scholarly journals NAD + Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

2021 ◽  
Author(s):  
Ying Ann Chiao ◽  
Akash Deep Chakraborty ◽  
Christine M. Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Mouse Models ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Nicotinamide Adenine Dinucleotide ◽  
Redox Balance ◽  
Diabetic Mice ◽  
Redox Imbalance ◽  
Diastolic Velocity ◽  
Nadh Ratio ◽  
Fractional Shortening

Background: Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD + ) redox imbalance; however, the hypothesis that NAD + redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD + redox balance to test this hypothesis. Methods: Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD + redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used. Results: Diabetic stress caused cardiac dysfunction and lowered NAD + /NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD + /NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD + redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P <0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P <0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix–dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD + redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD + levels by NAMPT normalized NAD + redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P <0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P <0.05), and reversed pathogenic mechanisms in diabetic mice. Conclusions: Our results show that NAD + redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD + metabolism.

scholarly journals NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

2020 ◽  
Author(s):  
Ying Ann Chiao ◽  
Akash Deep Chakraborty ◽  
Christine M. Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Therapeutic Potential ◽  
Redox Balance ◽  
Diabetic Mice ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Regulate Protein

AbstractBackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+ redox balance to test the hypothesis.Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+ redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+ redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+ redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice.ConclusionOur results show that NAD+ redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+ metabolism in DCM.

Abstract 219: NAD Redox Imbalance Accelerates Diabetic Cardiomyopathy via Protein Acetylation and Oxidative Stress

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ying Ann Chiao ◽  
Christine Light ◽  
Xiaojian Shi ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Redox Balance ◽  
Protein Acetylation ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Systolic And Diastolic Function ◽  
And Oxidative Stress

Diabetes is long linked to lowered NAD/NADH ratio, aka NAD redox imbalance, but its causal role to diabetic cardiomyopathy is not established. We used mouse models with latent decrease in cardiac NAD/NADH ratio (cardiac-specific Ndufs4-KO, cKO) and elevated cardiac NAD levels to directly test whether cardiac NAD redox imbalance accelerates diabetic cardiomyopathy. Control and cKO mice were subjected to 8-week T1D stress, and longitudinal cardiac function was measured by echocardiography. Accelerated declines in systolic and diastolic function were observed in T1D cKO mice. Insulin depletion and hyperglycemia were similar in T1D control and T1D cKO mice, and serum metabolomic analyses showed unchanged aqueous and lipid metabolite levels. These metabolite results suggested that T1D control and cKO hearts were stressed under similar diabetic conditions. Importantly, elevation of cardiac NAD levels to attenuate NAD redox imbalance mitigated the accelerated functional declines in T1D cKO hearts. The data from mouse models with manipulated NAD redox states suggested that NAD redox imbalance accelerates diabetic cardiomyopathy. Cardiac fibrosis levels were not different in T1D control and cKO hearts, while transcript levels of fibrotic genes, including Adamts proteinases, integrins, laminins, matrix metalloproteinases and collagens, also showed no difference. Therefore, the accelerated functional declines in T1D cKO hearts are not due to altered extracellular matrix environment, but are rather due to cardiomyocyte dysfunction. We next determined whether the accelerated cardiac dysfunction is mediated via protein acetylation and oxidative stress. NAD-dependent global protein acetylation and inhibitory acetylation of superoxide dismutase 2 were elevated in T1D cKO hearts. Inhibition of SOD2 concomitantly promoted elevation of protein oxidation levels in T1D cKO hearts. The results suggested that NAD redox balance-dependent protein acetylation regulates oxidative stress to promote diabetic cardiomyopathy.

Abstract MP211: NAD Redox Imbalance Exacerbates Diabetic Cardiomyopathy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Chi Fung Lee
Keyword(s):  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Calcium Sensitivity ◽  
Redox Balance ◽  
Diabetic Control ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Streptozotocin Induced Diabetes ◽  
Systolic And Diastolic Function ◽  
Myofilament Calcium Sensitivity

