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. Author manuscript; available in PMC: 2015 Dec 1.
Published in final edited form as: Neurotoxicology. 2014 Oct 27;45:178–184. doi: 10.1016/j.neuro.2014.10.008

Differential effects of binge methamphetamine injections on the mRNA expression of histone deacetylases (HDACs) in the rat striatum

Oluwaseyi Omonijo 1, Pawaris Wongprayoon 2, Bruce Ladenheim 1, Michael T McCoy 1, Piyarat Govitrapong 2, Subramaniam Jayanthi 1, Jean Lud Cadet 1
PMCID: PMC4306289  NIHMSID: NIHMS643374  PMID: 25452209

Abstract

Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain.

Keywords: Epigenetics, sirtuins, neurotoxicity, gene expression

1. Introduction

Methamphetamine (METH) is a widely abused psychostimulant because it is cheap, readily accessible, and addictive (Cadet et al, 2003). In humans, large doses of METH induce cardiac arrhythmia, strokes, seizures, and hyperthermia (Krasnova and Cadet, 2009). Acute effects of METH in the brain are mediated by release of dopamine (DA) from DA terminals (O’Dell et al, 1993) and stimulation of DA receptors in dopaminergic projection areas (Jayanthi et al, 2005; Xu et al, 2005). These large increases in DA levels are associated with substantial depletion of dopaminergic markers in the dorsal striatum (Kuhn et al, 2008; Sonsalla et al, 1986). METH can also cause death of neurons located post-synaptic to monoaminergic terminals (Deng et al, 1999; 2001; Jayanthi et al, 2001; 2005; Thiriet et al, 2005). Injections of multiple doses of METH are also accompanied by significant changes in gene expression in the dorsal striatum (Beauvais et al, 2011; 2010)). Multiple high doses of the drug also affect the expression of immediate early genes (IEGs) in the brain (Beauvais et al, 2011). Specifically, this pattern of drug injections induces significant time-dependent increases in IEG mRNA and protein expression (Beauvais et al, 2011). Binge METH injections also caused time-dependent increases in the mRNA expression of heat shock proteins, Gadd34, CHOP/Gadd153, and Bad but decreases in Bcl2 expression (Beauvais et al, 2011). These transcriptional changes appear to occur via stimulation of the DA D1-like receptor subtypes that are found in high concentration in the dorsal striatum (Cadet et al, 2010).

Gene transcription is regulated by complex epigenetic changes that include post-translational histone modifications and DNA methylation (Murr, 2010). The N-tails of histones possess lysine residues that can be reversibly acetylated by histone acetyltransferases (HATs) or deacetylated by several histone deacetylases (HDACs). HDACs remove acetyl groups from lysine residues on histones and stimulate the recruitment of several repressor complexes that mediate transcriptional changes (Thiagalingam et al, 2003). HDACs are divided into four classes based on sequence similarities (Mottet and Castronovo, 2008). These include Class I (HDAC1, HDAC2, HDAC3, and HDAC8), Class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10), Class III (Sirtuins1-7) and Class IV (HDAC11) HDACs (Mottet and Castronovo, 2008). Class I, II and IV HDACs are referred to as “classical” HDACs and are Zn2+-dependent enzymes (Codd et al, 2009) whereas the sirtuins require NAD+ as a cofactor (Neugebauer et al, 2008). Because HDACs participate in gene regulation, we investigated whether binge METH injections might influence the expression of these HDACs in the brain.

2. Materials and methods

2.1. Animals

Male Sprague–Dawley rats (Charles River Labs, Raleigh, NC, USA), weighing 250–300 g were used in the present study. The animals were maintained in a room at temperature of 22 °C and had free access to food and water. They were divided into two groups of animals: 1) Saline and 2) METH (10 mg/kg × 4 intraperitoneal injections every 2 h). The animals were euthanized at 16 hours after the last injection. All animal use procedures were according to the NIH Guide for the Care and Use of Laboratory Animals and were approved by Animal Care Committee of NIDA, NIH.

