial relationships strongly suggest the transition from P1 to P3 veins reflects a broadly decreasing outward flux of (magmatic-derived?) fluid that passed through the fracture network and progressively reacted with country ro cks. Further support for this hypothesis comes from crosscutting relationships and Rb-Sr dating of epidote (returning an age of 450 ± 11 Ma), which demonstrate the bulk of propylitic Alteration was coeval with mineralization and potassic Alteration.Late-stage fluid evolution at each deposit was unique. Much of the E48 orebody, and locally the GRP314 deposit, was overprinted by texturally destructive, white sericite-albite-quartz-alunite ± chlorite Alteration. In the E26 deposit and in regions of the GRP314 deposit a series of quartz-anhydrite ± pyrite ± Cu sulfide veins with distinctive, vein-proximal, sericite-dominant Alteration halos cuts the primary, deposit-concentric Alteration facies. The vein-distal mineralogy of these Alteration halos is controlled by their distance from deposit centers, changing from K-feldspar ± biotite in deposit-proximal veins to chlorite ± epidote-albite in depositdistal veins. Late-mineralization quartz monzonite porphyries at E26 and GRP314 also appear to be related to the generation of anhydrite-quartz ± sphalerite veins and a set of quartz-calcite-pyrite-sphalerite ± chalcopyrite ± galena veins. Postmineralization magmatic activity produced relatively primitive and barren monzonite porphyries and younger alkali basalt dikes
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The anatomy of an alkalic Porphyry Cu-Au system: geology and Alteration at Northparkes Mines, New South Wales, Australia
2019Co-Authors: Pacey A, Jj Wilkinson, Owens J, Priest D, Cooke Dr, Il MillarAbstract:The Late Ordovician-early Silurian (~455–435 Ma) Northparkes system is a group of silica-saturated, alkalic porphyry deposits and prospects that developed within the Macquarie island arc. The system is host to a spectacular and diverse range of rocks and Alteration-mineralization textures that facilitate a detailed understanding of its evolution, in particular the nature and controls of porphyry-related propylitic Alteration. The first intrusive phase at Northparkes is a pre- to early-mineralization pluton that underlies all the deposits and varies in composition from a biotite quartz monzonite to alkali feldspar granite. Prior to total crystallization, this pluton was intruded by a more primitive quartz monzonite that marks the onset of a fertile fractionation series. Toward its upper levels, the quartz monzonite is porphyritic and locally rich in Cu sulfides. Subsequently, a complex series of synmineralization quartz monzonite porphyries was emplaced. The quartz monzonite porphyry intrusions have a distinct pipe-like morphology and are ubiquitously K-feldspar–altered with a crystal-crowded porphyritic texture. The textures of the quartz monzonite porphyries and common occurrence of porphyry-cemented contact breccias indicate they were forcibly emplaced and of relatively low viscosity. The quartz monzonite porphyries are therefore interpreted as crystal-bearing, silicate melt-aqueous fluid slurries that represent the conduits through which deep-seated magmatic-derived ore fluid was discharged into the shallow crust (1–2 km depth). Each deposit is centered on a multiphase cluster of quartz monzonite porphyry intrusions that drove discrete hydrothermal systems. Initial fluid evolution was similar in all the deposits, with three Major Alteration facies developed as largely concentric zones around the quartz monzonite porphyry complexes. The innermost zone is host to Cu sulfide ore and dominated by K-feldspar Alteration. This transitions outward through a shell of magnetite ± biotite Alteration, with pyrite and minor chalcopyrite, to an outer halo of propylitic Alteration. Generally, epidote, chlorite, and pyrite are abundant in the most deposit-proximal propylitic zone, with a decrease in the abundance of pyrite, and then epidote, with increasing distance away from deposit centers. Propylitic Alteration, particularly within relatively low permeability rocks, is fracture-controlled and a hierarchy of veins is observed. Veins of chlorite-quartz-pyrite ± calcite ± hematite ± epidote ± chalcopyrite (P1) appear to represent the principal fluid conduits. They are surrounded by pervasive and intense Alteration halos with a distinct mineralogical zonation from vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite, through hematite-sericite-chlorite ± epidote, ultimately to a vein-distal hematite-albite ± chlorite ± epidote assemblage. These P1 veins are surrounded by regions in which smaller epidote-chlorite ± calcite ± quartz ± pyrite veins (P2) are abundant, again with zoned Alteration envelopes: vein-proximal chlorite-sericite (phengite) ± epidote ± pyrite grades out into an epidote-rich zone, which in turn transitions into vein-distal albite-hematite ± chlorite ± epidote. Areas of weakest propylitic Alteration, distant from both P1 and P2 veins, are characterized by small epidote-only veinlets (P3) with albite-hematite halos. Mineralogical transitions across the propylitic zone are therefore repeated in the evolution from P1 to P3 veins, as well as in the halos around these veins. It is the overall vein abundance and overlap of associated Alteration halos that controls the intensity and appearance of propylitic Alteration in most rocks. Such scale invariance and spatial relationships strongly suggest the transition from P1 to P3 