Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors and ion channels. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. A novel dendritic protein, Homer, contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling (Brakeman, 1997).
Vesl-1S (186 amino acids, also called Homer) is a protein containing EVH1- and PDZ-like domains whose expression in the hippocampus is regulated during long term potentiation (LTP), one form of synaptic plasticity thought to underlie memory formation. This study reports additional members of the Vesl/Homer family of proteins, Vesl-1L and Vesl-2. Vesl-1L (366 amino acids), a splicing variant of Vesl-1S, shares N-terminal 175 amino acids with Vesl-1S and contains additional amino acids at the C terminus. Vesl-2 (354 amino acids) is highly related to Vesl-1L in that both contain EVH1- and PDZ-like domains at the N terminus (86% conservation) and an MCC (mutated in colorectal cancer)-like domain and a leucine zipper at the C terminus. In contrast to vesl-1S, no changes are observed in the levels of vesl-1L and vesl-2 mRNAs during dentate gyrus LTP. All these proteins interact with metabotropic glutamate receptors (mGluR1 and mGluR5) as well as several hippocampal proteins in vitro. Vesl-1L and Vesl-2, but not Vesl-1S, interact with each other through the C-terminal portion that is absent in Vesl-1S. Vesl-1L and Vesl-2 may mediate clustering of mGluRs at synaptic junctions. It is proposed that Vesl-1S may be involved in the structural changes that occur at metabotropic glutamatergic synapses during the maintenance phase of LTP by modulating the redistribution of synaptic components (Kato, 1998).
Homer is a neuronal immediate early gene (IEG) that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors (mGluRs). A family of Homer-related proteins is derived from three distinct genes. Like Homer IEG (now termed Homer 1a), all new members bind group 1 mGluRs. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil (CC) domain that mediates self-multimerization. CC-Homers form natural complexes that cross-link mGluRs and are enriched at the postsynaptic density. Homer 1a does not multimerize and blocks the association of mGluRs with CC-Homer complexes. These observations support a model in which the dynamic expression of Homer 1a competes with constitutively expressed CC-Homers to modify synaptic mGluR properties (Xiao, 1998).
A developmentally regulated Homer/Vesl isoform, Cupidin (Homer 2a/Vesl-2Delta11), was isolated from postnatal mouse cerebellum using a fluorescent differential display strategy. The strongest expression of Cupidin is detected in the cerebellar granule cells at approximately postnatal day 7. Cupidin is enriched in the postsynaptic density fraction, and its immunoreactivity is concentrated at glomeruli of the inner granular layer when active synaptogenesis occurs. Cupidin protein can be divided into two functional domains: the N-terminal portion that is highly conserved among Homer/Vesl family proteins, and the C-terminal portion that consists of a putative coiled-coil structure, including several leucine zipper motifs. The N-terminal fragment of Cupidin, which is able to associate with metabotropic glutamate receptor 1 (mGluR1), also interacts with F-actin in vitro. In keeping with this, F-actin immunocytochemically colocalizes with Cupidin in cultured cerebellar granule cells, and a Cupidin-mGluR1-actin complex was immunoprecipitated from crude cerebellar lysates using an anti-Cupidin antibody. The C-terminal portion of Cupidin binds to Cdc42, a member of Rho family small GTPases, in a GTP-dependent manner in vitro, and Cupidin functionally interacts with activated-Cdc42 in a heterologous expression system. Together, these findings indicate that Cupidin may serve as a postsynaptic scaffold protein that links mGluR signaling with actin cytoskeleton and Rho family proteins, perhaps during the dynamic phase of morphological changes that occur during synapse formation in cerebellar granule cells (Shiraishi, 1999).
