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EIF3A (eukaryotic translation initiation factor 3, subunit A)

Written2010-11Ji-Ye Yin, Zizheng Dong, Jian-Ting Zhang
Department of Pharmacology, Toxicology, IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesEIF3
EIF3S10
eukaryotic translation initiation factor 3, subunit 10 theta, 150/170kDa
eukaryotic translation initiation factor 3, subunit A
Alias_symbol (synonym)eIF3-theta
eIF3-p170
KIAA0139
eIF3a
TIF32
Other aliasP167
p180
p185
HGNC (Hugo) EIF3A
LocusID (NCBI) 8661
Atlas_Id 40425
Location 10q26.11  [Link to chromosome band 10q26]
Location_base_pair Starts at 119035029 and ends at 119080822 bp from pter ( according to hg19-Feb_2009)  [Mapping EIF3A.png]
Fusion genes
(updated 2016)
ATP2C2 (16q24.1) / EIF3A (10q26.11)CACUL1 (10q26.11) / EIF3A (10q26.11)EIF3A (10q26.11) / CSF1R (5q32)
EIF3A (10q26.11) / LRRFIP1 (2q37.3)EIF3A (10q26.11) / PRDX3 (10q26.11)EIF3A (10q26.11) / SFXN4 (10q26.11)
EIF3A (10q26.11) / SLCO1B1 (12p12.2)EIF3A (10q26.11) / SMARCC1 (3p21.31)OOEP (6q13) / EIF3A (10q26.11)
PSMD6 (3p14.1) / EIF3A (10q26.11)STAG2 (Xq25) / EIF3A (10q26.11)

DNA/RNA

Description The eIF3a gene spans over a region of 46 kbp DNA including 22 coding exons and 2 non-coding exons (exon 2 and exon 10).
Transcription The eIF3a mRNA consists of about 5256 nucleotides with an open reading frame (ORF) of 4149 bases.
Pseudogene No pseudogene has been identified.

Protein

 
  Schematic presentation of eIF3a domain structure. Human eIF3a consists of 1382 amino acid residues with three putative domains of PCI, spectrin, and 10-amino acid repeat.
Description Structure: The eIF3a protein consists of 1382 amino acid residues with an apparent molecular weight of ~170 kDa as determined using SDS-PAGE (Pincheira et al., 2001b). Its primary sequence contains a PCI (Proteasome, COP9, Initiation factor 3) domain, a spectrin domain, and a 10-amino acid repeat domain (Pincheira et al., 2001b). It has phosphorylation sites at Ser-881, Ser-1198, Ser-1336 and Ser-1364 (Damoc et al., 2007). The PCI domain spans from amino acid 405 to 495, which contains purely alpha-helix (Pincheira et al., 2001b). Since most of the proteins containing this domain are part of a multi-protein complex, it is tempting to speculate that this domain may be involved in the interaction of eIF3a with other molecules in eIF3 (Hofmann and Bucher, 1998). The spectrin domain, which consists of 112 amino acids, is a sequence almost identical to spectrin, an actin-binding protein (Pascual et al., 1997). Although the exact function of this domain remains unknown, it may be responsible for the binding of eIF3a to actin filaments (Pincheira et al., 2001a). The 10-amino acid repeat domain spanning 925-1172 amino acids is the largest domain of eIF3a. It can be divided into about 25 repeats of DDDRGPRRGA (Johnson et al., 1997; Pincheira et al., 2001b). This domain has been suggested to contribute to interaction of eIF4B and eIF3a (Methot et al., 1996).
Regulatory role in gene expression: eIF3a not only functions as a regular translation initiation factor and participates in translation initiation of global mRNAs, it also regulates the translation of a subset of mRNAs which are involved in cell cycle, tumorigenesis and DNA repair (Yin et al., 2010). It has been observed that overexpression of ectopic eIF3a increases the expression of ribonucleotide reductase M2 (RRM2) and alpha-tubulin, but decreases that of p27kip without affect their mRNA levels (Dong and Zhang, 2003; Dong et al., 2004). Recently, it has also been found that eIF3a suppresses the synthesis of DNA repair proteins including: XPA, XPC, RPA 14, RPA 32 and RPA 70 KDa (Yin et al., unpublished data). Although the detailed mechanism of eIF3a regulation in translational control is yet to be determined, it is thought that eIF3a may regulate these genes at their 5'- and 3'-UTRs (Dong and Zhang, 2003; Dong et al., 2004).
Binding with other molecule: Since eIF3a is the largest subunit of the eIF3 complex, the interaction between eIF3a and other subunits of eIF3 were intensively studied. It can bind with eIF3b (Methot et al., 1997), eIF3c (Valasek et al., 2002), eIF3f (Asano et al., 1997), eIF3h (Asano et al., 1997), eIF3j (Valasek et al., 1999) and eIF3k (Mayeur et al., 2003). During the translation initiation, the amino terminal domain of eIF3a can bind with 40S protein RPS0A, while the C terminal domain binds with the 18S rRNA (Valasek et al., 2003). Apart from above molecule, eIF3a has also been shown to interact with eIF4B (Methot et al., 1996), actin (Pincheira et al., 2001a), and cytokeratin 7 (Lin et al., 2001).
Expression eIF3a is ubiquitously expressed in all human tissues (Nagase et al., 1995; Scholler and Kanner, 1997; Pincheira et al., 2001b). However, its expression is higher in proliferating tissues such as bone marrow, thymus and fetal tissues (Pincheira et al., 2001b).
Localisation eIF3a has been found in both cytoplasmic and membrane fractions and the cytoplasmic eIF3a appears to be phosphorylated at its serine residues (Pincheira et al., 2001a). However, 70-80% of eIF3a is cytoplasmic.
Function eIF3a has been shown to play important roles in the biological processes: translational initiation (including generation of ribosomal subunit from 80S ribosomes, 43S pre-initiation complex formation and 48S pre-initiation complex formation) (Dong and Zhang, 2006), regulation of mRNA translation (Dong and Zhang, 2003; Dong et al., 2004), differentiation and development (Liu et al., 2007), apoptosis (Nakai et al., 2005), cell cycle regulation (Dong et al., 2009), oncogenesis (Dong and Zhang, 2006; Zhang et al., 2007), and drug response (unpublished observations).
Homology Centrosomin A and B have strong homology to eIF3a. The spectrin domain is essentially identical to spectrin.

