Affinage

WTIP

Wilms tumor protein 1-interacting protein · UniProt A6NIX2

Length
430 aa
Mass
45.1 kDa
Annotated
2026-06-11
22 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WTIP is a LIM-domain scaffold protein that operates at cell junctions, the basal body, and the nucleus to couple cytoskeletal architecture and mechanical tension to signaling and transcriptional control (PMID:21900451, PMID:23213452). At adherens junctions and focal adhesions it organizes the actin cytoskeleton, driving RhoA-dependent stress fiber formation and adherens junction assembly through direct binding to the RhoA-specific GEF ARHGEF12, an interaction mapped to its LIM and PDZ-binding domains (PMID:21900451, PMID:35862649). Through this junctional platform WTIP integrates Hippo signaling: phospho-nephrin recruits Nck to sequester WTIP together with LATS1, restraining LATS1 activation, and WTIP can compete with LIMD1 for junctional LATS1 recruitment to modulate YAP phosphorylation and nuclear localization (PMID:27033705, PMID:36439396). WTIP also localizes to basal bodies, where it is required for ciliogenesis, mitotic spindle orientation, and planar cell polarity in cooperation with Vangl2 and Prickle3, and it controls actomyosin-driven apical constriction during neural tube closure via the C-terminal LIM domain binding Shroom3, with junctional distribution itself being myosin II tension-sensitive (PMID:23213452, PMID:27062996, PMID:29661847). In the cytoplasm WTIP bridges the eIF4E-bound 5' cap to Ago1/2 within miRISC at P-bodies to facilitate miRNA-mediated silencing (PMID:20616046), and upon podocyte injury it undergoes JNK/dynein/microtubule-dependent nuclear translocation, where it intersects WT1-linked transcriptional programs (PMID:20086015). WTIP additionally functions in cancer contexts, inducing apoptosis in AML through direct FOXO3a interaction and PUMA induction, and suppressing AKT activity via PP2A in gastric cancer (PMID:34930905, PMID:40279682). A disease-causing WTIP variant (p.Y233F) is linked to calcium dysregulation and cardiomyocyte hypertrophy (PMID:35671065).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2009 Medium

    Established WTIP as a signaling effector by showing it binds the Ror2 receptor tyrosine kinase intracellular domain and inhibits canonical Wnt signaling, placing it in a receptor-coupled pathway.

    Evidence Co-IP, membrane localization, Wnt/β-catenin reporter in mammalian cells and Xenopus

    PMID:19785987

    Open questions at the time
    • Domain of WTIP mediating Ror2 binding not mapped
    • Mechanism by which WTIP represses β-catenin output unresolved
  2. 2010 High

    Defined a cytoplasmic post-transcriptional role: WTIP links the translationally repressed eIF4E-capped mRNA to Ago1/2-miRISC at P-bodies, answering how miRISC is coupled to the cap for silencing.

    Evidence Co-IP, m7GTP cap-binding assay, P-body imaging, knockdown silencing assays

    PMID:20616046

    Open questions at the time
    • Specificity for miRNA over siRNA silencing mechanism not fully explained
    • Stoichiometry within the closed-loop complex unknown
  3. 2010 High

    Showed how WTIP relocates from junctions to the nucleus upon injury, identifying a JNK/JIP3-dynein/microtubule-dependent transport mechanism.

    Evidence Live imaging, fractionation, JNK/dynein/microtubule inhibition, Co-IP of JIP3-dynein, shRNA

    PMID:20086015

    Open questions at the time
    • Nuclear transcriptional targets of WTIP not directly identified here
    • Cargo adaptor coupling WTIP to dynein not pinpointed
  4. 2011 High

    Connected WTIP to cytoskeletal control by demonstrating it directs RhoA-dependent actin/adhesion dynamics through direct ARHGEF12 binding.