Three Homer genes regulate the activity of metabotropic glutamate receptors mGluR1a and mGluR5 and their coupling to releasable intracellular Ca2+ pools and ion channels. Only the Homer 1 gene evolved bimodal expression of constitutive (Homer 1b and c) and immediate early gene (IEG) products (Homer 1a and Ania 3). The IEG forms compete functionally with the constitutive Homer proteins. The complex expression of the Homer 1 gene, unique for IEGs, focused the attention of this study on gene organization. In contrast to most IEGs, which have genes that are <5 kb, the Homer 1 gene was found to span approximately 100 kb. The constitutive Homer 1b/c forms are encoded by exons 1-10, whereas the IEG forms are encoded by exons 1-5 and parts of intron 5. RNase protection has demonstrated a >10-fold activity-dependent increase in mRNA levels exclusively for the IEG forms. Moreover, fluorescent in situ hybridization has documented that new primary Homer 1 transcripts are induced in neuronal nuclei within a few minutes after seizure, typical of IEGs, and that Homer 1b-specific exons are excluded from the activity-induced transcripts. Thus, at the resting state of the neurons, the entire gene is constitutively transcribed at low levels to yield Homer 1b/c transcripts. Neuronal activity sharply increases the rate of transcription initiation, with most transcripts now ending within the central intron. These coordinate transcriptional events rapidly convert a constitutive gene to an IEG and regulate the expression of functionally different Homer 1 proteins (Bottai, 2000).
Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. The crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF) has been determined. In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser-Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes (Beneken, 2000).
PSD-Zip45 (also named Homer 1c/Vesl-1L) is a synaptic scaffolding protein that interacts with neurotransmitter receptors and other scaffolding proteins to target them into post-synaptic density (PSD), a specialized protein complex at the synaptic junction. Binding of the PSD-Zip45 to the receptors and scaffolding proteins results in colocalization and clustering of its binding partners in PSD. It has an Ena/VASP homology 1 (EVH1) domain in the N terminus for receptor binding, two leucine zipper motifs in the C terminus for clustering, and a linking region whose function is unclear despite the high level of conservation within the Homer 1 family. The X-ray crystallographic analysis of the largest fragment of residues 1-163, including an EVH1 domain reported in this study, demonstrates that the EVH1 domain contains an alpha-helix longer than that of the previous models, and that the linking part included in the conserved region of Homer 1 (CRH1) of the PSD-Zip45 interacts with the EVH1 domain of the neighbor CRH1 molecule in the crystal. The results suggest that the EVH1 domain recognizes the PPXXF motif found in the binding partners, and the SPLTP sequence (P-motif) in the linking region of the CRH1. The two types of binding are partly overlapped in the EVH1 domain, implying a mechanism to regulate multimerization of Homer 1 family proteins (Irie, 2002).
The molecular basis for glutamate receptor trafficking to the plasma membrane is not understood. Homer 1b (H1b), a constitutively expressed splice form of the immediate early gene product Homer (now termed Homer 1a) regulates the trafficking and surface expression of group I metabotropic glutamate receptors. H1b inhibits surface expression of the metabotropic glutamate receptor mGluR5 in heterologous cells, causing mGluR5 to be retained in the endoplasmic reticulum (ER). In contrast, mGluR5 alone or mGluR5 coexpressed with Homer 1a successfully travels through the secretory pathway to the plasma membrane. In addition, point mutations that disrupt mGluR5 binding to H1b eliminate ER retention of mGluR5, demonstrating that H1b affects metabotropic receptor localization via a direct protein-protein interaction. Electron microscopic analysis reveals that the group I metabotropic receptor mGluR1alpha is significantly enriched in the ER of Purkinje cells, suggesting that a similar mechanism may exist in vivo. Because H1b is found in dendritic spines of neurons, local retention of metabotropic receptors within dendritic ER provides a potential mechanism for regulating synapse-specific expression of group I metabotropic glutamate receptors (Roche, 1999).
Several scaffold proteins for neurotransmitter receptors have been identified as candidates for receptor targeting. However, the molecular mechanism underlying such receptor clustering and targeting to postsynaptic specializations remains unknown. PSD-Zip45 (also named Homer 1c/vesl-1L) consists of the NH(2) terminus containing the enabled/VASP homology 1 domain and the COOH terminus containing the leucine zipper. It has been demonstrated immunohistochemically that metabotropic glutamate receptor 1alpha (mGluR1alpha) and PSD-Zip45/Homer 1c are colocalized to synapses in the cerebellar molecular layer but not in the hippocampus. In cultured hippocampal neurons, PSD-Zip45/Homer1c and N-methyl-D-aspartate receptors are preferentially colocalized to dendritic spines. Cotransfection of mGluR1alpha or mGluR5 and PSD-Zip45/Homer 1c into COS-7 cells results in mGluR clustering induced by PSD-Zip45/Homer 1c. An in vitro multimerization assay shows that the extreme COOH-terminal leucine zipper is involved in self-multimerization of PSD-Zip45/Homer 1c. A clustering assay of mGluRs in COS-7 cells also reveals a critical role of this leucine-zipper motif of PSD-Zip45/Homer 1c in mGluR clustering. These results suggest that the leucine zipper of subsynaptic scaffold protein is a candidate motif involved in neurotransmitter receptor clustering at the central synapse (Tadokoro, 1999).
