Key PointsQuestion
Is monoamine oxidase B (MAO-B) distribution volume, an index of MAO-B density, greater in the prefrontal cortex during major depressive episodes of MDD?
Findings
This case-control study demonstrated that MAO-B distribution volume was significantly elevated in the prefrontal cortex of patients with major depressive episodes (n = 20) compared with healthy controls (n = 20) (mean, 26%). Duration of illness was significantly and positively correlated with MAO-B distribution volume in the prefrontal cortex.
Meaning
Results suggest that there is a novel phenotype of elevated MAO-B level in the prefrontal cortex of patients with major depressive episodes secondary to major depressive disorder for which low-cost identifiers and selective therapeutics compatible with serotonin reuptake inhibitors should be developed.
Importance
Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala.
Objective
To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder.
Design, Setting, and Participants
This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11–labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy.
Main Outcomes and Measures
The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness.
Results
Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus.
Conclusions and Relevance
Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.
Major depressive disorder (MDD) is the leading cause of death and disability across moderate- to high-income nations as a result of a high lifetime prevalence of 15% and rates of treatment resistance of 50%.1,2 Although dysfunction of several key systems in MDD have been identified, such as signal transduction, neuroplasticity, hypothalamic-pituitary-adrenal axis function, glutamate cycling, inflammation, hippocampal volume, and monoamine availability, a plausible reason for the lack of progress in creating new therapeutics for MDD is that it is heterogeneous and some fundamental pathologies remain elusive.3-6
Monoamine oxidase B (MAO-B), a protein of 520 amino acids, is an important enzyme largely overlooked in the pathophysiology of MDD. In the brain, MAO-B is a high-density protein mainly located on the outer mitochondrial membrane within astrocytes and serotonin-releasing neurons that has key roles in generating oxidative signaling by hydrogen peroxide production and metabolizing monoamines, such as dopamine, norepinephrine, benzylamine, and phenylethylamine.7-9 In brain tissue, the density of MAO-B is highly positively correlated with its activity.9,10 There are only 2 previous studies of MAO-B in postmortem brain tissue of MDD (by the same group of researchers) measuring [3H]lazabemide binding in overlapping samples of individuals with MDD, with the first study11 evaluating the dorsal raphe nucleus in 12 individuals with MDD and the second study12 investigating the amygdala in 15 individuals with MDD. Both investigations reported negative results, but the sensitivity may have been reduced by concurrent cigarette smoking in 40% of the individuals because cigarette smoke contains MAO-B binding chemicals and is associated with lower [3H]lazabemide binding.12 Moreover, because these 2 studies sampled a combination of early- and late-onset MDD, the question of whether MAO-B level or activity is altered in early-onset MDD is unknown.
There are several compelling reasons why MAO-B level may be elevated in the brain of early-onset MDD, particularly in the prefrontal cortex (PFC), a region not previously studied in MDD to date. Many biological abnormalities of MDD are consequent to increased glucocorticoid exposure, and greater MAO-B expression is inducible by paradigms increasing glucocorticoid exposure. Glucocorticoids increase transcription of MAO-B through diverse mechanisms, including (1) glucocorticoid binding to the glucocorticoid response element 4 (GRE4) site of the MAO-B promoter and (2) reduction of transcription factors EAPP and R1, which are 2 transcription factors that repress MAO-B transcription through binding to Sp1 sites in the central core promoter region of MAO-B. With less binding of EAPP and R1, as well as greater binding of glucocorticoids to GRE4, endogenous Sp1 is able to cooperatively increase transcription of MAO-B.13 Also, glucocorticoids promote the expression of transforming growth factor-β-inducible early gene (TIEG2), which bind to proximal Sp1 binding sites on the core promoter region of MAO-B,14 leading to greater MAO-B transcription. These mechanisms, identified in glioblastoma and neuroblastoma cell lines, are particularly relevant to the PFC because brain-penetrant doses of dexamethasone and chronic unpredictable stress are consistently associated with greater MAO-B messenger RNA when this region is prioritized in the analyses.13,15-19 Furthermore, in the PFC of major depressive episodes (MDEs), R1 (also known as RAM2/CDCA7L/JPO2), which inhibits transcription of MAO-B in cell culture,13 is low, while TIEG2, which increases transcription of MAO-B in cell culture,13,18 is elevated. Hence, both transcription factors (R1 and TIEG2) are altered in the PFC of MDEs in directions consistent with glucocorticoid agonism that increase MAO-B transcription.18,20
