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1.
Nat Genet ; 24(2): 171-4, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10655064

ABSTRACT

Smad proteins are intracellular mediators of signalling initiated by Tgf-betasuperfamily ligands (Tgf-betas, activins and bone morphogenetic proteins (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific type I receptors, and associate with the common partner Smad4 to trigger transcriptional responses. The inhibitory Smads (6 and 7) are transcriptionally induced in cultured cells treated with Tgf-beta superfamily ligands, and downregulate signalling in in vitro assays. Gene disruption in mice has begun to reveal specific developmental and physiological functions of the signal-transducing Smads. Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities. Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants. These defects highlight the importance of Smad6 in the tissue-specific modulation of Tgf-beta superfamily signalling pathways in vivo.


Subject(s)
Cardiovascular Abnormalities/genetics , Cardiovascular System/embryology , Cardiovascular System/growth & development , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Muscle, Smooth, Vascular/physiology , Signal Transduction/physiology , Trans-Activators/genetics , Trans-Activators/metabolism , Animals , DNA-Binding Proteins/deficiency , Female , Genomic Library , Homeostasis , Homozygote , Male , Mice , Mice, Inbred BALB C , Mice, Inbred Strains , Mice, Knockout , Mice, Transgenic , Muscle, Smooth, Vascular/pathology , Mutagenesis, Insertional , Recombinant Fusion Proteins/metabolism , Restriction Mapping , Smad6 Protein , Trans-Activators/deficiency
2.
Oncogene ; 18(39): 5363-72, 1999 Sep 23.
Article in English | MEDLINE | ID: mdl-10498890

ABSTRACT

Transforming growth factor-beta (TGF-beta) signaling is dependent on the heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Activated TbetaRI then mediates TGF-beta signals by inducing the phosphorylation of Smad2 and/or Smad3, which separately hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of Smad2/Smad3 by activated TbetaRI is inhibited by two newly discovered members of the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells with a full-length Smad7 construct leads to complete loss of the growth inhibitory response to TGF-beta1, without altering TGF-beta1-mediated induction of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced anchorage-independent growth and accelerated growth in nude mice. These findings point to a previously unrecognized mechanism for selective suppression of TGF-beta-mediated growth inhibition in cancer cells that allows for continued activation of the PAI-I promoter by TGF-beta1, which may act to enhance the tumorigenicity of certain cancer cells.


Subject(s)
DNA-Binding Proteins/metabolism , Pancreatic Neoplasms/metabolism , Signal Transduction , Trans-Activators/metabolism , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Cell Division , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasm Transplantation , Pancreas/metabolism , Pancreatic Neoplasms/pathology , Plasminogen Activator Inhibitor 1 , RNA, Messenger/metabolism , Smad7 Protein , Trans-Activators/biosynthesis , Trans-Activators/genetics , Tumor Cells, Cultured
3.
Biochem Biophys Res Commun ; 255(2): 268-73, 1999 Feb 16.
Article in English | MEDLINE | ID: mdl-10049697

ABSTRACT

Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells.


Subject(s)
Antineoplastic Agents/antagonists & inhibitors , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/physiology , Growth Inhibitors/antagonists & inhibitors , Pancreatic Neoplasms/pathology , Trans-Activators/biosynthesis , Trans-Activators/physiology , Transforming Growth Factor beta/pharmacology , Adolescent , Adult , Aged , Antineoplastic Agents/pharmacology , Blotting, Northern , Cell Division/drug effects , DNA-Binding Proteins/genetics , Female , Growth Inhibitors/pharmacology , Humans , Male , Middle Aged , Pancreatic Neoplasms/chemistry , Pancreatic Neoplasms/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Smad6 Protein , Trans-Activators/genetics , Tumor Cells, Cultured
4.
Circulation ; 98(22): 2396-403, 1998 Dec 01.
Article in English | MEDLINE | ID: mdl-9832484

