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1.
Bioessays ; 46(2): e2300125, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38059789

RESUMO

DREAM complexes are transcriptional regulators that control the expression of hundreds to thousands of target genes involved in the cell cycle, quiescence, differentiation, and apoptosis. These complexes contain many subunits that can vary according to the considered target genes. Depending on their composition and the nature of the partners they recruit, DREAM complexes control gene expression through diverse mechanisms, including chromatin remodeling, transcription cofactor and factor recruitment at various genomic binding sites. This complexity is particularly high in mammals. Since the discovery of the first dREAM complex (drosophila Rb, E2F, and Myb) in Drosophila melanogaster, model organisms such as Caenorhabditis elegans, and plants allowed a deeper understanding of the processes regulated by DREAM-like complexes. Here, we review the conservation of these complexes. We discuss the contribution of model organisms to the study of DREAM-mediated transcriptional regulatory mechanisms and their relevance in characterizing novel activities of DREAM complexes.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica , Drosophila/genética , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Mamíferos/metabolismo , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo
2.
Ann Rheum Dis ; 78(12): 1653-1662, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31563893

RESUMO

OBJECTIVES: The human leucocyte antigen (HLA)-B27 confers an increased risk of spondyloarthritis (SpA) by unknown mechanism. The objective of this work was to uncover HLA-B27 non-canonical properties that could explain its pathogenicity, using a new Drosophila model. METHODS: We produced transgenic Drosophila expressing the SpA-associated HLA-B*27:04 or HLA-B*27:05 subtypes, or the non-associated HLA-B*07:02 allele, alone or in combination with human ß2-microglobulin (hß2m), under tissue-specific drivers. Consequences of transgenes expression in Drosophila were examined and affected pathways were investigated by the genetic interaction experiments. Predictions of the model were further tested in immune cells from patients with SpA. RESULTS: Loss of crossveins in the wings and a reduced eye phenotype were observed after expression of HLA-B*27:04 or HLA-B*27:05 in Drosophila but not in fruit flies expressing the non-associated HLA-B*07:02 allele. These HLA-B27-induced phenotypes required the presence of hß2m that allowed expression of well-folded HLA-B conformers at the cell surface. Loss of crossveins resulted from a dominant negative effect of HLA-B27 on the type I bone morphogenetic protein (BMP) receptor saxophone (Sax) with which it interacted, resulting in elevated mothers against decapentaplegic (Mad, a Drosophila receptor-mediated Smad) phosphorylation. Likewise, in immune cells from patients with SpA, HLA-B27 specifically interacted with activin receptor-like kinase-2 (ALK2), the mammalian Sax ortholog, at the cell surface and elevated Smad phosphorylation was observed in response to activin A and transforming growth factor ß (TGFß). CONCLUSIONS: Antagonistic interaction of HLA-B27 with ALK2, which exerts inhibitory functions on the TGFß/BMP signalling pathway at the cross-road between inflammation and ossification, could adequately explain SpA development.


Assuntos
Regulação da Expressão Gênica , Antígeno HLA-B27/genética , RNA/genética , Espondilartrite/genética , Fator de Crescimento Transformador beta/genética , Receptores de Ativinas Tipo I/biossíntese , Receptores de Ativinas Tipo I/genética , Animais , Animais Geneticamente Modificados , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Drosophila melanogaster , Antígeno HLA-B27/biossíntese , Humanos , Transdução de Sinais , Espondilartrite/metabolismo , Espondilartrite/patologia , Fator de Crescimento Transformador beta/metabolismo
3.
J Cell Sci ; 128(17): 3239-49, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26208635

RESUMO

In accordance with its tumor suppressor role, the retinoblastoma protein pRb can ensure pro-apoptotic functions. Rbf1, the Drosophila homolog of Rb, also displays a pro-apoptotic activity in proliferative cells. We have previously shown that the Rbf1 pro-apoptotic activity depends on its ability to decrease the level of anti-apoptotic proteins such as the Bcl-2 family protein Buffy. Buffy often acts in an opposite manner to Debcl, the other Drosophila Bcl-2-family protein. Both proteins can localize at the mitochondrion, but the way they control apoptosis still remains unclear. Here, we demonstrate that Debcl and the pro-fission gene Drp1 are necessary downstream of Buffy to trigger a mitochondrial fragmentation during Rbf1-induced apoptosis. Interestingly, Rbf1-induced apoptosis leads to a Debcl- and Drp1-dependent reactive oxygen species production, which in turn activates the Jun Kinase pathway to trigger cell death. Moreover, we show that Debcl and Drp1 can interact and that Buffy inhibits this interaction. Notably, Debcl modulates Drp1 mitochondrial localization during apoptosis. These results provide a mechanism by which Drosophila Bcl-2 family proteins can control apoptosis, and shed light on a link between Rbf1 and mitochondrial dynamics in vivo.