2.2. RNA Isolation

Dorsal striatal tissues were rapidly dissected, put on dry ice, and kept frozen at −80 C. Total RNA was extracted using Qiagen RNeasy Midi kit (Qiagen, Valencia, CA, USA) according to the company’s protocol. The RNA quality and quantity were assessed using an Agilent 2100 Bioanalyzer 2 (Agilent, Palo Alto, CA, USA) and showed no degradation.

2.3. Quantitative RT-PCR

Individual total RNA obtained from 6–8 rats per group was reverse-transcribed with oligo dT primers and RT for PCR kit (Clontech, Palo Alto, CA). PCR experiments were performed on Lightcycler 480 II (Roche, Indianapolis, IN), using and iQ SYBR Green Supermix (BioRad, Hercules, CA) according to the manufacturer’s protocol. Sequences for rat gene-specific primers corresponding to PCR targets were obtained using LightCycler Probe Design software (Roche). The primers were synthesized and HPLC-purified at the Synthesis and Sequencing Facility of Johns Hopkins University (Baltimore, MD). The sequences for these primers are shown in Table 1. Quantitative PCR values were normalized using OAZ1 (ornithine decarboxylase antizyme 1) based on the paper by de Jonge et al. (2007) who had reported that OAZ1 showed very stable expression in the mouse based on their analyses of 2,543 tissue samples hybridized to Affymetrix Mouse GeneChips after exposure to various experimental manipulations. The results are reported as relative changes calculated as the ratios of normalized gene expression data of METH-treated group compared to the control group.

Table 1.

List of RT-PCR Primers.

Gene Name Forward Reverse
HDAC1 GCC CTT CCA ATA TGA CTA AC GAG CAG ATG GAA ATT CGT
HDAC2 TGT TAA GGA AGA AGA CAA ATC CA ACA GCG AAG GTT TCT TAT C
HDAC3 ATG AAA CAT CTC TGC TGG TA GGC GGA TCT GGT CTA GAT A
HDAC4 GAA CAA GGA GAA GGG CA TGT CTT CCC ATA CCA GTA G
HDAC5 TGG ACT GGG ACA TTC AC CAC GCC ACA TTT ACG TT
HDAC6 GTC TCA TCC TAC CTG CTC GGC AGA TGT AGA TGG ACT
HDAC7 CTG CTT TCA GGA TAG TGG CAG CTG CTG TGT CAT GTA
HDAC8 CTC AGG CTG AGT CTG AAA CTT CAC AAG GGA ATC GCA
HDAC9 TCT GAA CAT CAC TCA CTA CT GTG CAG CTC ATT CCA AA
HDAC10 GTG CCC TGG AGT CTA TC CCA AGG CAA CAG CTA TG
HDAC11 TCA CAC TGG CTA TCA AGT T GTA GAT GTG GCG GTT GTA AA
SIRT1 CCA GAT CCT CAA GCC ATG TT CCA AAA TTG CTT TCC TTC CA
SIRT2 TTG AAG GAG TGA CAC GCT A GTA TGG AAG GTG GTA TTT CT
SIRT3 CAA TGT CGC TCA CTA CT GCA CGT AGC TGA TAC AAA
SIRT4 TCC GGT TAC AGG TTC AT CTG TCA CTG TGG GTC TA
SIRT5 TGT ACC TCG TGT GGC AAT GT CAG GAT CCA GGT TTT CTC CA
SIRT6 GCT GAG AGA CAC CAT TC GTT GAC AAT GAC CAG ACG
SIRT7 CAG CCT CTA TCC CAG ATT TGT TGC ACC AGC TTA TG
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2.4. Statistical analysis

Statistical analysis for the qRT-PCR data was performed by StatView (SAS Institute, Cary, NC, USA) using unpaired student’s T-test. The null hypothesis was rejected at p < 0.05.