ABSTRACT

BACKGROUND: biomechanical forces generated by blood flow within the cardiovascular system have been proposed as important modulators of regional endothelial phenotype and function. This process is thought to involve the regulation of vascular gene expression by physiological fluid mechanical stimuli such as fluid shear stresses. METHODS AND RESULTS: We demonstrate sustained upregulation of a recently identified gene encoding a human prostaglandin transporter (hPGT) in cultured human vascular endothelium exposed to a physiological fluid mechanical stimulus in vitro. This biomechanical induction is selective in that steady laminar shear stress is sufficient to upregulate the hPGT gene at the level of transcriptional activation, whereas a comparable level of turbulent shear stress (a nonphysiological stimulus) is not. Various biochemical stimuli, such as bacterial endotoxin and the inflammatory cytokines recombinant human interleukin 1beta cytokines (rhIL-1beta) and tumor necrosis factor-alpha (TNF-alpha), did not significantly induce hPGT. Using a specific antiserum to hPGT, we demonstrate endothelial expression within the arterial vasculature and the microcirculation of highly vascularized tissues such as the heart. CONCLUSIONS: Our results identify hPGT as an inducible gene in vascular endothelium and suggest that biomechanical stimuli generated by blood flow in vivo may be important determinants of hPGT expression. Furthermore, this demonstration of regulated endothelial expression of hPGT implicates this molecule in the regional metabolism of prostanoids within the cardiovascular system.


Subject(s)
Antiporters/genetics , Antiporters/physiology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Antiporters/biosynthesis , Cells, Cultured , DNA, Complementary/analysis , DNA-Binding Proteins/biosynthesis , Endothelium, Vascular/chemistry , Gene Expression Regulation , Gene Library , Humans , Infant, Newborn , Organic Anion Transporters , Peptides/analysis , RNA, Messenger/analysis , Stress, Mechanical , Up-Regulation
5.
Proc Natl Acad Sci U S A ; 95(16): 9506-11, 1998 Aug 04.
Article in English | MEDLINE | ID: mdl-9689110

ABSTRACT

The transforming growth factor-beta (TGF-beta) superfamily of growth factors and cytokines has been implicated in a variety of physiological and developmental processes within the cardiovascular system. Smad proteins are a recently described family of intracellular signaling proteins that transduce signals in response to TGF-beta superfamily ligands. We demonstrate by both a mammalian two-hybrid and a biochemical approach that human Smad2 and Smad4, two essential Smad proteins involved in mediating TGF-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator CREB binding protein (CBP). This interaction is specific in that it requires ligand (TGF-beta) activation and is mediated by the transcriptional activation domains of the Smad proteins. A closely related, but distinct endothelial-expressed Smad protein, Smad7, which does not activate transcription in endothelial cells, does not interact with CBP. Furthermore, Smad2,4-CBP interactions involve the COOH terminus of CBP, a region that interacts with other regulated transcription factors such as certain signal transduction and transcription proteins and nuclear receptors. Smad-CBP interactions are required for Smad-dependent TGF-beta-induced transcriptional responses in endothelial cells, as evidenced by inhibition with overexpressed 12S E1A protein and reversal of this inhibition with exogenous CBP. This report demonstrates a functional interaction between Smad proteins and an essential component of the mammalian transcriptional apparatus (CBP) and extends our insight into how Smad proteins may regulate transcriptional responses in many cell types. Thus, functional Smad-coactivator interactions may be an important locus of signal integration in endothelial cells.


Subject(s)
Cyclic AMP Response Element-Binding Protein/metabolism , DNA-Binding Proteins/metabolism , Endothelium, Vascular/metabolism , Trans-Activators/metabolism , Transcription, Genetic , Transforming Growth Factor beta/metabolism , Animals , Base Sequence , Cattle , Cells, Cultured , DNA Primers , Endothelium, Vascular/cytology , Humans , Smad2 Protein , Smad4 Protein
6.
Proc Natl Acad Sci U S A ; 94(17): 9314-9, 1997 Aug 19.
Article in English | MEDLINE | ID: mdl-9256479

ABSTRACT

Vascular endothelium is an important transducer and integrator of both humoral and biomechanical stimuli within the cardiovascular system. Utilizing a differential display approach, we have identified two genes, Smad6 and Smad7, encoding members of the MAD-related family of molecules, selectively induced in cultured human vascular endothelial cells by steady laminar shear stress, a physiologic fluid mechanical stimulus. MAD-related proteins are a recently identified family of intracellular proteins that are thought to be essential components in the signaling pathways of the serine/threonine kinase receptors of the transforming growth factor beta superfamily. Smad6 and Smad7 possess unique structural features (compared with previously described MADs), and they can physically interact with each other, and, in the case of Smad6, with other known human MAD species, in endothelial cells. Transient expression of Smad6 or Smad7 in vascular endothelial cells inhibits the activation of a transfected reporter gene in response to both TGF-beta and fluid mechanical stimulation. Both Smad6 and Smad7 exhibit a selective pattern of expression in human vascular endothelium in vivo as detected by immunohistochemistry and in situ hybridization. Thus, Smad6 and Smad7 constitute a novel class of MAD-related proteins, termed vascular MADs, that are induced by fluid mechanical forces and can modulate gene expression in response to both humoral and biomechanical stimulation in vascular endothelium.