Assuntos
Apoptose/fisiologia , Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Fatores de Transcrição/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Proteínas de Ligação ao GTP/genética , Proteínas de Membrana/genética , Mitocôndrias/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína do Retinoblastoma , Fatores de Transcrição/genética
4.
Apoptosis ; 21(3): 239-51, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26679112

RESUMO

It is now well established that the mitochondrion is a central regulator of mammalian cell apoptosis. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, mainly because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and cell death in Drosophila occurs at the mitochondrial level. Numerous proteins, including RHG proteins and proteins of the Bcl-2 family that are key regulators of Drosophila apoptosis, constitutively or transiently localize in mitochondria. These proteins participate in the cell death process at different levels such as degradation of Diap1, a Drosophila IAP, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. Here, we review these mitochondrial events that might have their counterpart in human.


Assuntos
Apoptose/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Proteínas Inibidoras de Apoptose/metabolismo , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/genética , Caspases/metabolismo , Citocromos c/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Proteínas Inibidoras de Apoptose/genética , Mitocôndrias/genética , Mutação , Transdução de Sinais
5.
Apoptosis ; 19(10): 1444-56, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25208640

RESUMO

The ubiquitin-proteasome system is one of the main proteolytic pathways. It inhibits apoptosis by degrading pro-apoptotic regulators, such as caspases or the tumor suppressor p53. However, it also stimulates cell death by degrading pro-survival regulators, including IAPs. In Drosophila, the control of apoptosis by Bcl-2 family members is poorly documented. Using a genetic modifier screen designed to identify regulators of mammalian bax-induced apoptosis in Drosophila, we identified the ubiquitin activating enzyme Uba1 as a suppressor of bax-induced cell death. We then demonstrated that Uba1 also regulates apoptosis induced by Debcl, the only counterpart of Bax in Drosophila. Furthermore, we show that these apoptotic processes involve the same multimeric E3 ligase-an SCF complex consisting of three common subunits and a substrate-recognition variable subunit identified in these processes as the Slimb F-box protein. Thus, Drosophila Slimb, the homologue of ß-TrCP targets Bax and Debcl to the proteasome. These new results shed light on a new aspect of the regulation of apoptosis in fruitfly that identifies the first regulation of a Drosophila member of the Bcl-2 family.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas de Membrana/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Proteínas de Ciclo Celular/genética , Drosophila/citologia , Drosophila/enzimologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Membrana/genética , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Transporte Proteico , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
6.
Arthritis Res Ther ; 26(1): 131, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39010233

RESUMO

BACKGROUND: Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-ß2 microglobulin (hß2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. METHODS: Genetic interaction was studied between activin/transforming growth factor ß (TGFß) pathway and HLA-B27/hß2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hß2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFß pathways induced by its ligands, and the transcript level of target genes of the TGFß pathway, were evaluated. RESULTS: In HLA-B27/hß2m transgenic Drosophila, inappropriate signalling through the activin/TGFß pathway, involving Baboon (Babo), the type I activin/TGFß receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hß2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hß2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFß receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFß1 was increased in T cells from B27 rats, showing evidence for deregulated TGFß pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFß exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. CONCLUSIONS: This study shows that HLA-B27 alters the TGFß pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.


Assuntos
Animais Geneticamente Modificados , Antígeno HLA-B27 , Transdução de Sinais , Espondilartrite , Fator de Crescimento Transformador beta , Animais , Transdução de Sinais/fisiologia , Espondilartrite/metabolismo , Espondilartrite/imunologia , Humanos , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Antígeno HLA-B27/imunologia , Fator de Crescimento Transformador beta/metabolismo , Ratos , Drosophila , Drosophila melanogaster , Asas de Animais/metabolismo
7.
Semin Immunopathol ; 43(2): 207-219, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33449154

RESUMO

Understanding the complex mechanisms underlying a disorder such as spondyloarthritis (SpA) may benefit from studying animal models. Several suitable models have been developed, in particular to investigate the role of genetic factors predisposing to SpA, including HLA-B27, ERAP1, and genes related to the interleukin (IL)-23/IL-17 axis. One of the best examples of such research is the HLA-B27 transgenic rat model that fostered the emergence of original theories regarding HLA-B27 pathogenicity, including dysregulation of innate immunity, contribution of the adaptive immune system to chronic inflammation, and influence of the microbiota on disease development. Very recently, a new model of HLA-B27 transgenic Drosophila helped to expand further some of those theories in an unexpected direction involving the TGFß/BMP family of mediators. On the other hand, several spontaneous, inducible, and/or genetically modified mouse models-including SKG mouse, TNFΔARE mouse and IL-23-inducible mouse model of SpA-have highlighted the importance of TNFα and IL-23/IL-17 axis in the development of SpA manifestations. Altogether, those animal models afford not only to study disease mechanism but also to investigate putative therapeutic targets.