Recent advances in positron emission tomography (PET) radioligand development for MAO-B in humans enable robust quantitation of MAO-B distribution volume (VT), an index of MAO-B density. Carbon 11–labeled [11C]deprenyl, the first radiotracer for MAO-B imaging with PET,21 had poor reversibility and radioactive metabolites found in both brain and periphery. To improve reversibility, newer analogues were created, such as deuterium-labeled [11C]deprenyl and then deuterium-labeled [18F]deprenyl, the latter of which has been modeled in monkeys, although there may be some bias from brain-penetrant metabolites of these compounds.22,23 Bramoullé et al24 discovered a radiotracer with a different structure, [11C]SL25.1188, then modeled it in baboons.25 Unfortunately, the first production method for [11C]SL25.1188 required the esoteric carbon 11–labeled phosgene, making it difficult to use for clinical translation studies,24 so a new synthesis method was discovered by Vasdev and colleagues, and then the radiotracer was modeled in humans.26-28 [11C]SL25.1188 has outstanding properties, including high reversibility, brain uptake, and selectivity for MAO-B, as well as no brain-penetrant metabolites and a very reproducible total VT measure that is highly correlated with the known concentration of MAO-B in postmortem human brain (r2 > 0.9).25-28
Given that dexamethasone and chronic stress increase MAO-B gene expression and activity transcription and that 2 nuclear transcription factors (R1 and TIEG2) are dysregulated in the PFC of MDEs in a manner associated with increasing MAO-B transcription, our primary hypothesis was that MAO-B VT, measured with [11C]SL25.1188 PET, is elevated in the PFC of MDEs secondary to early-onset MDD. The second hypothesis was that greater MAO-B VT in the PFC is associated with longer duration of illness because increased expression of MAO-B also occurs in glial fibrillary acidic protein–positive (GFAP) reactive astrocytes during reactive astrogliosis and because age-associated increase in GFAP immunoreactivity and protein level is greater in MDD.29,30 Moreover, astrogliosis, a common response to injury in central nervous system disease, may also be associated with greater microglial activation,10,31 and later-stage MDD is associated with the highest level of microglial activation.32 The third objective, which is more exploratory, was to investigate differences in MAO-B VT between MDEs and health in other gray matter brain regions, including those with roles associated with symptoms of MDD and/or which have high MAO-B density, such as the anterior cingulate cortex (ACC), ventral striatum, and dorsal putamen.
This case-control study was performed from April 1, 2014, to August 30, 2018. Twenty patients with unmedicated MDEs secondary to MDD without current psychiatric comorbidities and 20 age-matched healthy controls completed the study (Table 1). Participants were recruited from the community (Toronto, Ontario, Canada) and a tertiary care psychiatric hospital (Centre for Addiction and Mental Health, Toronto). Participants provided written informed consent after all procedures were fully explained. The protocol and informed consent forms were approved by the Research Ethics Board of the Centre for Addiction and Mental Health.
Participants ranged in age from 19 to 66 years, were nonsmoking, and had good physical health. None had concurrent active Axis I disorders, and none had a history of neurological illness, cerebrovascular disease, autoimmune disease, Axis II disorders, psychotic symptoms, or substance abuse. None had used herbal remedies in the previous month. All were drug and medication free within the past month except for oral contraceptives. Healthy controls were age matched within 5 years to patients with MDEs.
Diagnosis was verified by the Structured Clinical Interview for DSM-IV33 and confirmed by consultation with a psychiatrist (J.H.M.). Patients had early-onset type MDEs (before age 45 years), were antidepressant free for at least 1 month (6 weeks if previously taking fluoxetine), and had a minimum score of 16 on the 17-item Hamilton Depression Rating Scale at screening.34 None had active comorbid Axis I disorders or a history of psychotic symptoms or mania. All participants were requested to abstain from alcohol for 2 days before the PET scan and to consume no grapefruit juice or caffeinated products on the PET scan day.