Diabetes and heart failure are linked to NAD redox imbalance, whose role in diabetic cardiomyopathy has not been directly tested. Streptozotocin-induced diabetes in WT mice for 16 weeks promoted declines in systolic and diastolic function, which associated with lowered cardiac NAD/NADH ratio (NAD redox imbalance). To test the hypothesis that , we employed mouse models with cardiac-specific manipulations of NAD redox states. Cardiac-specific Ndufs4-KO mice (cKO) exhibit lowered cardiac NAD/NADH ratio with normal baseline function, geometry and energetics. Control and cKO mice were challenged with 8-week diabetic stress. Metabolomic analyses of plasma collected after the diabetic stress showed similar hyperglycemia and dyslipidemia stresses in diabetic control and diabetic cKO mice. Chronic diabetic stress promoted systolic and diastolic dysfunctions in control mice, which were further exacerbated in diabetic cKO mice in both male and female cohorts. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways showed no change in diabetic cKO hearts, suggesting that cardiomyocyte dysfunction is a likely culprit for the exacerbated dysfunction. Increased protein acetylation, including SOD2-K68Ac, was observed in diabetic cKO hearts. Inhibited antioxidant function by SOD2-K68Ac promoted protein oxidation in diabetic cKO hearts, suggesting oxidative stress as a pathogenic mechanism. We next examined phosphorylation status of myofilament proteins in these diabetic hearts. MyBPC-S282Pi levels are suppressed in failing hearts and remained unchanged in diabetic cKO hearts. TnI-S150Pi increases myofilament calcium sensitivity and prolongs calcium dissociation, while TnI-S23/24Pi imposes the opposite effects. TnI-S150Pi levels were elevated in diabetic cKO hearts, while TnI-S23/24Pi levels unchanged. Therefore, exacerbated diastolic dysfunction in diabetic cKO hearts is due to the selective phosphorylation at TnI-S150. AMPK is activated by energetic stress and phosphorylates TnI-S150. ATP levels decreased, and AMP/ATP ratio increased in diabetic cKO hearts, implicating impaired energetics to promote TnI-S150Pi and dysfunction. Elevation of NAD levels normalized cardiac NAD redox balance in diabetic cKO hearts. Elevated levels of SOD2-K68Ac and TnI-S150Pi, exacerbated systolic and diastolic dysfunction in diabetic cKO hearts were all reversed by elevation of NAD levels. Dysfunction in diabetic control hearts was also ameliorated by elevation of NAD levels. These data collectively conclude that NAD redox imbalance is a positive mediator of the progression of diabetic cardiomyopathy.

Abstract 220: Emerging Roles of Altered NAD Metabolism in Diabetic Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Chi Fung Lee
Keyword(s):  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Redox Balance ◽  
Heart Weight ◽  
Mrna Levels ◽  
Nad Metabolism ◽  
Redox Imbalance ◽  
Nad Synthesis

Diabetes is linked to altered NAD metabolism whose causal roles in cardiac dysfunction are poorly understood. Synthesis, consumption and redox balance of NAD dictate NAD metabolism and its homeostasis, and we here explored their roles in diabetic cardiomyopathy. 16 week of Type 1 diabetes (T1D) to C57BL6N mice was associated with lowered cardiac NAD/NADH, mild systolic and more severe diastolic dysfunction. We next used mouse models with altered NAD metabolism to determine how NAD redox balance impacts diabetic cardiomyopathy. Using cardiac-specific Ndufs4-KO mice (cKO) as a model of latent decrease in cardiac NAD/NADH, we observed accelerated systolic and diastolic dysfunction (lowered fractional shortening, E’/A’ ratio, and increased e/E’ ratio) in male cKO mice stressed with chronic T1D. Cardiac hypertrophy (heart weight/tibia length), insulin depletion and hyperglycemia levels were similar in these mice. Serum metabolomic analyses (~240 metabolites) also showed unchanged aqueous and lipid metabolite levels, suggesting that the diabetic stresses on these hearts were similar. The accelerated dysfunction of T1D cKO hearts was also observed in another female cohort. Importantly, elevation of cardiac NAD levels to attenuate NAD redox imbalance mitigated the accelerated dysfunction of T1D cKO hearts. In another cohort, control and cKO mice were stressed by 16-week high fat diet feeding. Accelerated systolic and diastolic dysfunction, and increased hypertrophy were observed in T2D cKO mice with similar glycemic levels to control mice. The data suggested that NAD redox imbalance is a positive regulator of cardiac dysfunction induced by T1D or T2D. However, NAD-dependent pathogenic mechanism induced by T1D or T2D (e.g. hypertrophy) can be different, and is under further investigation. Tissue fibrosis and mRNA levels of pro-fibrotic genes, including Adamts proteinases, integrins, laminins, matrix metalloproteinases and collagens were unchanged in T1D cKO hearts. Therefore, the accelerated dysfunction of T1D cKO hearts is due to cardiomyocyte dysfunction. We examined how NAD metabolism, other than the redox balance, may alter cardiomyocyte function. Levels of metabolite and mRNA regulating NAD synthesis and consumption pathways were measured. Of 32 transcripts assayed, Nmrk2 levels were uniquely up-regulated in T1D cKO hearts, and lowered by elevation of cardiac NAD levels. NMRK product levels were concomitantly decreased in T1D cKO hearts. NAD-dependent global acetylation and inhibitory superoxide dismutase 2 acetylation were increased in T1D cKO hearts. Protein oxidation levels were concomitantly raised. Hyperacetylation in proteins like CaM kinase was associated with increased phosphorylation in troponin I, not in MyBPC or PLN in T1D cKO hearts. These data support the emerging, multifaceted roles of altered NAD metabolism in the progression of diabetic cardiomyopathy.