    Evidence shRNA, overexpression, C3/ROCK inhibition rescue, Co-IP, surface biotinylation in podocytes

    PMID:21900451

    Open questions at the time
    • Whether WTIP activates or localizes ARHGEF12 not resolved
    • Link between RhoA control and other WTIP pathways unclear
  5. 2012 High

    Revealed a basal-body/ciliary function: WTIP is required for ciliogenesis, spindle orientation, and PCP, with genetic interaction with the core PCP gene vangl2.

    Evidence Morpholino knockdown, immunolocalization, spindle/cilia assays, vangl2 epistasis in zebrafish

    PMID:23213452

    Open questions at the time
    • Molecular role of WTIP at the basal body not biochemically defined
    • Direct PCP partners not identified in this study
  6. 2014 Medium

    Extended WTIP's transcriptional repressor role by showing it binds ASXL2 and blocks retinoic acid-dependent transcription.

    Evidence Yeast two-hybrid, Co-IP, luciferase reporter in HeLa

    PMID:25065743

    Open questions at the time
    • Mechanism of repression of ASXL2 activity unknown
    • Physiological context not established
  7. 2015 Medium

    Linked WTIP to chromatin-associated regulation in vivo via ASXL1, with Asxl1 loss causing podocyte defects and dysregulation of Wt1/Wtip target genes.

    Evidence Co-IP, Asxl1 knockout mouse, target gene expression

    PMID:26385183

    Open questions at the time
    • Direct functional contribution of WTIP to ASXL1 activity not isolated
    • Target gene set not mechanistically defined
  8. 2016 High

    Defined a junction-to-Hippo mechanism: phospho-nephrin/Nck sequesters WTIP and LATS1 to restrain LATS1 activation, linking slit diaphragm integrity to YAP regulation.

    Evidence Mutational dissection of Nck/nephrin, Co-IP, mouse podocyte injury with phospho-LATS1/YAP readouts

    PMID:27033705

    Open questions at the time
    • How WTIP physically engages LATS1 not structurally resolved
    • Generality beyond podocytes not addressed
  9. 2016 Medium

    Showed WTIP cooperates with the PCP protein Prickle3 to organize the basal body and support ciliogenesis.

    Evidence Co-IP, morpholino knockdown, basal body marker imaging in Xenopus

    PMID:27062996

    Open questions at the time
    • Single-lab Xenopus model
    • Domain of WTIP binding Prickle3 not mapped
  10. 2016 Medium

    Linked WTIP to mitotic fidelity by showing it is required for BRCA2 centrosome localization.

    Evidence Yeast two-hybrid, Co-IP, GST pull-down, shRNA, immunofluorescence in HeLa S3

    PMID:27535760

    Open questions at the time
    • Functional consequence beyond abnormal division not detailed
    • Relationship to basal body role unclear
  11. 2016 Medium

    Connected WTIP basal-body function to organ patterning by showing it acts with WT1 in proepicardial specification and cardiac laterality in zebrafish.

    Evidence Morpholino knockdown, mRNA overexpression, immunolocalization, PE markers in zebrafish

    PMID:27484451

    Open questions at the time
    • Direct biochemical WTIP-WT1 interaction not shown here
    • Single model organism
  12. 2018 High

    Demonstrated WTIP couples mechanical tension to morphogenesis: its LIM domain binds Shroom3 to regulate actomyosin-driven apical constriction during neural tube closure, with tension-sensitive junctional localization.

    Evidence Morpholino depletion, live imaging, Co-IP, blebbistatin perturbation in Xenopus

    PMID:29661847

    Open questions at the time
    • Whether WTIP positively or negatively tunes Shroom3 in vivo not fully resolved
    • Mechanosensing mechanism not biochemically defined
  13. 2018 Medium

    Identified a UBA2-WTIP fusion in AML that disrupts WTIP P-body function and drives proliferative signaling, implicating WTIP loss-of-function in leukemogenesis.