The physiological actions of neurotransmitter receptors are intimately linked to their proper neuronal compartment localization. The effect of the metabotropic glutamate receptor (mGluR)-interacting proteins, Homer1a, b, and c, were examined in the targeting of mGluR5 in neurons. mGluR5 is exclusively localized in cell bodies when transfected alone in cultured cerebellar granule cells. In contrast, mGluR5 is found also in dendrites when coexpressed with Homer1b or Homer1c, and in both dendrites and axons when cotransfected with Homer1a. In dendrites, cotransfected mGluR5 and Homer1b/c form clusters that colocalize with the synaptic marker synaptophysin. Interestingly when transfected alone, the Homer proteins are also translocated to neurites but do not form such clusters. Depolarization of the neurons with a mixture of ionotropic glutamate receptor agonists, NMDA and kainate, or potassium channel blockers, tetraethylammonium and 4-aminopyridine, induces transient expression of endogenous Homer1a and persistent neuritic localization of transfected mGluR5 even long after degradation of Homer1a. These results suggest that Homer1a/b/c proteins are involved in the targeting of mGluR5 to dendritic synaptic sites and/or axons and that this effect can be regulated by neuronal activity. Because the activity-dependent effect of endogenous Homer1a is also long-lasting, the axonal targeting of mGluR5 by this protein is likely to play an important role in synaptic plasticity (Ango, 2000).
The metabotropic glutamate (mGlu) receptors are a family of receptors involved in the tuning of fast excitatory synaptic transmission in the brain. Experiments performed in heterologous expression systems suggest that cell surface expression of group I mGlu receptors is controlled by their auxiliary protein, Homer. However, whether or not this also applies to neurons has been controversial. In cultured cerebellar granule cells, the group I mGlu receptor subtype, mGlu5, transfected alone is functionally expressed at the surface of these neurons. Transfected Homer1b causes intracellular retention and clustering of this receptor at synaptic sites. Recombinant Homer1a alone does not affect cell surface expression of the receptor, but in neurons transfected with Homer1b, excitation-induced expression of native Homer1a reverses the intracellular retention of mGlu5 receptors, resulting in the receptor trafficking to synaptic membranes. Transfected Homer1a also increases the latency and amplitude of the mGlu5 receptor Ca2+ response. These results indicate that Homer1 proteins regulate synaptic cycling and Ca2+ signaling of mGlu5 receptors, in response to neuronal activity (Ango, 2002).
Shank is a family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex. Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors (Tu, 1999).
The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction (Sala, 2001).
A novel rat gene, tanc (GenBank Accession No. AB098072), has been cloned that encodes a protein containing three tetratricopeptide repeats (TPRs), ten ankyrin repeats and a coiled-coil region, and is possibly a rat homolog of Drosophila rolling pebbles. The tanc gene is expressed widely in the adult rat brain. Subcellular distribution, immunohistochemical study of the brain and immunocytochemical studies of cultured neuronal cells indicate the postsynaptic localization of TANC protein of 200 kDa. Pull-down experiments have shown that TANC protein binds PSD-95, SAP97, and Homer via its C-terminal PDZ-binding motif, -ESNV, and fodrin via both its ankyrin repeats and the TPRs together with the coiled-coil domain. TANC also binds the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. An immunoprecipitation study shows TANC association with various postsynaptic proteins, including guanylate kinase-associated protein (GKAP), alpha-internexin, and N-methyl-D-aspartate (NMDA)-type glutamate receptor 2B and AMPA-type glutamate receptor (GluR1) subunits. These results suggest that TANC protein may work as a postsynaptic scaffold component by forming a multiprotein complex with various postsynaptic density proteins (Suzuki, 2004).