Assuntos
Espondilartrite , Aminopeptidases , Animais , Modelos Animais de Doenças , Antígeno HLA-B27/genética , Humanos , Camundongos , Antígenos de Histocompatibilidade Menor , Ratos , Ratos Transgênicos
8.
Med Sci (Paris) ; 32(5): 478-84, 2016 May.
Artigo em Francês | MEDLINE | ID: mdl-27225920

RESUMO

The role of the mitochondrion in mammalian cell apoptosis has been established since the mid-1990s. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, notably because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and apoptosis in Drosophila cell death occurs at the mitochondrial level. Numerous proteins that appear key for Drosophila apoptosis regulation constitutively or transiently bind to mitochondria. They participate in the cell death process at different levels such as degradation of an IAP caspase inhibitor, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. The aim of this review is to take stock of these events that might have their counterpart in humans.


Assuntos
Apoptose/fisiologia , Drosophila/fisiologia , Mitocôndrias/fisiologia , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Caenorhabditis elegans , Citocromos c/fisiologia , Drosophila/metabolismo , Humanos , Dinâmica Mitocondrial/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia
9.
Cell Cycle ; 15(2): 283-94, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26825229

RESUMO

The Jun Kinase (JNK) signaling pathway responds to diverse stimuli by appropriate and specific cellular responses such as apoptosis, differentiation or proliferation. The mechanisms that mediate this specificity remain largely unknown. The core of this signaling pathway, composed of a JNK protein and a JNK kinase (JNKK), can be activated by various putative JNKK kinases (JNKKK) which are themselves downstream of different adaptor proteins. A proposed hypothesis is that the JNK pathway specific response lies in the combination of a JNKKK and an adaptor protein upstream of the JNKK. We previously showed that the Drosophila homolog of pRb (Rbf1) and a mutant form of Rbf1 (Rbf1(D253A)) have JNK-dependent pro-apoptotic properties. Rbf1(D253A) is also able to induce a JNK-dependent abnormal proliferation. Here, we show that Rbf1-induced apoptosis triggers proliferation which depends on the JNK pathway activation. Taking advantage of these phenotypes, we investigated the JNK signaling involved in either Rbf1-induced apoptosis or in proliferation in response to Rbf1-induced apoptosis. We demonstrated that 2 different JNK pathways involving different adaptor proteins and kinases are involved in Rbf1-apoptosis (i.e. Rac1-dTak1-dMekk1-JNK pathway) and in proliferation in response to Rbf1-induced apoptosis (i.e., dTRAF1-Slipper-JNK pathway). Using a transient induction of rbf1, we show that Rbf1-induced apoptosis activates a compensatory proliferation mechanism which also depends on Slipper and dTRAF1. Thus, these 2 proteins seem to be key players of compensatory proliferation in Drosophila.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , MAP Quinase Quinase Quinases/genética , Fator 1 Associado a Receptor de TNF/genética , Fatores de Transcrição/genética , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína do Retinoblastoma , Fator 1 Associado a Receptor de TNF/metabolismo , Fatores de Transcrição/metabolismo , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo
10.
PLoS One ; 9(8): e102902, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25089524

RESUMO

The tumor suppressor retinoblastoma protein (pRb) is inactivated in a wide variety of cancers. While its role during cell cycle is well characterized, little is known about its properties on apoptosis regulation and apoptosis-induced cell responses. pRb shorter forms that can modulate pRB apoptotic properties, resulting from cleavages at caspase specific sites are observed in several cellular contexts. A bioinformatics analysis showed that a putative caspase cleavage site (TELD) is found in the Drosophila homologue of pRb(RBF) at a position similar to the site generating the p76Rb form in mammals. Thus, we generated a punctual mutant form of RBF in which the aspartate of the TELD site is replaced by an alanine. This mutant form, RBFD253A, conserved the JNK-dependent pro-apoptotic properties of RBF but gained the ability of inducing overgrowth phenotypes in adult wings. We show that this overgrowth is a consequence of an abnormal proliferation in wing imaginal discs, which depends on the JNK pathway activation but not on wingless (wg) ectopic expression. These results show for the first time that the TELD site of RBF could be important to control the function of RBF in tissue homeostasis in vivo.