    Evidence RT-PCR, sequencing, ectopic expression, proliferation and phospho-signaling assays, P-body assay in KG-1a

    PMID:30179602

    Open questions at the time
    • Whether the fusion is driver or passenger not established
    • Mechanism of STAT/ERK activation unclear
  14. 2021 Medium

    Established a pro-apoptotic tumor-suppressor role: WTIP directly binds and transcriptionally activates FOXO3a to induce PUMA and intrinsic apoptosis in AML.

    Evidence Overexpression/knockdown, Co-IP, luciferase reporter, in vitro and in vivo apoptosis assays

    PMID:34930905

    Open questions at the time
    • How WTIP enhances FOXO3a transcription mechanistically unknown
    • Single-lab evidence
  15. 2021 Medium

    Showed WTIP N-terminus associates with the centriolar satellite protein SSX2IP, with functional interaction during neural tube closure, expanding its centrosome/basal body interactome.

    Evidence Targeted proximity biotinylation, Co-IP, colocalization, double morpholino depletion in Xenopus

    PMID:34710136

    Open questions at the time
    • Functional output of the WTIP-SSX2IP complex not defined
    • Aggregate formation physiological relevance unclear
  16. 2022 Medium

    Resolved the WTIP-ARHGEF12 interaction to LIM/PDZ-binding domains and established WTIP as essential in vivo via embryonic-lethal gene-trap homozygotes.

    Evidence Co-IP, domain mapping, Wtip gene trap mouse

    PMID:35862649

    Open questions at the time
    • Cause of embryonic lethality not pinpointed
    • Direct effect on Rho effector activity not measured
  17. 2022 Medium

    Showed WTIP competes with LIMD1 for junctional LATS1 recruitment, with overexpression increasing YAP1 phosphorylation, suggesting a Hippo-modulating tumor-suppressor mechanism.

    Evidence Overexpression in MCF10A, junctional localization and YAP1 phosphorylation/nuclear assays

    PMID:36439396

    Open questions at the time
    • Single overexpression approach
    • Endogenous competition dynamics not measured
  18. 2022 Medium

    Linked WTIP to cardiac disease by showing knockdown causes cardiomyocyte hypertrophy and a p.Y233F variant disrupts Wnt-protein binding and causes calcium dysregulation reversible by verapamil.

    Evidence shRNA in rat cardiomyocytes, zebrafish morpholino, iPSC-cardiomyocytes, calcium imaging, verapamil rescue

    PMID:35671065

    Open questions at the time
    • Identity of the Wnt protein partner not specified
    • Mechanism connecting variant to calcium handling unresolved
  19. 2025 Medium

    Defined a kinase-suppressing role: WTIP binds PP2A to inhibit AKT T308 phosphorylation and reduce stemness/chemoresistance in gastric cancer, regulated upstream by a TET2-PATZ1 axis.

    Evidence Co-IP, AKT kinase activity assay, TET2/PATZ1 transcriptional assays, shRNA functional assays

    PMID:40279682

    Open questions at the time
    • Whether WTIP recruits PP2A directly to AKT not shown
    • Single-lab evidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WTIP's distinct activities — junctional RhoA/Hippo scaffolding, basal-body/PCP function, cytoplasmic miRISC bridging, and nuclear transcriptional regulation — are coordinated within one protein, and how its domains partition among these roles, remains unresolved.
  • No structural model integrating LIM and PDZ-binding domain functions
  • Mechanism switching WTIP between junctional, ciliary, and nuclear pools not defined
  • Tissue-specific partner selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005815 microtubule organizing center 4 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-8953854 Metabolism of RNA 1
Complex memberships
P-bodymiRISC