Group I metabotropic glutamate receptors (mGluRs) activate PI turnover and thereby trigger intracellular calcium release. mGluRs form natural complexes with members of a family of Homer-related synaptic proteins. Homer proteins form a physical tether linking mGluRs with the inositol trisphosphate receptors (IP3R). A novel proline-rich 'Homer ligand' (PPXXFr) is identified in group 1 mGluRs and IP3R, and these receptors coimmunoprecipitate as a complex with Homer from brain. Expression of the IEG form of Homer, which lacks the ability to cross-link, modulates mGluR-induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an IEG, whose expression is driven by synaptic activity, can directly modify a specific synaptic function (Tu, 1998).
Group I metabotropic glutamate receptors (mGluR1 and 5) couple to intracellular calcium pools by a family of proteins, termed Homer, that cross-link the receptor to inositol trisphosphate receptors. mGluRs also couple to membrane ion channels via G-proteins. The role of Homer proteins in channel modulation was investigated by expressing mGluRs and various forms of Homer in rat superior cervical ganglion (SCG) sympathetic neurons by intranuclear cDNA injection. Expression of cross-linking-capable forms of Homer (Homer 1b, 1c, 2, and 3, termed long forms) occludes group I mGluR-mediated N-type calcium and M-type potassium current modulation. This effect is specific for group I mGluRs. mGluR2 (group II)-mediated inhibition of N-channels was unaltered. Long forms of Homer decrease modulation of N- and M-type currents but do not selectively block distinct G-protein pathways. Short forms of Homer, which cannot self-multimerize (Homer 1a and a Homer 2 C-terminal deletion), do not alter mGluR-ion channel coupling. When coexpressed with long forms of Homer, short forms restore the mGluR1a-mediated calcium current modulation in an apparent dose-dependent manner. Homer 2b induces cell surface clusters of mGluR5 in SCG neurons. Conversely, a uniform distribution was observed when mGluR5 was expressed alone or with Homer short forms. These studies indicate that long and short forms of Homer compete for binding to mGluRs and regulate their coupling to ion channels. In vivo, the immediate early Homer 1a is anticipated to enhance ion channel modulation and to disrupt coupling to releasable intracellular calcium pools. Thus, Homer may regulate the magnitude and predominate signaling output of group I mGluRs (Kammermeier, 2000).
Homer proteins form an adapter system that regulates coupling of group 1 metabotropic glutamate receptors (mGluR) with intracellular inositol trisphosphate receptors (IP3R), and is modified by neuronal activity. Homer proteins also physically associate with ryanodine receptors type 1 (RyR1) and regulate gating responses to Ca2+, depolarization, and caffeine. In contrast to the prevailing notion of Homer function, Homer1c (long form) and Homer1-EVH1 (short form) evoke similar changes in RyR activity. The EVH1 domain mediates these actions of Homer, and is selectively blocked by a peptide that mimics the Homer ligand. 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain, exhibit significantly reduced (~33%) amplitude in their responses to K+ depolarization compared to cells expressing wild-type protein. These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca2+ release gain. Homer is the first example of an 'adapter' that also modifies signaling properties of its target protein. The present work reveals a novel mechanism by which Homer directly modulates the function of its target protein RyR1 and E-C coupling in skeletal myotubes. This form of regulation may be important in other cell types that express Homer and RyR1 (Feng, 2002).
Homers are scaffolding proteins that bind G protein-coupled receptors (GPCRs), inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), ryanodine receptors, and TRP channels. However, their role in Ca2+ signaling in vivo is not known. Characterization of Ca2+ signaling in pancreatic acinar cells from Homer2-/- and Homer3-/- mice show that Homer 3 has no discernible role in Ca2+ signaling in these cells. In contrast, Homer 2 tunes intensity of Ca2+ signaling by GPCRs to regulate the frequency of [Ca2+]i oscillations. Thus, deletion of Homer 2 increases stimulus intensity by increasing the potency for agonists acting on various GPCRs to activate PLCbeta and evoke Ca2+ release and oscillations. This is not due to aberrant localization of IP3Rs in cellular microdomains or IP3R channel activity. Rather, deletion of Homer 2 reduces the effectiveness of exogenous regulators of G proteins signaling proteins (RGS) to inhibit Ca2+ signaling in vivo. Moreover, Homer 2 preferentially binds to PLCbeta in pancreatic acini and brain extracts and stimulates GAP activity of RGS4 and of PLCbeta in an in vitro reconstitution system, with minimal effect on PLCbeta-mediated PIP2 hydrolysis. These findings describe a novel, unexpected function of Homer proteins, demonstrate that RGS proteins and PLCbeta GAP activities are regulated functions, and provide a molecular mechanism for tuning signal intensity generated by GPCRs and, thus, the characteristics of [Ca2+]i oscillations (Shin, 2003).