3. Results

Figure 1 shows the effects of METH on the expression of class I HDACs. METH did not cause any changes in the expression of HDAC1, HDAC2 or HDAC3 (Fig. 1A–1C). However, there were significant changes in the expression of HDAC8 (−51%, p = 0.018).

Figure 1.

Figure 1

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Toxic METH binges caused decreased HDAC8 mRNA levels in the rat striatum. Rats were injected with METH (10 mg/kg) given 4 times at 2-hr interval within one day. The animals were euthanized 16 hours after the last injection. RNA extraction and quantitative PCR were conducted as described in the text. Statistical analysis was done by Student’s T test. Key to statistics: * < 0.05, in comparison to control animals.

Figure 2 shows the effects of METH on the mRNA levels for Class IIA HDACs. There were no significant METH effects on HDAC4, 5, or 7 (Fig. 2A–2C). In contrast, METH caused significant decreases in HDAC9 mRNA levels (−42%, p= 0.031). The results of class IIB HDACs are reported in Fig. 3. Both HDAC6 (−31%, p = 0.022) and HDAC10 (−25%, p = 0.042) were significantly impacted by the toxic dose of METH (Fig. 3).

Figure 2.

Figure 2

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Differential effects of toxic doses of METH on Class IIA HDAC mRNA levels. Rats were treated as described in the text and in Figure 1. Key to statistics: * < 0.05 in comparison to control rats.

Figure 3.

Figure 3

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METH caused decreased expression of HDAC6 and HDAC10 mRNA expression. Rats were treated as described in the text and in Figure 1. Key to statistics: * < 0.05 in comparison to control rats.

The METH injections also influenced the expression of class III HDACs called sirtuins (Figs. 4 and 5). The data on the sirtuins are presented in terms of their subcellular localization. The effects of METH on cytoplasmic and nuclear sirtuins are shown in figure 4. METH did not cause any changes in the expression of Sirt1 (Fig. 4A) or Sirt7 (Fig. 4D). However, METH caused significant decreases in Sirt2 (−75%, p =0.041, Fig. 4B) and Sirt6 (−27%, p = 0.029, Fig. 4C) mRNA levels. The effects of METH on the mitochondrial sirtuins are shown in Figure 5. There were no significant changes in Sirt3 and Sirt4 expression (Figs 5A and 5B). However, METH caused significant decreases in Sirt5 mRNA levels (−24%, p = 0.026, Fig. 5C). Finally, figure 6 shows that the METH injections caused significant decreases (−33%, p = 0.024) in the mRNA expression of the class IV HDAC, HDAC11.

Figure 4.

Figure 4

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Differential effects of METH on cytoplasmic and nuclear Class III HDAC mRNA levels. Rats were treated as described in the text and in Figure 1. Key to statistics: * < 0.05 in comparison to control rats.

Figure 5.

Figure 5

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METH caused decreased mRNA expression of the mitochondrial Class III HDAC, Sirt5. Rats were treated as described in the text and in Figure 1. Key to statistics: * < 0.05 in comparison to control rats.

Figure 6.

Figure 6

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METH decreases HDAC11 mRNA expression. Rats were treated as described in the text and in Figure 1. Key to statistics: * < 0.05 in comparison to control rats.

4. Discussion

The main findings are that injections of toxic METH doses can cause decreased mRNA levels of several HDACs that include HDAC6, HDAC8, HDAC9, and HDAC10. In addition, the METH injections caused substantial changes in Sirt2, Sirt5, and Sirt6. These observations suggest that toxic doses of METH that are known to cause DA depletion in the striatum can also impact genes that are involved in epigenetic regulation of gene expression and in the maintenance of metabolic homeostasis.