Assuntos
Apoptose , Proteínas de Drosophila/genética , Homeostase , Mutação/genética , Especificidade de Órgãos , Proteína do Retinoblastoma/genética , Fatores de Transcrição/genética , Envelhecimento , Animais , Caspases/metabolismo , Proliferação de Células , Sequência Consenso , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Discos Imaginais/citologia , Discos Imaginais/crescimento & desenvolvimento , Discos Imaginais/metabolismo , Larva/citologia , Larva/metabolismo , Sistema de Sinalização das MAP Quinases , Fenótipo , Proteína do Retinoblastoma/metabolismo , Fatores de Transcrição/metabolismo , Asas de Animais/citologia , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo , Proteína Wnt1/metabolismo
11.
Cell Cycle ; 9(1): 97-103, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-20016284

RESUMO

The retinoblastoma protein, pRb, plays important roles in many processes implicated in cell fate decisions, including cell cycle, differentiation and apoptosis. In cell cycle regulation, pRb interacts principally with the E2F transcription factor family members to inhibit the transcription of many genes controlling cell cycle progression. In this study, we focused on the role of pRb in apoptosis, which is much less clear than its role in cell cycle regulation. Indeed, pRb has been found to be either pro- or anti-apoptotic. To clarify how the proliferative status of the cells impacts the role of pRb in apoptosis, we used Drosophila to induce RBF (the pRb fly homologue) expression in different cellular and developmental contexts. We found that RBF expression induces apoptosis in different proliferative tissues in a caspase-dependent manner, whereas this effect was not observed in differentiated post-mitotic cells. Furthermore, RBF-induced apoptosis in proliferating cells was inhibited by co-expression of dE2F1, an antagonistic partner of RBF in cell cycle regulation. These results are in agreement with the view that the apoptotic properties of pRb are tightly linked to, and are probably a consequence of, an effect on cell cycle progression. Moreover, we show for the first time that RBF has a direct anti-apoptotic effect on Dmp53-induced cell death in post-mitotic cells only. Taken together, these data clearly show that RBF can exert a dual role in the control of apoptotic processes, and that its properties depend on the proliferative status of the cells.


Assuntos
Apoptose/fisiologia , Proteínas de Drosophila/metabolismo , Mitose/fisiologia , Proteína do Retinoblastoma/metabolismo , Animais , Apoptose/genética , Western Blotting , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proliferação de Células , Drosophila , Proteínas de Drosophila/genética , Marcação In Situ das Extremidades Cortadas , Mitose/genética , Ligação Proteica/genética , Ligação Proteica/fisiologia , Proteína do Retinoblastoma/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
J Dairy Res ; 69(1): 13-26, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12047104

RESUMO

Secretory IgA found in external secretions are constituted by polymeric IgA (pIgA) bound to the extra-cellular part of the polymeric immunoglobulin receptor (pIgR). The receptor mediates transcytosis of pIgA across epithelial cells. The aim of the present study was to analyse the evolution of pIgR expression in the sheep mammary gland during the development of the mammary gland and to analyse its hormonal regulation. Gene expression of the pIgR was analysed in sheep mammary gland during pregnancy and lactation. By Northern Blot analysis, we observed that low levels of pIgR mRNA are expressed until day 70 of pregnancy. Accumulation of pIgR mRNA started during the third part of pregnancy and intensified 3 d after parturition to reach highest levels during established lactation (day 70). In situ hybridization analysis was used to confirm the increase in pIgR gene expression per mammary epithelial cell. In order to examine the hormonal regulation of the pIgR expression, virgin ewes were hormonally treated. Treatment with oestradiol and progesterone increased pIgR mRNA levels slightly. Subsequent addition of gluocotricoids induced a significant accumulation of pIgR mRNA in the mammary gland of the treated animals. Immunohistochemical analysis was performed to verify that the increase of pIgR mRNA level was associated with enhancement of the pIgR protein in mammary cells. No increase of pIgR mRNA levels were observed if PRL secretion was blocked by bromocryptine injections throughout the hormonal procedure. In conclusion, the present experiments suggest that the enhancement of pIgR levels during lactation result from combined effects of both prolactin and glucocorticoids.


Assuntos
Glucocorticoides/farmacologia , Glândulas Mamárias Animais/metabolismo , Prolactina/farmacologia , Receptores Fc/genética , Ovinos/genética , Animais , Northern Blotting/veterinária , Sondas de DNA , Estradiol/farmacologia , Estradiol/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Glucocorticoides/fisiologia , Imunoglobulina A Secretora/metabolismo , Imuno-Histoquímica/veterinária , Hibridização In Situ , Lactação/metabolismo , Lactação/fisiologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Gravidez , Progesterona/farmacologia , Progesterona/fisiologia , Prolactina/fisiologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores Fc/metabolismo , Componente Secretório/genética , Componente Secretório/metabolismo , Ovinos/imunologia , Ovinos/metabolismo
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