PET and Magnetic Resonance Imaging Acquisition and Image Analysis
A 3-dimensional high-resolution research tomograph (HRRT; CPS/Siemens) PET scanner system, which provides radioactivity in 207 slices with an interslice distance of 1.22 mm, was used for all patients and healthy controls. After the transmission scan, [11C]SL25.1188 was infused intravenously over a 30-second period at a constant rate using a Harvard infusion pump (Harvard Apparatus). Data were acquired as previously described.28 For the anatomic delineation of regions of interest, a brain magnetic resonance image was acquired for each individual (eAppendix in the Supplement). The MAO-B VT was calculated using a 2-tissue compartment model previously shown to be optimal for [11C]SL25.1188 PET quantification.28
For the first main hypothesis, the PFC MAO-B VT was compared across groups (patients with MDEs vs healthy controls) using analysis of variance (ANOVA) to assess the effect of group. Also, to compare MAO-B VT between MDEs and health across a broader range of regions, including the PFC, ACC, ventral striatum, and dorsal putamen, a repeated-measures ANOVA was applied with regional MAO-B VT as the repeated measure, assessing the effect of group and region. For the second main hypothesis, to assess the association of illness duration with MAO-B VT in the PFC, an analysis of covariance (ANCOVA) was applied with duration of illness as the covariate. Duration of illness is calculated as the date of onset of first MDE subtracted from the date of the PET scan. Then, the association of duration of illness with MAO-B VT was explored in each brain region applying a repeated-measures ANCOVA with duration of illness as the covariate and region as the repeated measure. For the 2 main hypotheses, a corrected threshold of 2-sided P = .025 was required, and remaining analyses were exploratory. Exploratory analyses of the association of MAO-B VT in each brain region with other clinical variables, such as age, Hamilton Depression Rating Scale severity, and the number of previous MDEs, were also investigated applying an ANCOVA with MAO-B VT in the PFC and repeated-measures ANCOVA with regional MAO-B VT as the repeated dependent variable.
Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. The PFC MAO-B VT was a mean of 26% greater in patients with MDEs (ANOVA effect of group with MAO-B VT, F1,38 = 19.6; P < .001; Cohen d = 1.4). Given that the lowest VT value in the PFC among healthy controls was notably lower than the others, we investigated the sensitivity of our model to removing this value, and the statistical significance remained (ANOVA effect of group with MAO-B VT, F1,37 = 19.7; P < .001). The highest VT values in each region for patients with MDEs were not from the same individual. A broader comparison of MAO-B VT between MDEs and health across subregions of the PFC and a number of additional gray matter brain regions found a significant effect of diagnosis (repeated-measures ANOVA, F1,38 = 8.7; P = .005) and a significant interaction with region (F7,32 = 6.5; P < .001). The interaction with region reflected a relatively greater difference between groups in the ventrolateral PFC (mean, 26%; ANOVA, F1,38 = 12.2; P = .001), dorsolateral PFC (mean, 16%; ANOVA, F1,38 = 7.4; P = .01), orbitofrontal cortex (mean, 13%; ANOVA, F1,38 = 4.7; P = .04), thalamus (mean, 17%; ANOVA, F1,38 = 8.8; P = .005), and inferior parietal cortex (mean, 16%; ANOVA, F1,38 = 9.0; P = .005) (Figure 1, Figure 2, Table 2, and eFigure 1 and eFigure 2 in the Supplement).
In the PFC in MDEs, longer duration of illness was associated with greater MAO-B VT (ANCOVA, r = 0.68, F1,18 = 15.2; P = .001) (Figure 3). Given that 95% of our sample was aged 18 to 55 years and associations of age with MAO-B density are not observed before age 55 years,9,35 as expected there was no association herein between MAO-B VT and age in the PFC (F1,38 = 0.7; P = .40).
In MDEs, longer duration of illness was also associated with greater MAO-B VT in other brain regions. A general regional evaluation of the association of MAO-B VT with duration of illness applying a repeated-measures ANCOVA found a significant association of duration of illness (F1,18 = 18.1; P < .001) and a significant interaction with region (F7,12 = 9.1; P = .02). In MDEs, longer duration of illness was associated with greater MAO-B VT in the ventrolateral PFC, dorsolateral PFC, orbitofrontal cortex, ACC, thalamus, inferior parietal cortex, temporal cortex, and occipital cortex (eTable in the Supplement).
Our primary finding is that MAO-B VT is robustly elevated in the PFC during MDEs of MDD (Cohen d = 1.4). The differences between MDEs and health were more prominent in cortical regions proximal to the ventrolateral PFC and in the thalamus. The secondary finding is that longer duration of MDD illness is associated with greater PFC MAO-B VT. This latter finding was prominent across cortical regions and the thalamus. These results have important implications for MAO-B in the pathophysiology of MDD, neuroprogression in MDD, and therapeutic development.