Class I HDACs including HDAC8 are known to be involved in the regulation of gene expression (Hayakawa and Nakayama, 2011). Previous studies from this laboratory had reported that chronic administration of non-toxic METH doses for two weeks increased the mRNA expression of HDAC1 and HDAC2 in the striatum (Jayanthi et al, 2014). In the present study, we did not detect any significant changes in HDAC1, HDAC2, or HDAC3 in animals euthanized 16 hours after toxic METH injections. Together, these observations suggest that the patterns of METH administration can significantly impact the presence and direction of METH-induced alterations in epigenetic markers. In contrast to the lack of changes in these three genes, we found marked decreases in HDAC8 expression. The cloning and characterization of HDAC8 was first published by several investigators in 2000 and was shown to share homologies with other known Class I HDACs (Buggy et al, 2000; Hu et al, 2000). HDAC8 is located in the nucleus and has histone deacetylase activity that can be blocked by β-hydroxybutyrate and trichostatin A (Buggy et al, 2000; Hu et al, 2000). HDAC8 preferentially deacetylates histones H3 and H4 to regulate gene expression. HDAC8 can be phosphorylated by protein kinase A, resulting in a significant inhibition of its activity (Lee et al, 2004). In the central nervous system (CNS), HDAC8-like immunoreactivity was reported to show a nucleo-cytoplasmic staining pattern in neurons located in various brain regions (Takase et al, 2013). HDAC8 is also found in the cytoplasm of smooth muscle cells (de Leval et al, 2006).

Phosphorylated HDAC8 recruits the chaperone proteins, HSP70/HSP90, to a complex that can block an E3 ligase-mediated degradative pathway (Lee et al, 2006). Interestingly, overexpression of HDAC8 was shown to cause cell proliferation and inhibition of liver cancer cells (Wu et al, 2013). In contrast, HDAC8 inhibition causes apoptosis of T-cell lymphomas (Balasubramanian et al, 2008) and of hepatocellular carcinoma (Wu et al, 2013). These observations suggest that the METH-induced decreased HDAC8 expression might play a role in promoting cell death in this model of METH toxicity (Deng et al, 1999; Krasnova and Cadet, 2009).

Another gene that showed METH-induced decreased expression was HDAC9. HDAC9 was cloned in 2001 and reported to show similarities of class IIA HDACs (Zhou et al, 2001). Class IIA HDACs shuttle between the cytosol and the nucleus (Lahm et al, 2007; Martin et al, 2007). HDAC9 is highly expressed in the brain and skeletal muscle where it serves to repress myocyte enhancer factor 2 (MEF2)-mediated gene transcription (Zhou et al, 2001). HDAC9 co-localizes and binds to several transcription repressors, co-repressors, and transcription factors including mSin3A, mSin3B, and N-CoR (Petrie et al, 2003). HDAC9 also interacts with HDAC3 and HDAC4 (Petrie et al, 2003). HDAC9 is also a signal-responsive repressor that is downregulated in the denervated muscle, leading to increased MEF2-dependent gene expression (Mejat et al, 2005). Thus, the METH-induced downregulation suggests that there might be an increase in the expression of specific MEF2-regulated genes in intrinsic striatal cells since members of the MEF2 family of transcription factors are also highly expressed in the brain and participate in the regulation of genes involved in neuronal survival (Akhtar et al, 2012; Dietrich, 2013), a process that is regulated, in part, by the cAMP-PKA signaling pathway (Wang et al, 2005). Interestingly, MEF2 family members have been reported to regulate depolarization-induced BDNF expression (Lyons et al, 2012). MEF2 also regulates the expression of activity-dependent genes including Arc (Flavell et al, 2006). Other genes of interest include Homer1, JNK and adenyl cyclase 8 (Flavell et al, 2008), some of which have been shown to be regulated by METH in various contexts (Cadet et al, 2014; Martin et al, 2012). Taken together, these observations implicate HDAC9 and MEF2 in the regulation of the survival of specific classes of striatal neurons after toxic doses of METH since enkephalinergic neurons seem to be more susceptible than other striatal cells to the toxic effects of the drug (Jayanthi et al, 2005; Thiriet et al, 2005).