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 WTIP (along with LIMD1 and Ajuba) localizes to processing bodies (P-bodies) and binds Ago1/2, RCK, Dcp2, and eIF4E in vivo, acting as a molecular link between the translationally inhibited eIF4E-m7GTP-5' cap and Ago1/2 within the miRISC complex to facilitate miRNA-mediated (but not siRNA-mediated) gene silencing via an inhibitory closed-loop complex. Co-immunoprecipitation, m7GTP cap-binding assay, P-body localization imaging, knockdown functional assays Proceedings of the National Academy of Sciences of the United States of America High 20616046
2010 Upon LPS-induced podocyte injury, WTIP translocates from cell contacts to the nucleus via a mechanism requiring JNK activity, assembly of a JNK-interacting protein 3/dynein scaffolding complex, intact microtubule networks, and dynein motor activity. Loss of WTIP from cell contacts alters podocyte morphology and actin assembly. Live imaging, cellular fractionation, pharmacological inhibition of JNK/dynein/microtubules, shRNA knockdown, co-immunoprecipitation of JIP3-dynein complex The Journal of biological chemistry High 20086015
2011 WTIP regulates podocyte actin dynamics and adherens junction assembly: it targets focal adhesions in isolated cells and shifts to adherens junctions upon cell-cell contact; knockdown disrupts actin stress fiber formation, focal adhesion maturation, and stable adherens junction assembly. WTIP overexpression induces RhoA-dependent stress fibers and directly interacts with the RhoA-specific GEF ARHGEF12. shRNA knockdown, overexpression, RhoA inhibition (C3 toxin, ROCK inhibitor), co-immunoprecipitation, cell surface biotinylation American journal of physiology. Renal physiology High 21900451
2009 WTIP physically interacts with the intracellular domain of the receptor tyrosine kinase Ror2; full-length Ror2 recruits WTIP to the cell membrane, while a disease-causing Ror2 mutant fails to do so. WTIP inhibits canonical Wnt signaling in mammalian cells and in Xenopus embryos. Co-immunoprecipitation, cell membrane localization assay, Wnt/β-catenin luciferase reporter assay, Xenopus overexpression Biochemical and biophysical research communications Medium 19785987
2012 In zebrafish, Wtip is enriched at the basal body; wtip knockdown causes pronephric cyst formation, mitotic spindle orientation defects (in anterior/middle pronephros), cloaca malformation with reduced ciliated cells, loss of striated rootlet from basal bodies, and impaired cilia motility. Genetic interaction with vangl2 (a core PCP protein) was demonstrated. Morpholino knockdown, immunolocalization, spindle orientation assay, cilia motility analysis, genetic epistasis (double knockdown) Biology open High 23213452
2016 Nephrin signaling suppresses Hippo pathway activity through WTIP: phosphorylated nephrin recruits Nck, which sequesters WTIP and its binding partner Lats1, resulting in decreased phospho-activation of Lats1. Upon nephrin dephosphorylation during podocyte injury, Lats1 is rapidly activated, preceding YAP downregulation. Mutational analysis of Nck/nephrin interaction, co-immunoprecipitation, mouse podocyte injury model with phospho-Lats1 and YAP quantification The Journal of biological chemistry High 27033705
2016 Wtip physically associates with Prickle3 and cooperates with it to regulate ciliogenesis; Wtip is required for basal body organization in Xenopus GRP cells, and co-depletion or interference phenotypes link Wtip to Prickle3-mediated cilia growth. Co-immunoprecipitation, morpholino knockdown in Xenopus, immunolocalization of basal body markers (γ-tubulin, Nedd1) Scientific reports Medium 27062996
2018 Wtip regulates actomyosin contractility and apical constriction during neural tube closure in Xenopus: depletion inhibits apical constriction in neuroepithelial cells and causes neural tube defects. The C-terminal LIM domain fragment of Wtip physically associates with Shroom3 and interferes with Shroom3-induced apical constriction. Wtip junctional distribution is reorganized by myosin II activity, indicating tension-sensitive localization. Morpholino depletion, fluorescent protein tagging/live imaging, co-immunoprecipitation, myosin II inhibition (blebbistatin) Journal of cell science High 29661847
2014 WTIP directly interacts with ASXL2 and represses ASXL2-mediated activation of retinoic acid-dependent transcription in HeLa cells, blocking ASXL2's stimulatory effect on retinoic acid signaling. Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay Biochemical and biophysical research communications Medium 25065743