Subject(s)
DNA-Binding Proteins/genetics , Endothelium, Vascular/physiology , Gene Expression , Trans-Activators , Amino Acid Sequence , Cells, Cultured , DNA-Binding Proteins/biosynthesis , Humans , Immunohistochemistry , In Situ Hybridization , Molecular Sequence Data , Sequence Alignment , Signal Transduction/genetics , Smad6 Protein , Smad7 Protein , Stress, Mechanical
7.
J Clin Invest ; 99(12): 2941-9, 1997 Jun 15.
Article in English | MEDLINE | ID: mdl-9185518

ABSTRACT

In vascular endothelium, the electroneutral Na-K-Cl cotransport system is thought to function in the maintenance of a selective permeability barrier in certain vascular beds (e.g., brain), as well as in the preservation of endothelial homeostasis in the face of fluctuating osmotic conditions that may accompany certain pathophysiological conditions (e.g., diabetes mellitus). Here we demonstrate that the gene encoding the bumetanide-sensitive cotransporter BSC2, one of the two major isoforms of Na-K-Cl cotransporters present in mammalian cells, can be differentially regulated by inflammatory cytokines and fluid mechanical forces in cultured endothelium. Interleukin-1beta and tumor necrosis factor-alpha significantly upregulate expression of BSC2 mRNA and protein in human umbilical vein endothelial cells, a response that is inhibited by pretreatment with interferon-gamma. Steady laminar fluid shear stress, at a physiologic magnitude (10 dyn/cm2), is also able to induce and maintain elevated expression of BSC2 in cultured human umbilical vein endothelial cells, while a comparable time-averaged magnitude of turbulent fluid shear stress is not. In vivo, BSC2 mRNA is upregulated after intraperitoneal administration of bacterial endotoxin (LPS) in murine lung and kidney, but not in cardiac tissue. These results provide the first experimental evidence that the BSC2 gene can be selectively regulated by different inflammatory cytokine and fluid mechanical stimuli in endothelium, and support a role for BSC2 in vascular homeostasis and inflammation.


Subject(s)
Bumetanide/pharmacology , Carrier Proteins/genetics , Cytokines/pharmacology , Endothelium, Vascular/metabolism , Gene Expression Regulation , Animals , Biomechanical Phenomena , Cell Line , Humans , Interferon-gamma/pharmacology , Interleukin-1/pharmacology , Kidney/metabolism , Lipopolysaccharides/pharmacology , Lung/metabolism , Mice , RNA, Messenger/metabolism , Rheology , Sodium-Potassium-Chloride Symporters , Tumor Necrosis Factor-alpha/pharmacology , Umbilical Veins
8.
Cell ; 89(7): 1165-73, 1997 Jun 27.
Article in English | MEDLINE | ID: mdl-9215638

ABSTRACT

TGFbeta signaling is initiated when the type I receptor phosphorylates the MAD-related protein, Smad2, on C-terminal serine residues. This leads to Smad2 association with Smad4, translocation to the nucleus, and regulation of transcriptional responses. Here we demonstrate that Smad7 is an inhibitor of TGFbeta signaling. Smad7 prevents TGFbeta-dependent formation of Smad2/Smad4 complexes and inhibits the nuclear accumulation of Smad2. Smad7 interacts stably with the activated TGFbeta type I receptor, thereby blocking the association, phosphorylation, and activation of Smad2. Furthermore, mutations in Smad7 that interfere with receptor binding disrupt its inhibitory activity. These studies thus define a novel function for MAD-related proteins as intracellular antagonists of the type I kinase domain of TGFbeta family receptors.