Abstract 17069: NAD+Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Akash Deep D Chakraborty ◽  
Ying Ann Chiao ◽  
Christine M Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Diabetic Control ◽  
Causal Role ◽  
Protein Acetylation ◽  
Specific Expression ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Systolic And Diastolic Function

Diabetes is a risk factor of heart failure and leads to cardiac dysfunction, a condition named diabetic cardiomyopathy (DCM). NAD redox imbalance is observed in diabetic tissues. However, whether NAD redox imbalance promotes cardiac dysfunction in DCM remains unknown. The objective of this study is to determine the causal role of NAD redox imbalance in DCM.Type 1 diabetes was induced in C57BL6 mice by streptozotocin (STZ) injections, and DCM was allowed to develop for 16 weeks. Diabetes-induced chronic stress led to systolic and diastolic cardiac dysfunction along with a lowered NAD/NADH ratio. The diabetogenic protocol was applied to control and cardiac-specific Ndufs4-KO mice (cKO), a mouse model with lowered cardiac NAD/NADH without baseline cardiac dysfunction. Analyses of blood glucose and >200 metabolites in plasma showed no significant change in diabetic control and diabetic cKO mice, suggesting that their hearts experienced similar diabetic stress. Diabetic cKO hearts showed lowered NAD/NADH, aggravated contractile and relaxation dysfunction compared to the diabetic control hearts in both sexes. The data suggest that NAD redox imbalance exacerbated DCM. Collagen staining and transcript analyses of fibrosis-related genes showed no change in diabetic cKO hearts, signifying that the exacerbated dysfunction was due to cardiomyocyte dysfunction. A global protein acetylation was promoted in the diabetic cKO hearts with an increase in SOD2 acetylation levels at lysine-68 (SOD2-K68Ac) and enhanced protein oxidation. Diabetic cKO mice displayed enhanced levels of TnI S150 phosphorylation (TnI-S150Pi), but not phosphorylation of TnI-S23/24 or MyBPc-S282. These data suggest that enhanced oxidative stress and altered myofilament Ca 2+ sensitivity via TnI-S150Pi are responsible for the NAD redox imbalance-exacerbated DCM.To confirm the role of NAD redox imbalance in DCM, we elevated cardiac NAD levels in diabetic cKO mice by cardiac-specific expression of NAMPT. Expression of NAMPT in the heart improved cardiac systolic and diastolic function in diabetic cKO hearts. This was due to increased NAD/NADH ratio and reversed pathogenic mechanisms (lowered SOD2-K68Ac and TnI-S150Pi). This study supports the causal role of NAD redox imbalance in DCM.

Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB

2013 ◽  
Vol 304 (4) ◽  
pp. H567-H578 ◽  
Author(s):  
Yuehui Wang ◽  
Weixia Sun ◽  
Bing Du ◽  
Xiao Miao ◽  
Yang Bai ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Nuclear Accumulation ◽  
Left Ventricular Ejection ◽  
Heart Weight ◽  
Diabetic Mice ◽  
Antioxidant Genes ◽  
Antioxidative Function

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2–3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

Abstract 87: Loss of Mir-155 Attenuates Sepsis Induced Cardiac Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Wei Sun ◽  
Peipei Huang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Foam Cell ◽  
Cardiac Metabolism ◽  
Significant Inhibition ◽  
Gene Expressions ◽  
Over Expression ◽  
Pathological Cardiac Hypertrophy ◽  
Lps Treatment ◽  
Fractional Shortening