2015 WTIP physically interacts with ASXL1; in Asxl1-null mouse kidneys, defects in podocyte morphology and upregulation of Wt1/Wtip target genes are observed, implicating Asxl1 in maintaining podocyte structure via its association with Wtip. Co-immunoprecipitation, Asxl1 knockout mouse analysis, target gene expression Biochemical and biophysical research communications Medium 26385183
2013 Dendrin physically interacts with WTIP (and Gadd45a) at the podocyte slit diaphragm, as demonstrated by yeast two-hybrid and co-immunoprecipitation. Dendrin relocalizes to the nucleus in adriamycin nephropathy, paralleling WTIP nuclear translocation behavior. Yeast two-hybrid, co-immunoprecipitation, dendrin knockout mouse, immunolocalization PloS one Medium 24376653
2016 WTIP interacts with BRCA2 (amino acids 2750–2864) and is required for BRCA2 centrosome localization; knockdown of WTIP abolishes BRCA2 centrosomal localization and causes abnormal cell division in HeLa S3 cells. Yeast two-hybrid, co-immunoprecipitation, GST pull-down, shRNA knockdown, immunofluorescence Archives of gynecology and obstetrics Medium 27535760
2018 A UBA2-WTIP fusion gene (containing UBA2 N-terminal domains fused to WTIP C-terminal LIM domains) was identified in AML; ectopic expression enhances cell proliferation, induces phosphorylation of STAT3, STAT5, and ERK1/2, and abrogates WTIP-mediated P-body formation. RT-PCR, Sanger sequencing, ectopic expression in KG-1a cells, proliferation assay, Western blot for phospho-signaling, P-body formation assay Experimental cell research Medium 30179602
2021 WTIP induces apoptosis in AML cells through transcriptional upregulation and nuclear translocation of FOXO3a; WTIP directly interacts with FOXO3a, activates FOXO3a transcriptionally, which increases PUMA expression and activates the intrinsic apoptotic pathway. Overexpression/knockdown, co-immunoprecipitation (WTIP-FOXO3a), luciferase reporter, in vitro and in vivo proliferation/apoptosis assays Cell death & disease Medium 34930905
2021 WTIP N-terminal domain physically associates with SSX2IP (a centriolar satellite protein/cell junction component); the two proteins form mixed aggregates when overexpressed, and double depletion of Wtip and SSX2IP in Xenopus embryos shows functional interaction during neural tube closure. Targeted proximity biotinylation (TPB), co-immunoprecipitation, colocalization imaging, double morpholino depletion PloS one Medium 34710136
2022 WTIP interacts with ARHGEF12 (a RhoA-specific GEF) through LIM and PDZ-binding domains with high affinity; this interaction is proposed to regulate slit diaphragm and foot process function through Rho effector proteins. Wtip gene trap homozygotes are embryonic lethal. Co-immunoprecipitation, domain mapping, Wtip gene trap mouse model American journal of physiology. Renal physiology Medium 35862649
2022 Overexpression of WTIP in MCF10A cells competes with LIMD1 for junctional localization, reduces junctional localization of LATS1, and is associated with increased YAP1 phosphorylation and decreased YAP1 nuclear localization, suggesting WTIP cannot efficiently recruit Lats kinases to junctions (unlike LIMD1) and may act as a tumor suppressor partly by competing with LIMD1. Overexpression in MCF10A cells, immunofluorescence quantification of junctional localization, YAP1 phosphorylation and nuclear localization assay microPublication biology Medium 36439396
2022 WTIP knockdown in neonatal rat ventricular myocytes causes cardiomyocyte hypertrophy; a disease-causing variant WTIP p.Y233F disrupts binding to a Wnt signaling protein, causes increased resting calcium and cellular hypertrophy in iPSC-derived cardiomyocytes (ameliorated by verapamil), linking WTIP to calcium dysregulation and cardiac hypertrophy. lentiviral shRNA knockdown in neonatal rat cardiomyocytes, morpholino knockdown in zebrafish, iPSC-derived cardiomyocyte characterization, calcium imaging, verapamil rescue Circulation. Genomic and precision medicine Medium 35671065
2025 WTIP interacts with PP2A to inhibit T308 phosphorylation and kinase activity of AKT, thereby suppressing stemness and chemoresistance in gastric cancer. TET2 and PATZ1 cooperate to transcriptionally activate WTIP expression, and this TET2-WTIP axis is frequently silenced in gastric cancer. Co-immunoprecipitation (WTIP-PP2A), AKT kinase activity assay, TET2/PATZ1 transcriptional activation assays, shRNA knockdown functional assays Neoplasia (New York, N.Y.) Medium 40279682
2016 In zebrafish, Wtip protein localizes to the basal body of proepicardial organ (PE) cells; Wtip signaling in conjunction with WT1 is essential for PE specification. Wtip knockdown disrupts cardiac looping, left-right asymmetry, and atrioventricular boundary formation. Morpholino knockdown in zebrafish, mRNA overexpression, immunolocalization, PE marker expression analysis Molecular medicine reports Medium 27484451