Subject(s)
Carrier Proteins/genetics , Receptors, Transforming Growth Factor beta/metabolism , Signal Transduction/physiology , Trans-Activators , Transforming Growth Factor beta/physiology , Amino Acid Sequence , Animals , COS Cells , Carrier Proteins/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endothelium, Vascular/chemistry , Endothelium, Vascular/cytology , Humans , Liver Neoplasms , Molecular Sequence Data , Phosphorylation , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Signal Transduction/drug effects , Smad2 Protein , Tumor Cells, Cultured , Umbilical Veins/cytology
9.
Proc Natl Acad Sci U S A ; 93(19): 10417-22, 1996 Sep 17.
Article in English | MEDLINE | ID: mdl-8816815

ABSTRACT

Early atherosclerotic lesions develop in a topographical pattern that strongly suggests involvement of hemodynamic forces in their pathogenesis. We hypothesized that certain endothelial genes, which exhibit differential responsiveness to distinct fluid mechanical stimuli, may participate in the atherogenic process by modulating, on a local level within the arterial wall, the effects of systemic risk factors. A differential display strategy using cultured human endothelial cells has identified two genes, manganese superoxide dismutase and cyclooxygenase-2, that exhibit selective and sustained up-regulation by steady laminar shear stress (LSS). Turbulent shear stress, a nonlaminar fluid mechanical stimulus, does not induce these genes. The endothelial form of nitric oxide synthase also demonstrates a similar LSS-selective pattern of induction. Thus, three genes with potential atheroprotective (antioxidant, antithrombotic, and antiadhesive) activities manifest a differential response to distinct fluid mechanical stimuli, providing a possible mechanistic link between endothelial gene expression and early events in atherogenesis. The activities of these and other LSS-responsive genes may have important implications for the pathogenesis and prevention of atherosclerosis.


Subject(s)
Endothelium, Vascular/enzymology , Gene Expression Regulation, Enzymologic , Isoenzymes/biosynthesis , Nitric Oxide Synthase/biosynthesis , Prostaglandin-Endoperoxide Synthases/biosynthesis , Superoxide Dismutase/biosynthesis , Blotting, Western , Cell Nucleus/metabolism , Cells, Cultured , Cyclooxygenase 1 , Cyclooxygenase 2 , DNA Primers , Humans , Membrane Proteins , Oligonucleotide Probes , Polymerase Chain Reaction , Stress, Mechanical , Transcription, Genetic , Umbilical Veins
10.
Eur J Immunol ; 26(1): 130-5, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8566055

ABSTRACT

T cell tolerance can be induced in adult mice by injection of soluble antigenic peptide. The underlying mechanism has been difficult to establish in normal mice due to the low precursor frequency of T cells specific for any given antigen. Therefore, we examined peripheral tolerance in mice transgenic for a T cell receptor specific for a cytochrome c peptide bound to I-Ek. Antigen-specific hyporesponsiveness could be induced in the transgenic mice. We followed the transgene-bearing T cells with a clonotypic monoclonal antibody and found similar numbers of clonotypic T cells in tolerized and control mice. To prevent de novo differentiation of T cells we analyzed thymectomized mice in which antigen-specific hyporesponsiveness was induced. Our analysis of thymectomized transgenic mice showed that antigen-specific T cell hyporesponsiveness following injection of peptide intravenously is not caused by gross elimination of T cells. These data provide evidence for the role of anergy in peripheral tolerance.


Subject(s)
Clonal Anergy/genetics , Immune Tolerance/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, alpha-beta/immunology , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , Cytochrome c Group/immunology , Epitopes/administration & dosage , Injections, Intravenous , Injections, Subcutaneous , Lymphocyte Activation/genetics , Mice , Mice, Transgenic , Molecular Sequence Data , Moths , Thymectomy
11.
Pharmacol Biochem Behav ; 46(2): 483-5, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8265705

ABSTRACT

The effects of saccharin on morphine-induced temperature change was examined in Long-Evans rats. Rats were given free access to 0.15% saccharin for 15 days, followed by saccharin deprivation for 9 days. Saccharin was then returned to one group, while a second group received water. All rats were then injected with morphine sulfate (2 mg/kg), and postinjection temperatures were assessed over 75 min. The results showed that saccharin enhanced the biphasic effects of morphine by significantly increasing the hypothermic phase. The findings support the view that sweet substances influence endogenous opioid release.