Homer proteins are members of a family of multidomain cytosolic proteins that have been postulated to serve as scaffold proteins that affect responses to extracellular signals by regulating protein-protein interactions. Whether Homer proteins are involved in axon pathfinding in vivo was tested by expressing both wild-type and mutant isoforms of Homer in Xenopus optic tectal neurons. Time-lapse imaging has demonstrated that interfering with the ability of endogenous Homer to form protein-protein interactions results in axon pathfinding errors at stereotypical choice points. These data demonstrate a function for scaffold proteins such as Homer in axon guidance. Homer may facilitate signal transduction from cell-surface receptors to intracellular proteins that govern the establishment of axon trajectories (Foa, 2001).
The vesl-1S/homer-1a gene is up-regulated during seizure and long term potentiation. Other members of the Vesl family, Vesl-1L, -2, and -3, are constitutively expressed in the brain. The regulatory mechanisms governing the expression level of Vesl-1S protein, either an exogenously introduced one in COS7 or human embryonic kidney 293T cells or an endogenous one in rat brain neurons, were examined in cultures. In both cases, application of proteasome inhibitors increases the amount of Vesl-1S protein but not that of Vesl-1L, -2, or -3 protein. Deletion analyses revealed that the C-terminal 11-amino acid region is responsible for the proteolysis of Vesl-1S by proteasomes. Application of proteasome inhibitors promotes ubiquitination of Vesl-1S protein but not that of the Vesl-1S deletion mutant, which evades proteasome-mediated degradation. These results indicate that ubiquitin-proteasome systems are involved in the regulation of the expression level of Vesl-1S protein (Ageta, 2001).
Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Deletion of Homer1 or Homer2 in mice causes the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reverses the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine (Szumlinski, 2004).
The effect of deleting other genes on cocaine-induced behaviors has been examined. Deleting RGS9-2 or 5HT1B produces augmented behavioral responses to cocaine that are akin to those elicited by Homer1 or Homer2 deletion, while ß-arrestin and DARP-32 deletions are without effect and mGluR5 deletion results in mice that are apparently insensitive to the behavioral effects of cocaine. The sensitization that is associated with the reduced capacity of mGluR1/5 stimulation to induce extracellular glutamate in Homer2 KO mice would seem to contradict the lack of cocaine responsiveness produced by mGluR5 deletion. However, the increase in extracellular glutamate by DHPG is mediated by mGluR1, not mGluR5. In contrast with Homer, RGS9-2 is elevated by repeated cocaine administration and is postulated to serve a compensatory rather than facilitatory role in regulating cocaine behaviors. Deletion of Homer2 elicits effects that appear to be selective for cocaine behaviors and apparently do not impact natural reward, aggression, anxiety, or learning and memory, while 5HT1B KO mice show elevated levels of aggression. The detailed neurochemical adaptations that are describe in the Homer2 KO mice have not been reported in these other genetic models, but the convergence of Homer2 focuses attention on G protein signaling. A role for altered G protein signaling is further implicated by the similar elevation in AGS3 produced by Homer2 deletion and withdrawal from repeated cocaine administration and that inactivation of Gialpha by elevated AGS3 sensitizes cocaine-induced behaviors and increases in extracellular glutamate in the accumbens (Szumlinski, 2004 and references therein).
While it can be anticipated that additional genetic models may be discovered that mimic or block behaviors associated with cocaine addiction, the striking concordant neurochemical phenotype between Homer2 deletion and withdrawal from chronic cocaine treatment indicates that Homer is a particularly good candidate to play a central role in cocaine addiction. Moreover, Homer gene products are regulated by acute and repeated cocaine administration, and Homer1a is dynamically responsive to environmental cues and stress. Thus, not only does Homer provide an important window to understand cocaine-induced neuroplasticity and addiction, but also to study the molecular basis of the important link between environmental stress and cocaine addiction (Szumlinski, 2004 and references therein).
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