veins reflects a broadly decreasing outward flux of (magmatic-derived?) fluid that passed through the fracture network and progressively reacted with country rocks. Further support for this hypothesis comes from crosscutting relationships and Rb-Sr dating of epidote (returning an age of 450 ± 11 Ma), which demonstrate the bulk of propylitic Alteration was coeval with mineralization and potassic Alteration. Late-stage fluid evolution at each deposit was unique. Much of the E48 orebody, and locally the GRP314 deposit, was overprinted by texturally destructive, white sericite-albite-quartz-alunite ± chlorite Alteration. In the E26 deposit and in regions of the GRP314 deposit a series of quartz-anhydrite ± pyrite ± Cu sulfide veins with distinctive, vein-proximal, sericite-dominant Alteration halos cuts the primary, deposit-concentric Alteration facies. The vein-distal mineralogy of these Alteration halos is controlled by their distance from deposit centers, changing from K-feldspar ± biotite in deposit-proximal veins to chlorite ± epidote-albite in depositdistal veins. Late-mineralization quartz monzonite porphyries at E26 and GRP314 also appear to be related to the generation of anhydrite-quartz ± sphalerite veins and a set of quartz-calcite-pyrite-sphalerite ± chalcopyrite ± galena veins. Postmineralization magmatic activity produced relatively primitive and barren monzonite porphyries and younger alkali basalt dikes. GeoRef Subject alkali granites Australasia copper ores absolute age basalts Australia igneous rocks gold ores metal ores metamorphism fractures geochemistry granites mid-ocean ridge basalts faults ignimbrite intrusions quartz monzonite Northparkes Mine metasomatism mineral deposits, genesis New South Wales Australia Ordovician plutonic rocks Paleozoic Rb/Sr volcaniclastics metals rare earths pyroclastics volcanic rocks trachyte
Laura Salavessa - One of the best experts on this subject based on the ideXlab platform.
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shigella promotes Major Alteration of gut epithelial physiology and tissue invasion by shutting off host intracellular transport
2019Co-Authors: Mariana L Ferrari, Valerie Malarde, Alexandre Grassart, Laura Salavessa, Giulia NigroAbstract:Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work, we report the multiple effects of two S. flexneri effectors, IpaJ and VirA, which target small GTPases of the Arf and Rab families, consequently inhibiting several intracellular trafficking pathways. IpaJ and VirA induce large-scale impairment of host protein secretion and block the recycling of surface receptors. Moreover, these two effectors decrease clathrin-dependent and -independent endocytosis. Therefore, S. flexneri infection induces a global blockage of host cell intracellular transport, affecting the exchange between cells and their external environment. The combined action of these effectors disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, promotes multiple invasion events, and enhances the pathogen capacity to penetrate into the colonic tissue in vivo.
Mariana L Ferrari - One of the best experts on this subject based on the ideXlab platform.
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shigella promotes Major Alteration of gut epithelial physiology and tissue invasion by shutting off host intracellular transport
2019Co-Authors: Mariana L Ferrari, Valerie Malarde, Alexandre Grassart, Laura Salavessa, Giulia NigroAbstract:Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work, we report the multiple effects of two S. flexneri effectors, IpaJ and VirA, which target small GTPases of the Arf and Rab families, consequently inhibiting several intracellular trafficking pathways. IpaJ and VirA induce large-scale impairment of host protein secretion and block the recycling of surface receptors. Moreover, these two effectors decrease clathrin-dependent and -independent endocytosis. Therefore, S. flexneri infection induces a global blockage of host cell intracellular transport, affecting the exchange between cells and their external environment. The combined action of these effectors disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, promotes multiple invasion events, and enhances the pathogen capacity to penetrate into the colonic tissue in vivo.
Giulia Nigro - One of the best experts on this subject based on the ideXlab platform.
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shigella promotes Major Alteration of gut epithelial physiology and tissue invasion by shutting off host intracellular transport
2019Co-Authors: Mariana L Ferrari, Valerie Malarde, Alexandre Grassart, Laura Salavessa, Giulia NigroAbstract:Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work, we report the multiple effects of two S. flexneri effectors, IpaJ and VirA, which target small GTPases of the Arf and Rab families, consequently inhibiting several intracellular trafficking pathways. IpaJ and VirA induce large-scale impairment of host protein secretion and block the recycling of surface receptors. Moreover, these two effectors decrease clathrin-dependent and -independent endocytosis. Therefore, S. flexneri infection induces a global blockage of host cell intracellular transport, affecting the exchange between cells and their external environment. The combined action of these effectors disorganizes the epithelial cell polarity, disturbs epithelial barrier integrity, promotes multiple invasion events, and enhances the pathogen capacity to penetrate into the colonic tissue in vivo.