The two class IIB HDACs, HDAC6 and HDAC10, were also impacted by the binge METH injections. HDAC6 is a microtubule-associated cytoplasmic deacetylase (Grozinger and Schreiber, 2000; Hubbert et al, 2002). Interestingly, tubulin deacetylase have been reported to modulate the formation of aggresomes and the accumulation of misfolded proteins, processes that might serve to maintain cellular viability (Boyault et al, 2007; Kawaguchi et al, 2003). Indeed, HDAC6 provides an important link between autophagy and the unfolded protein response (UPR) (Pandey et al, 2007). These observations are of interest because toxic doses of METH cause significant changes in the expression of proteins involved in the UPR (Beauvais et al, 2011; Jayanthi et al, 2004; Jayanthi et al, 2009) and suggest that METH-induced decreased HDAC6 expression might serve to increase acetylation of some chaperone proteins (Bali et al, 2005). The other class IIB member, HDAC10, was identified in 2002 (Guardiola and Yao, 2002; Kao et al, 2002; Tong et al, 2002). HDAC10 is located in the cytoplasm and nucleus, possesses TCA-sensitive deacetylase activity, and is involved in transcription regulation (Guardiola and Yao, 2002; Kao et al, 2002; Tong et al, 2002). Interestingly, HDAC10 inhibition causes accumulation of reactive oxygen species in gastric cancer cells (Lee et al, 2010), findings that are consistent with the demonstration that HDAC10 can promote autophagy-induced cell survival (Oehme et al, 2013). Thus, METH-induced decreases in HDAC10 mRNA expression might also serve to promote toxicity in the striatum.

The METH injections also caused decreased HDAC11 mRNA expression. The class IV HDAC, HDAC11, was cloned and characterized by Gao et al.(Gao et al, 2002) and is the only member of that class at present. HDAC11 contains residues within its catalytic domain that are shared by classes I and II HDACs (Gao et al, 2002). HDAC11 is highly expressed in the brain (Takase et al, 2013) and is differentially regulated during development (Liu et al, 2008). HDAC11 is also involved in the regulation of gene expression in maturing oligodendrocyte cultures that showed increased expression of the enzyme (Liu et al, 2009). Increased HDAC11 expression was also associated with decreased abundance of histone H3 acetylated at lysine 9 (H3K9) and at lysine 14 (H3K14). Suppressing HDAC11 expression produced increased H3K9Ac and H3K14Ac (Liu et al, 2009). These results suggest that toxic doses of METH might cause similar increases in histone H3 acetylation by suppressing HDAC11 expression, as shown in our results. Interestingly, a recent study has reported that acute injection of ethanol (3 g/kg), a known neurotoxin (Jacobus and Tapert, 2013), also caused significant decreases in HDAC11 expression (Finegersh and Homanics, 2014). Taken together, these results suggest that other neurotoxic compounds might impact HDAC11 expression in the brain.

The injections of METH also caused significant decreases in the expression of 3 class III HDACs, Sirt2, Sirt5, and Sirt6. Sirt2 is localized predominantly in the cytoplasm (Afshar and Murnane, 1999) where it deacetylates FOXO3 in response to oxidative stress (Wang et al, 2007). Sirt2 is also an alpha-tubulin deacetylase (North et al, 2003), a function that appears to be dependent, in part, on its interaction with the class IIB deacetylase, HDAC6 (Nahhas et al, 2007). Thus, the downregulation of both of these HDACs by METH suggest the possibility that these doses of the drug might increase tubulin acetylation, thereby influencing microtubule dynamics in the rat striatum. Also of interest is the fact that Sirt2 also shuttles from the cytoplasm to the nucleus where it is involved in deacetylation of histone H4 at lysine 16 (H4K16ac) (Vaquero et al, 2006). METH-induced decreased Sirt2 expression might thus lead to increased H4K16 acetylation, with substantial impact on chromatin structure and function (Dion et al, 2005).