Mutations

Note Two SNPs (rs10787899 and rs3824830) were found to be associated with higher risk of breast cancers (Olson et al., 2009).

Implicated in

Note
  
Entity Breast cancer
Note eIF3a was overexpressed in breast cancer tissues.
Oncogenesis The eIF3a was highly expressed in all tested tissues from breast cancer patients compared with normal control tissues, which indicated that it may contribute to the oncogenesis of breast cancer (Bachmann et al., 1997).
  
  
Entity Cervical carcinoma
Note eIF3a was found to be a molecular parameter of predicting cervical carcinoma progression and prognoses.
Prognosis Patients with high eIF3a expression have better prognosis than those with lower ones, thus it will be useful in predicting cervical cancer prognosis (Dellas et al., 1998).
  
  
Entity Gastric carcinoma
Note eIF3a is an early tumor maker of gastric carcinoma.
Oncogenesis eIF3a was highly expressed in well differentiated, early invasive stage and no-metastases gastric carcinoma (Chen and Burger, 2004).
  
  
Entity Lung cancer
Note eIF3a is highly expressed in lung cancer compared with normal tissues.
Prognosis eIF3a expression in human lung cancers negatively correlates with patient response to platinum-based chemotherapy, suggesting that lung cancer patients with higher eIF3a expression level respond better to platinum-based chemotherapy (Yin et al., unpublished findings).
Oncogenesis eIF3a was over-expressed in all types of human lung cancer. Furthermore, it is ubiquitously highly expressed in proliferating and developing tissues. This suggested eIF3a may be involved in oncogenesis of lung cancer (Pincheira et al., 2001b).
  
  
Entity Esophagus squamous-cell carcinoma
Note eIF3a may be a biomaker of esophagus squamous-cell carcinoma.
Prognosis Patients with higher eIF3a expression have better overall survival and fewer tumor metastases than those with lower ones (Chen and Burger, 1999).
  

Bibliography

Structure of cDNAs encoding human eukaryotic initiation factor 3 subunits. Possible roles in RNA binding and macromolecular assembly.
Asano K, Vornlocher HP, Richter-Cook NJ, Merrick WC, Hinnebusch AG, Hershey JW.
J Biol Chem. 1997 Oct 24;272(43):27042-52.
PMID 9341143
 
Cloning of a novel protein overexpressed in human mammary carcinoma.
Bachmann F, Banziger R, Burger MM.
Cancer Res. 1997 Mar 1;57(5):988-94.
PMID 9041205
 
p150 overexpression in gastric carcinoma: the association with p53, apoptosis and cell proliferation.
Chen G, Burger MM.
Int J Cancer. 2004 Nov 10;112(3):393-8.
PMID 15382063
 
Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry.
Damoc E, Fraser CS, Zhou M, Videler H, Mayeur GL, Hershey JW, Doudna JA, Robinson CV, Leary JA.
Mol Cell Proteomics. 2007 Jul;6(7):1135-46. Epub 2007 Feb 23.
PMID 17322308
 
Expression of p150 in cervical neoplasia and its potential value in predicting survival.
Dellas A, Torhorst J, Bachmann F, Banziger R, Schultheiss E, Burger MM.
Cancer. 1998 Oct 1;83(7):1376-83.
PMID 9762939
 
Role of eIF3a in regulating cell cycle progression.
Dong Z, Liu Z, Cui P, Pincheira R, Yang Y, Liu J, Zhang JT.
Exp Cell Res. 2009 Jul 1;315(11):1889-94. Epub 2009 Mar 24.
PMID 19327350
 
Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer.
Dong Z, Zhang JT.
Crit Rev Oncol Hematol. 2006 Sep;59(3):169-80. Epub 2006 Jul 7. (REVIEW)
PMID 16829125
 
The PCI domain: a common theme in three multiprotein complexes.
Hofmann K, Bucher P.
Trends Biochem Sci. 1998 Jun;23(6):204-5. (REVIEW)
PMID 9644972
 
Identification of cDNA clones for the large subunit of eukaryotic translation initiation factor 3. Comparison of homologues from human, Nicotiana tabacum, Caenorhabditis elegans, and Saccharomyces cerevisiae.
Johnson KR, Merrick WC, Zoll WL, Zhu Y.
J Biol Chem. 1997 Mar 14;272(11):7106-13.
PMID 9054404
 
Molecular interaction between human tumor marker protein p150, the largest subunit of eIF3, and intermediate filament protein K7.
Lin L, Holbro T, Alonso G, Gerosa D, Burger MM.
J Cell Biochem. 2001;80(4):483-90.
PMID 11169732
 
Role of eIF3a (eIF3 p170) in intestinal cell differentiation and its association with early development.
Liu Z, Dong Z, Yang Z, Chen Q, Pan Y, Yang Y, Cui P, Zhang X, Zhang JT.
Differentiation. 2007 Sep;75(7):652-61. Epub 2007 Mar 23.
PMID 17381544
 
Characterization of eIF3k: a newly discovered subunit of mammalian translation initiation factor elF3.
Mayeur GL, Fraser CS, Peiretti F, Block KL, Hershey JW.
Eur J Biochem. 2003 Oct;270(20):4133-9.
PMID 14519125
 
The human homologue of the yeast Prt1 protein is an integral part of the eukaryotic initiation factor 3 complex and interacts with p170.
Methot N, Rom E, Olsen H, Sonenberg N.
J Biol Chem. 1997 Jan 10;272(2):1110-6.
PMID 8995410
 
A region rich in aspartic acid, arginine, tyrosine, and glycine (DRYG) mediates eukaryotic initiation factor 4B (eIF4B) self-association and interaction with eIF3.
Methot N, Song MS, Sonenberg N.
Mol Cell Biol. 1996 Oct;16(10):5328-34.
PMID 8816444
 
Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1.
Nagase T, Seki N, Tanaka A, Ishikawa K, Nomura N.
DNA Res. 1995 Aug 31;2(4):167-74, 199-210.
PMID 8590280
 
Externalization and recognition by macrophages of large subunit of eukaryotic translation initiation factor 3 in apoptotic cells.
Nakai Y, Shiratsuchi A, Manaka J, Nakayama H, Takio K, Zhang JT, Suganuma T, Nakanishi Y.
Exp Cell Res. 2005 Sep 10;309(1):137-48.
PMID 15979069
 
Variation in genes required for normal mitosis and risk of breast cancer.
Olson JE, Wang X, Goode EL, Pankratz VS, Fredericksen ZS, Vierkant RA, Pharoah PD, Cerhan JR, Couch FJ.
Breast Cancer Res Treat. 2010 Jan;119(2):423-30. Epub 2009 Apr 18.
PMID 19377877
 
Evolution of the spectrin repeat.
Pascual J, Castresana J, Saraste M.
Bioessays. 1997 Sep;19(9):811-7. (REVIEW)
PMID 9297972
 
Identification of a 170-kDa protein over-expressed in lung cancers.
Pincheira R, Chen Q, Zhang JT.
Br J Cancer. 2001b Jun 1;84(11):1520-7.
PMID 11384103
 