Robustly elevated MAO-B VT in the PFC of MDD is important because elevated MAO-B level is implicated in impairment of mitochondrial function, synthesis of neurotoxic products, and dysregulation of nonserotonergic monoamines. In cell lines, rodent transgenic models of overexpression, and postmortem human brain, greater level of MAO-B is associated with increased MAO-B activity.9,10,36,37 Overexpression of MAO-B is also associated with greater production of hydrogen peroxide, which may adversely influence mitochondrial function and reserve capacity as implicated by reductions in pyruvate dehydrogenase, succinate dehydrogenase, and mitochondrial aconitase, as well as downstream inhibition of mitochondrial complex 1 activity through formation of dopaminochrome from dopamine.36,37 Reduced mitochondrial complex 1 occurs in the PFC of MDD.38 A pathological role for elevated MAO-B in neurodegeneration was proposed through its function in metabolizing rare endogenous neurochemicals, leading to neurotoxic metabolic products, such as aldehydes,36,39,40 and it is known that MAO-B metabolizes exogenously administered 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, leading to neurotoxic and behavioral sequelae of reduced and slowed movement.41,42 In a transgenic mouse model of globally increased MAO-B in astrocytes, abnormal behaviors compatible with several psychiatric syndromes, including those in MDD, were found during open field assessment, such as reduced total movement, less distance traveled, lower movement speed, and decreased duration of time spent moving.36,43 In humans, when MAO-B substrates dopamine and norepinephrine are depleted with the tyrosine hydroxylase inhibitor α-methylparatyrosine, depressed mood occurs with concurrent activation networks of structures that generate depressed mood, including subregions of the PFC.44,45 For these reasons, it is widely believed that in neuropsychiatric diseases elevated MAO-B level is a pathological target.
With 50% (10 of 20) of MDE cases herein having PFC MAO-B VT values exceeding the highest MAO-B VT values of healthy controls, there is an opportunity to develop and repurpose selective MAO-B inhibitors for MDD. Treatment of early-onset MDD most commonly involves selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), which are not well matched to the aforementioned potentially harmful sequelae of elevated MAO-B level, such as greater oxidative stress and reduced mitochondrial function, increased metabolism of nonserotonergic monoamines, and production of toxic metabolic products. While traditional nonselective and partially selective MAO-B inhibitors are not frequently used because they inhibit MAO-A, which is incompatible with SSRI and SNRI use due to the risk of serotonin syndrome, and because their reduction of peripheral tissue metabolism of tyramine creates risk for a hypertensive crisis, MAO-B inhibitors with high selectivity for MAO-B over MAO-A, such as sembragiline (completed phase 2 studies for Alzheimer disease46) and pioglitazone (approved for type 2 diabetes47) demonstrate compatibility with SSRI use. Although a recent meta-analysis of double-blind placebo-controlled studies favors pioglitazone,47 neither sembragiline nor pioglitazone has been developed for MDD.
Longer duration of illness was associated with greater MAO-B VT in the PFC, as well as most other cortical regions and the thalamus. The association between longer duration of illness and greater regional MAO-B VT is not accounted for by age because the association of age with MAO-B VT is negligible in this sample, with age-related influences on MAO-B density not beginning until ages 55 to 70 years.9,35 Greater MAO-B density may occur during reactive astrogliosis and may be associated with progression of neuropsychiatric diseases, such as Alzheimer disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy.10,48,49 In these conditions, GFAP and MAO-B levels are often highly correlated, which led to the argument that greater MAO-B density may be an in vivo marker of reactive astrogliosis49,50; however, development of in vivo PET markers of astrogliosis is an active area of ongoing investigation.51 Astrogliosis would not account for differences between MDD and health because GFAP is reduced in the orbitofrontal, dorsolateral, and subgenual PFC in MDE samples inclusive of younger individuals.52-54 However, such differences are not established for later stages of MDD because reduced GFAP was not present in late-life MDEs.55 Moreover, 2 studies29,30 that investigated GFAP in relation to age and duration of illness found a much greater rise in GFAP with age in MDD than health in the region sampled, the dorsolateral PFC. Hence, a plausible explanation for the association between greater MAO-B and duration of illness is gradually increasing astrogliosis.