Sirt5 is a mitochondrial protein that is involved in regulating metabolic adaptations (Gertz and Steegborn, 2010). Mitochondrial proteins that are involved in oxidative phosphorylation, nucleotide metabolism, and in the urea cycle are subject to substantial lysine modifications (Kim et al, 2006; Newman et al, 2012). Sirt5 also deacetylates and activates carbamoyl phosphate synthase (CPS1) to modulate the function of the urea cycle (Nakagawa et al, 2009; Ogura et al, 2010). Sirt5 is also known to be a NAD-dependent remover of malonyl and succinyl groups from specific lysines (Du et al, 2011). These actions of Sirt5 repress cellular respiration through its effects of the pyruvate dehydrogenase protein complex (Park et al, 2013). Together, these observations suggest that METH injections can significantly impact mitochondrial functions, an idea supported by the observed effects of the drug on mitochondrial proteins and enzymatic activities (Beauvais et al, 2011; Brown et al, 2005; Jayanthi et al, 2001; Jayanthi et al, 2004).

Sirt6 is a class III HDAC that is located mainly in the nucleus (Michishita et al, 2005). It is a NAD+-dependent deacetylase that associates with heterochromatin (Michishita et al, 2005). The enzyme is involved in DNA repair and its absence in mice causes premature aging (Mostoslavsky et al, 2006). Sirt6 exerts this function by forming a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-dependent protein kinase (PK), thereby promoting DNA DSB repair (McCord et al, 2009). Aging-induced decline in homologous recombination (HR) is accompanied by decreased Sirt6 expression, with this decline in HR being rescuable by overexpression of Sirt6 in pre-senescent cells (Mao et al, 2012). These findings suggest that binge METH injections can promote aging-dependent processes in the rat striatum by interfering with the normal Sirt6 functions. This suggestion is supported by a recent report that showed that METH exposure led to impaired recognition memory and abnormalities in monoaminergic systems that were similar to those observed in aged animals (Melo et al, 2012).

In summary, we are reporting, for the first time, that toxic METH doses can have substantial but differential effects on the mRNA expression of several proteins that are members of several HDAC classes. Specifically, while we found significant changes in HDAC6, HDAC8, HDAC9, HDAC10 and HDAC11, the other class I, II, and IV HDACs were not significantly affected, with HDAC4 not even showing any trend for being affected by the toxic METH dose. We also showed significant decreases in Sirt2, Sirt5, and Sirt6 expression. Interestingly, some of these HDACs are involved in the regulation of gene expression whereas others are involved in the regulation of microtubule dynamics. Importantly, several of these HDACs have been shown to participate in degenerative processes in the brain (Simoes-Pires et al, 2013). Of significant interest to the field of METH toxicity, our observations of METH-induced decreased Sirt5 expression are consistent with the accumulated evidence that the drug can negatively impact mitochondrial functions in the brain (Jayanthi et al, 2001). The effects on Sirt6 expression also support the notion that METH can affect DNA repair functions (Cadet et al, 2003). Finally, these results support, in part, the idea that METH may cause substantial transcriptional changes in the brain (Cadet et al, 2014). Future studies will investigate which specific roles that these METH-induced alterations in HDAC expression might play in drug-induced neurotoxicity.

Highlights.

  • Methamphetamine (METH) is an addictive and toxic agent.

  • Toxic doses of METH cause significant decreased HDAC6, 8, 9, 10 and 11 mRNA levels in the rat striatum.

  • METH also decreases the expression of the mitochondrial HDAC, SIRT5.

  • In addition, the expression of the nuclear HDACs, SIRT2 and SIRT6, is also decreased by the METH injections.

  • The present observations add to the accumulating evidence that METH can substantially influence epigenetic landscapes in the brain.

Acknowledgments

This research was supported by funds of the Intramural Research Program of the DHHS/NIH/NIDA. Pawaris Wongprayoon and Dr. Piyarat Govitrapong were supported by funds from the Thailand Research Fund (TRF) - Royal Golden Jubilee Ph.D. Program and Mahidol University. The authors also thank the comments of two reviewers who help make this a better paper.

Footnotes

Conflict of interest

The authors declare that there are no conflicts of interest.

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