The human p167 gene encodes a unique structural protein that contains centrosomin A homology and associates with a multicomponent complex.
Scholler JK, Kanner SB.
DNA Cell Biol. 1997 Apr;16(4):515-31.
PMID 9150439
 
The Saccharomyces cerevisiae HCR1 gene encoding a homologue of the p35 subunit of human translation initiation factor 3 (eIF3) is a high copy suppressor of a temperature-sensitive mutation in the Rpg1p subunit of yeast eIF3.
Valasek L, Hasek J, Trachsel H, Imre EM, Ruis H.
J Biol Chem. 1999 Sep 24;274(39):27567-72.
PMID 10488093
 
The yeast eIF3 subunits TIF32/a, NIP1/c, and eIF5 make critical connections with the 40S ribosome in vivo.
Valasek L, Mathew AA, Shin BS, Nielsen KH, Szamecz B, Hinnebusch AG.
Genes Dev. 2003 Mar 15;17(6):786-99.
PMID 12651896
 
Direct eIF2-eIF3 contact in the multifactor complex is important for translation initiation in vivo.
Valasek L, Nielsen KH, Hinnebusch AG.
EMBO J. 2002 Nov 1;21(21):5886-98.
PMID 12411506
 
Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments.
Yin JY, Dong Z, Liu ZQ, Zhang JT.
Biosci Rep. 2010 Oct;31(1):1-15.
PMID 20964625
 
Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells.
Zhang L, Pan X, Hershey JW.
J Biol Chem. 2007 Feb 23;282(8):5790-800. Epub 2006 Dec 14.
PMID 17170115
 

Citation

This paper should be referenced as such :
Yin, JY ; Dong, Z ; Zhang, JT
EIF3A (eukaryotic translation initiation factor 3, subunit A)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(7):544-546.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/EIF3AID40425ch10q26.html