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for microRNA-mediated gene silencing. Proceedings of the National Academy of Sciences of the United States of America 53 20616046
2012 19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadias. European journal of human genetics : EJHG 43 22378287
2012 Wtip and Vangl2 are required for mitotic spindle orientation and cloaca morphogenesis. Biology open 32 23213452
2016 Prickle3 synergizes with Wtip to regulate basal body organization and cilia growth. Scientific reports 31 27062996
2010 Podocyte injury induces nuclear translocation of WTIP via microtubule-dependent transport. The Journal of biological chemistry 25 20086015
2011 WT1-interacting protein (Wtip) regulates podocyte phenotype by cell-cell and cell-matrix contact reorganization. American journal of physiology. Renal physiology 24 21900451
2016 Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP. The Journal of biological chemistry 23 27033705
2021 WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia. Cell death & disease 19 34930905
2018 The Ajuba family protein Wtip regulates actomyosin contractility during vertebrate neural tube closure. Journal of cell science 18 29661847
2009 The LIM domain protein Wtip interacts with the receptor tyrosine kinase Ror2 and inhibits canonical Wnt signalling. Biochemical and biophysical research communications 16 19785987
2021 Identification of the centrosomal maturation factor SSX2IP as a Wtip-binding partner by targeted proximity biotinylation. PloS one 12 34710136
2015 Role of Asxl1 in kidney podocyte development via its interaction with Wtip. Biochemical and biophysical research communications 11 26385183
2014 WTIP interacts with ASXL2 and blocks ASXL2-mediated activation of retinoic acid signaling. Biochemical and biophysical research communications 9 25065743
2011 Out on a LIM: chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP). Transactions of the American Clinical and Climatological Association 9 21686224
2013 Wtip- and gadd45a-interacting protein dendrin is not crucial for the development or maintenance of the glomerular filtration barrier. PloS one 8 24376653
2018 Identification of the UBA2-WTIP fusion gene in acute myeloid leukemia. Experimental cell research 5 30179602
2016 Wtip is required for proepicardial organ specification and cardiac left/right asymmetry in zebrafish. Molecular medicine reports 5 27484451
2022 Essential role of Wtip in mouse development and maintenance of the glomerular filtration barrier. American journal of physiology. Renal physiology 4 35862649
2016 WTIP interacts with BRCA2 and is essential for BRCA2 centrosome localization in cervical cancer cell. Archives of gynecology and obstetrics 4 27535760
2022 Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine 3 35671065
2022 AJUBA and WTIP can compete with LIMD1 for junctional localization and LATS regulation. microPublication biology 3 36439396
2025 DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer. Neoplasia (New York, N.Y.) 2 40279682

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