Objective: Sepsis induced cardiac dysfunction is featured by inflammation and metabolic repression. miR-155 is a typical multifunctional miRNA and loss of miR-155 has been shown to protect the heart from pathological cardiac hypertrophy while increased miR-155 could promote the formation of foam cell in atherogenesis. However, the role of miR-155 in sepsis induced cardiac dysfunction is unclear. Methods: E.coli lipopolysaccharide (LPS) (5mg/kg) was administered to C57BL/6 mice to create a sepsis-induced cardiac dysfunction model. Cardiac function was assessed by echocardiography 5-6 h post-LPS administration. Heart tissues were collected within 7-9 h after LPS treatment for the analysis of gene expressions. Tail vein injection of miR-155 antagomir (80mg/kg/d) or miR-155 agomirs (30mg/kg/d) for 3 consecutive days were used to decrease or increase miR-155 expressions in heart. Results: LPS induced a reduction of 15% in fractional shortening (%FS) and 25% in ejection fraction (%EF). Expression of miR-155 was increased by 2 fold in sepsis-induced cardiac dysfunction mouse model. Over-expression of miR-155 agomirs led to a decrease of 5% in FS and 10% in EF as compared to scramble controls. Aggravation of LPS induced cardiac dysfunction by miR-155 agomir was not associated with alteration in inflammation or cardiac metabolism. However, miR-155 agomir increased LPS- induced myocardium apoptosis and also elevated the ratio of Bax/Bcl-2 at the protein level. Intravenous injection of cholesterol-modified antisense oligonucleorides antagomirs of miR-155 markedly rescued the LPS induced heart failure and apoptosis. Western bloting indicated that miR-155 overexpression in vivo led to a significant inhibition of Pea15a while miR-155 knock-down caused a significant upregulation of Pea15a, indicating that Pea15a was a potential target gene of miR-155. Interestingly, plasma miR-155 levels were also found to be significantly increased in critically ill patients with sepsis compared to healthy controls. Conclusion: This study demonstrates that miR-155 regulates sepsis induced cardiac dysfunction and Pea15a is a potential targer gene of miR-155. Loss of miR-155 represents a novel therapeutic method for sepsis induced cardiac dysfunction

scholarly journals Cesium Treatment Depresses Glycolysis Pathway in HeLa Cell

2021 ◽  
Vol 55 (4) ◽  
pp. 477-488
Keyword(s):  
Hela Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Aerobic Glycolysis ◽  
Biological Effects ◽  
Glycolytic Enzyme ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Dependent Manner ◽  
Nadh Ratio ◽  
Glycolysis Pathway

Background/Aims: Cesium (Cs) is an alkali metal element that is of no essential use for humans; it has no known beneficial function that is verified by clinical research. When used as an alternative cancer therapy, it even causes toxicity in high doses. Thus, before using Cs as treatment in clinical settings, it is important to clearly determine its biological effects on cells. However, Cs was found to suppress the proliferation of human cervical cancer cells in a dose-dependent manner, and it was assumed that Cs inhibits the glycolysis pathway. In this study, we clearly determined the step of the glycolysis pathway that is affected by Cs. Methods: The glycolytic enzyme expressions, activities, and metabolite concentrations in HeLa cells were measured by PCR, western blotting, and enzymatic methods, after treating the cells with Cs for 3 days. Results: Cs treatment decreased transcriptional and expression levels of hexokinase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase (PK), and lactate dehydrogenase and the activity of PK. Analysis of glycolysis pathway metabolites revealed that Cs treatment reduces lactate level and increases the level of nicotinamide adenine dinucleotide (oxidized form, NAD+); however, it did not affect the levels of pyruvate and nicotinamide adenine dinucleotide (reduced form, NADH). Increase of the [NAD+]/[NADH] ratio and decrease of the [lactate]/[pyruvate] ratio indicate that Cs treatment inhibits the aerobic glycolysis pathway. Conclusion: Cs treatment inhibits PK activity and increases the [NAD+]/[NADH] ratio. Hence, Cs has been determined to inhibit glycolysis, especially the aerobic glycolysis pathway. These results suggest that suppression of HeLa cell proliferation following Cs treatment was caused by inhibition of aerobic glycolysis by Cs.

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