External links

Nomenclature
HGNC (Hugo)EIF3A   3271
Cards
AtlasEIF3AID40425ch10q26
Entrez_Gene (NCBI)EIF3A  8661  eukaryotic translation initiation factor 3 subunit A
AliasesEIF3; EIF3S10; P167; TIF32; 
eIF3-p170; eIF3-theta; p180; p185
GeneCards (Weizmann)EIF3A
Ensembl hg19 (Hinxton)ENSG00000107581 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000107581 [Gene_View]  chr10:119035029-119080822 [Contig_View]  EIF3A [Vega]
ICGC DataPortalENSG00000107581
TCGA cBioPortalEIF3A
AceView (NCBI)EIF3A
Genatlas (Paris)EIF3A
WikiGenes8661
SOURCE (Princeton)EIF3A
Genetics Home Reference (NIH)EIF3A
Genomic and cartography
GoldenPath hg38 (UCSC)EIF3A  -     chr10:119035029-119080822 -  10q26.11   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EIF3A  -     10q26.11   [Description]    (hg19-Feb_2009)
EnsemblEIF3A - 10q26.11 [CytoView hg19]  EIF3A - 10q26.11 [CytoView hg38]
Mapping of homologs : NCBIEIF3A [Mapview hg19]  EIF3A [Mapview hg38]
OMIM602039   
Gene and transcription
Genbank (Entrez)AJ227915 AK302575 AK307610 AK309542 AU279600
RefSeq transcript (Entrez)NM_003750
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)EIF3A
Cluster EST : UnigeneHs.713331 [ NCBI ]
CGAP (NCI)Hs.713331
Alternative Splicing GalleryENSG00000107581
Gene ExpressionEIF3A [ NCBI-GEO ]   EIF3A [ EBI - ARRAY_EXPRESS ]   EIF3A [ SEEK ]   EIF3A [ MEM ]
Gene Expression Viewer (FireBrowse)EIF3A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8661
GTEX Portal (Tissue expression)EIF3A
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14152   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14152  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14152
Splice isoforms : SwissVarQ14152
PhosPhoSitePlusQ14152
Domains : Interpro (EBI)EIF3A    PCI_dom    WHTH_DNA-bd_dom   
Domain families : Pfam (Sanger)PCI (PF01399)   
Domain families : Pfam (NCBI)pfam01399   
Domain families : Smart (EMBL)PINT (SM00088)  
Conserved Domain (NCBI)EIF3A
DMDM Disease mutations8661
Blocks (Seattle)EIF3A
PDB (SRS)3J8B    3J8C   
PDB (PDBSum)3J8B    3J8C   
PDB (IMB)3J8B    3J8C   
PDB (RSDB)3J8B    3J8C   
Structural Biology KnowledgeBase3J8B    3J8C   
SCOP (Structural Classification of Proteins)3J8B    3J8C   
CATH (Classification of proteins structures)3J8B    3J8C   
SuperfamilyQ14152
Human Protein AtlasENSG00000107581
Peptide AtlasQ14152
HPRD03618
IPIIPI00029012   IPI01014951   
Protein Interaction databases
DIP (DOE-UCLA)Q14152
IntAct (EBI)Q14152
FunCoupENSG00000107581
BioGRIDEIF3A
STRING (EMBL)EIF3A
ZODIACEIF3A
Ontologies - Pathways
QuickGOQ14152
Ontology : AmiGOformation of cytoplasmic translation initiation complex  translation reinitiation  RNA binding  mRNA binding  translation initiation factor activity  translation initiation factor activity  structural molecule activity  protein binding  nucleus  nucleolus  cytoplasm  cytosol  cytosol  eukaryotic translation initiation factor 3 complex  microtubule  translational initiation  translational initiation  membrane  receptor tyrosine kinase binding  multi-eIF complex  negative regulation of ERK1 and ERK2 cascade  eukaryotic translation initiation factor 3 complex, eIF3e  eukaryotic translation initiation factor 3 complex, eIF3m  IRES-dependent viral translational initiation  viral translational termination-reinitiation  
Ontology : EGO-EBIformation of cytoplasmic translation initiation complex  translation reinitiation  RNA binding  mRNA binding  translation initiation factor activity  translation initiation factor activity  structural molecule activity  protein binding  nucleus  nucleolus  cytoplasm  cytosol  cytosol  eukaryotic translation initiation factor 3 complex  microtubule  translational initiation  translational initiation  membrane  receptor tyrosine kinase binding  multi-eIF complex  negative regulation of ERK1 and ERK2 cascade  eukaryotic translation initiation factor 3 complex, eIF3e  eukaryotic translation initiation factor 3 complex, eIF3m  IRES-dependent viral translational initiation  viral translational termination-reinitiation  
Pathways : BIOCARTAInternal Ribosome entry pathway [Genes]    Eukaryotic protein translation [Genes]    mTOR Signaling Pathway [Genes]   
Pathways : KEGGRNA transport   
NDEx NetworkEIF3A
Atlas of Cancer Signalling NetworkEIF3A
Wikipedia pathwaysEIF3A
Orthology - Evolution
OrthoDB8661
GeneTree (enSembl)ENSG00000107581
Phylogenetic Trees/Animal Genes : TreeFamEIF3A
HOVERGENQ14152
HOGENOMQ14152
Homologs : HomoloGeneEIF3A
Homology/Alignments : Family Browser (UCSC)EIF3A
Gene fusions - Rearrangements
Fusion : MitelmanCACUL1/EIF3A [10q26.11/10q26.11]  [t(10;10)(q26;q26)]  
Fusion : MitelmanEIF3A/SFXN4 [10q26.11/10q26.11]  [t(10;10)(q26;q26)]  
Fusion: TCGAC10orf46 EIF3A 10q26.11 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerEIF3A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EIF3A
dbVarEIF3A
ClinVarEIF3A
1000_GenomesEIF3A 
Exome Variant ServerEIF3A
ExAC (Exome Aggregation Consortium)EIF3A (select the gene name)
Genetic variants : HAPMAP8661
Genomic Variants (DGV)EIF3A [DGVbeta]
DECIPHEREIF3A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisEIF3A 
Mutations
ICGC Data PortalEIF3A 
TCGA Data PortalEIF3A 
Broad Tumor PortalEIF3A
OASIS PortalEIF3A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICEIF3A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDEIF3A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch EIF3A
DgiDB (Drug Gene Interaction Database)EIF3A
DoCM (Curated mutations)EIF3A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)EIF3A (select a term)
intoGenEIF3A
NCG5 (London)EIF3A
Cancer3DEIF3A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602039   
Orphanet
MedgenEIF3A
Genetic Testing Registry EIF3A
NextProtQ14152 [Medical]
TSGene8661
GENETestsEIF3A
Target ValidationEIF3A
Huge Navigator EIF3A [HugePedia]
snp3D : Map Gene to Disease8661
BioCentury BCIQEIF3A
ClinGenEIF3A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8661
Chemical/Pharm GKB GenePA27699
Clinical trialEIF3A
Miscellaneous
canSAR (ICR)EIF3A (select the gene name)
Probes
Litterature
PubMed127 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineEIF3A
EVEXEIF3A
GoPubMedEIF3A
iHOPEIF3A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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