Some limitations of the present study should be addressed. First, as is standard with PET imaging studies, the measure of MAO-B VT reflects binding of the radiotracer to MAO-B plus nonspecific binding. However, our latest estimate of nonspecific binding based on blocking studies in humans is low in the PFC at 7% (J.H.M., unpublished data, 2018), so it is unlikely to account for a mean 26% elevation in MAO-B VT because this would require extremely robust elevations in free and nonspecific binding, plausibly exceeding 300%. Second, the specific binding compartment of the MAO-B VT reflects both density and affinity of the radiotracer to MAO-B, although empirically MAO-B VT quantitated with [11C]SL25.1188 PET is highly correlated with MAO-B density in human brain.28 Third, the association between duration of illness and MAO-B VT is based on cross-sectional data, so it is possible that the association with long histories of MDEs could reflect another closely related phenomenon of illness persistence, such as treatment resistance, a direction that may be investigated further in the future. Fourth, while a strength of our study is that we restricted comorbidity to assess the associations of MDEs vs health, future study will need to ascertain the extent to which our results also apply to MDEs with specific comorbid illnesses.
We found higher MAO-B VT in MDEs secondary to MDD, primarily in the PFC. Differences were largest in the ventrolateral PFC and nearby cortical regions, as well as in the thalamus. In the PFC, but also throughout the cortex and in the thalamus, MAO-B VT was more elevated in those with longer duration of illness, a common finding in neuroprogressive illnesses. The collective findings argue that MAO-B, which when overexpressed is implicated in mitochondrial dysfunction, excessive generation of hydrogen peroxide, nonserotonergic monoamine metabolism, and production of toxic metabolites, should be considered a distinct target in MDD and receive greater attention in therapeutic development. This is especially recommended given that well-tolerated MAO-B inhibitors with preferential selectivity compared with MAO-A inhibitors are compatible with use of commonly prescribed SSRI and SNRI antidepressants.
Accepted for Publication: December 18, 2018.
Published Online: March 6, 2019. doi:10.1001/jamapsychiatry.2019.0044
Correction: This article was corrected on April 10, 2019, to fix the y-axis of Figure 2.
Corresponding Author: Jeffrey H. Meyer, MD, PhD, FRCP(C), Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St, Room B26, Toronto, ON M5T 1R8, Canada (jeff.meyer@camhpet.ca).
Author Contributions: Dr Meyer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Vasdev, Bagby, Varughese, Meyer.
Acquisition, analysis, or interpretation of data: Moriguchi, Wilson, Miler, Rusjan, Kish, Rajkowska, Wang, Bagby, Mizrahi, Houle, Meyer.
Drafting of the manuscript: Moriguchi, Rusjan, Kish, Varughese, Meyer.
Critical revision of the manuscript for important intellectual content: Moriguchi, Wilson, Miler, Vasdev, Kish, Rajkowska, Wang, Bagby, Mizrahi, Varughese, Houle, Meyer.
Statistical analysis: Moriguchi, Miler, Bagby, Meyer.
Obtained funding: Meyer.
Administrative, technical, or material support: Moriguchi, Wilson, Miler, Rusjan, Vasdev, Varughese, Houle.
Supervision: Mizrahi, Meyer.
Conflict of Interest Disclosures: Drs Wilson, Houle, and Meyer reported receiving operating grant funds for studies unrelated to the present work from Janssen in the past 5 years. Dr Mizrahi reported receiving a speaker’s fee from Otsuka-Lundbeck Canada in the past 5 years. Dr Houle reported receiving grants from the Canadian Institutes of Health Research. Dr Meyer reported receiving grants from the National Institute of Mental Health, Canadian Institutes of Health Research, Brain and Behavior Research Foundation, and Janssen; reported receiving other support from Lundbeck/Takeda and Venessance outside the submitted work; reported being a consultant to Mylan, Lundbeck/Takeda, Teva, and Trius in the past 7 years; and reported being an inventor on several patents, including inflammation markers, to predict brain inflammation and/or affective disorders. No other disclosures were reported.
Funding/Support: This study was supported by the National Institutes of Mental Health (grant 1R01MH115014-01), Brain and Behavior Research Foundation, and Canadian Institutes of Health Research (CIHR). Key infrastructure support was from the Azrieli Foundation, Canada Foundation for Innovation, and Ontario Ministry of Research and Innovation. Dr Moriguchi is a CIHR Fellow and has also received funding from the Uehara Memorial Foundation and Society of Nuclear Medicine and Molecular Imaging (Wagner Torizuka Fellowship). Drs Vasdev and Meyer are CIHR Canada Research Chairs.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other agencies listed above.
Additional Contributions: The following contributors are paid employees of the Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada: Alvina Ng, BSc, and Laura Nguyen, BSc, worked as study technicians. Jun Parkes, MSc, and Armando Garcia, BSc, served as chemistry staff. Terry Bell, BSc, provided engineering support.
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