Subject(s)
Body Temperature/drug effects , Morphine/pharmacology , Saccharin/pharmacology , Animals , Dose-Response Relationship, Drug , Female , Male , Rats
12.
Genetics ; 132(4): 1071-9, 1992 Dec.
Article in English | MEDLINE | ID: mdl-1459428

ABSTRACT

The Adh-2 gene of Drosophila mulleri is expressed in the larval fat body and the adult fat body and hindgut, and a 1500-bp element located 2-3 kb upstream of the Adh-2 promoter is necessary for maximal levels of transcription. Previous work demonstrated that deletion of sequences between this upstream element and the Adh-2 promoter results in Adh-2 gene expression in a novel larval tissue, the middle midgut. In this study we show that the upstream element possesses all of the characteristics of a transcriptional enhancer: its activity is independent of orientation, it acts on a heterologous promoter, and it functions at various positions both 5' and 3' to the Adh-2 gene. Full enhancer function can be localized to a 750-bp element, although other regions possess some redundant activity. The ectopic expression pattern is dependent on the proximity of at least two sequence elements. Thus, tissue-specific transcription can involve complex proximity-dependent interactions among combinations of regulatory elements.


Subject(s)
Drosophila/genetics , Enhancer Elements, Genetic , Gene Expression Regulation , Regulatory Sequences, Nucleic Acid , Animals , Gene Deletion , Gene Rearrangement , Genes, Insect , Intestines/enzymology , Pseudogenes , RNA, Messenger/genetics , Restriction Mapping , Transcription, Genetic
13.
Mol Cell Biol ; 12(9): 4093-103, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1508206

ABSTRACT

Expression of the Drosophila melanogaster Adh gene in adults requires a fat body-specific enhancer called the Adh adult enhancer (AAE). We have identified a protein in Drosophila nuclear extracts that binds specifically to a site within the AAE (adult enhancer factor 1 [AEF-1]). In addition, we have shown that AEF-1 binds specifically to two other Drosophila fat body enhancers. Base substitutions in the AEF-1 binding site that disrupt AEF-1 binding in vitro result in a significant increase in the level of Adh expression in vivo. Thus, the AEF-1 binding site is a negative regulatory element within the AAE. A cDNA encoding the AEF-1 protein was isolated and shown to act as a repressor of the AAE in cotransfection studies. The AEF-1 protein contains four zinc fingers and an alanine-rich sequence. The latter motif is found in other eukaryotic proteins known to be transcriptional repressors.


Subject(s)
DNA-Binding Proteins/metabolism , Drosophila melanogaster/genetics , Enhancer Elements, Genetic , Fat Body/metabolism , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Transcription, Genetic , Alcohol Dehydrogenase/genetics , Amino Acid Sequence , Animals , Base Sequence , Binding Sites , Cell Nucleus , DNA/metabolism , Drosophila Proteins , Female , Gene Expression Regulation, Enzymologic , Molecular Sequence Data , Organ Specificity/genetics , Ovary/metabolism , Transcription Factors , Zinc Fingers
14.
Genes Dev ; 6(3): 454-65, 1992 Mar.
Article in English | MEDLINE | ID: mdl-1547943

ABSTRACT

The Drosophila melanogaster alcohol dehydrogenase (Adh) gene is expressed in a specific set of tissues during larval development and in adults. Expression in the adult fat body is controlled by the Adh adult enhancer (AAE). Previous studies identified a negative regulatory element in the AAE and a protein that binds specifically to this sequence [adult enhancer factor-1 (AEF-1)]. Here, we show that the AEF-1-binding site in the AAE and in two other Drosophila fat body enhancers overlaps a sequence recognized by the mammalian transcription factor CCAAT/enhancer-binding protein (C/EBP). Remarkably, these two proteins also bind specifically to overlapping sites in a liver-specific regulatory element of the human Adh gene. Cotransfection experiments in mammalian cells reveal that C/EBP stimulates the activity of the AAE by 50-fold, and this activity can be suppressed by AEF-1. In addition, AEF-1 prevents C/EBP binding in vitro, and displaces prebound C/EBP. Thus, a tissue-specific regulatory unit consisting of one positive and one negative regulatory element has been conserved between Drosophila and man.


Subject(s)
Alcohol Dehydrogenase/genetics , Drosophila melanogaster/enzymology , Gene Expression , Animals , Base Sequence , Binding Sites , Biological Evolution , CCAAT-Enhancer-Binding Proteins , DNA/genetics , DNA Fingerprinting , DNA-Binding Proteins/metabolism , Drosophila Proteins , Enhancer Elements, Genetic , Fat Body/enzymology , Female , Molecular Sequence Data , Mutation , Nuclear Proteins/metabolism , Ovary/metabolism , Promoter Regions, Genetic , Regulatory Sequences, Nucleic Acid , Transcription Factors/metabolism , Transcription, Genetic
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