Affinage

ESRRG

Estrogen-related receptor gamma · UniProt P62508

Length
458 aa
Mass
51.3 kDa
Annotated
2026-06-09
28 papers in source corpus 18 papers cited in narrative 18 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

ESRRG (ERRγ) is an orphan nuclear receptor that acts as a constitutive transcriptional activator at ERR response elements, coordinating mitochondrial metabolic programs, developmental transitions, and tissue-specific gene expression across multiple organ systems (PMID:17761695, PMID:41265451). Its ligand-binding domain adopts an active conformation in the absence of a known endogenous ligand, and it serves as a high-affinity receptor for the endocrine disruptor bisphenol A (KD = 5.5 nM), which is anchored within the LBD by hydrogen bonds to Glu275, Arg316, and Asn346 and stabilizes the active helix-12 conformation (PMID:17761695). ERRγ exerts its effects largely by directly binding target gene promoters: it represses the glycolytic gene PKM2 to suppress the Warburg effect in carcinoma cells (PMID:37679788), represses PDE3B in airway epithelium (PMID:40153608), and activates KCNN1 in sensory neurons to control potassium currents and nociceptive excitability (PMID:38912580) and HSD11B2 in hippocampal neurons to maintain mitochondrial integrity (PMID:41197937). A recurrent theme across tissues is its control of mitochondrial homeostasis and oxidative capacity — in regulatory T cells, where loss disrupts respiration and ATP/NAD+ levels and provokes autoimmunity (PMID:34156979), in beige/brown adipocytes through the PGC1α network (PMID:32595605), and in trophoblasts (PMID:41623023). ERRγ is required for ureteric bud branching and renal papilla formation (PMID:21138943), for zygotic genome activation in 2-cell embryos downstream of TRPS1 (PMID:42248279), and is induced in the liver by IL-6 to drive FGF23 production during acute kidney injury (PMID:33853949). Its transcriptional activity is held in check by direct interaction with RB1 (PMID:35984874). De novo heterozygous ESRRG variants in the DNA- and ligand-binding domains alter transcriptional activity and dysregulate cell proliferation, implicating the receptor in a human developmental disorder (PMID:41265451).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 High

    Established the structural basis for ERRγ's constitutive activity and its capture by an environmental xenoestrogen, answering how a receptor without an endogenous ligand stays active and how BPA hijacks it.

    Evidence X-ray crystallography of the ERRγ-LBD/BPA complex plus biochemical binding (KD determination)

    PMID:17761695

    Open questions at the time
    • No endogenous ligand identified
    • Does not address physiological consequences of BPA binding in tissues
  2. 2009 Medium

    Showed that N-terminal isoform variation tunes ERRγ's basal transcriptional output and that the placenta selectively expresses a higher-activity isoform, linking isoform choice to tissue-specific activity.

    Evidence Luciferase reporter assay and RT-PCR isoform mapping in human reproductive tissues

    PMID:19304792

    Open questions at the time
    • Target genes affected by the activity difference not defined
    • Single-study reporter quantification
  3. 2010 High

    Defined ERRγ as an in vivo developmental regulator, demonstrating it is required for ureteric bud branching and renal papilla formation.

    Evidence siRNA, pharmacological agonist, and germline knockout in embryonic mouse kidney

    PMID:21138943

    Open questions at the time
    • Direct transcriptional targets in branching morphogenesis not identified
    • Mechanism linking activity to branching unresolved
  4. 2016 Medium

    Connected ERRγ to podocyte survival, establishing PI3K/Akt as the effector pathway through which it protects against injury-induced apoptosis.

    Evidence Gain/loss-of-function with PI3K inhibitor rescue in podocytes and PAN rat model

    PMID:27417234

    Open questions at the time
    • Direct transcriptional targets upstream of PI3K not identified
    • Single lab
  5. 2020 Medium

    Placed ERRγ within the PGC1α mitochondrial network as an early inducer of brite/beige adipocyte formation, and separately as a mediator of β-catenin degradation in gastric cancer.

    Evidence Adipocyte transcriptome profiling with in vitro/in vivo overexpression and mitochondrial respiration; siRNA and fractionation in gastric cancer cells

    PMID:32571331 PMID:32595605

    Open questions at the time
    • Direct promoter targets in adipocytes not defined
    • Mechanism of ESRRG-driven β-catenin degradation not molecularly resolved
  6. 2021 High

    Demonstrated that ERRγ governs mitochondrial homeostasis required for Treg maintenance, and is induced in liver by IL-6 to drive FGF23 production in AKI, establishing two distinct in vivo physiological axes.

    Evidence Conditional knockout with metabolic readouts in Tregs; liver-specific depletion, overexpression, inverse agonist, and IL-6 neutralization in AKI mice

    PMID:33853949 PMID:34156979

    Open questions at the time
    • Direct ERRγ target genes mediating Treg mitochondrial program not enumerated
    • Direct binding to the FGF23 promoter not shown
  7. 2022 Medium

    Identified RB1 as a direct negative regulator of ESRRG and showed ESRRG drives hypoxic retinoblastoma cell survival, framing it as an actionable dependency when RB1 is lost.

    Evidence Protein interaction assay, genomic/single-cell transcriptomics, and ESRRG depletion/inhibition with cell-death readout in retinoblastoma

    PMID:35984874

    Open questions at the time
    • Interaction interface and stoichiometry not detailed
    • Direct ERRγ targets in retinogenesis/oxygen metabolism not mapped
  8. 2023 Medium

    Showed ERRγ directly represses PKM2 to suppress glycolysis in esophageal carcinoma, defining a direct transcriptional mechanism for its tumor-suppressive metabolic effect.

    Evidence Promoter luciferase assay, expression manipulation, and glycolysis metabolic assays with DY131 agonist in ESCC cells

    PMID:37679788

    Open questions at the time
    • ChIP-level promoter occupancy not shown
    • Single lab
  9. 2024 High

    Established ESRRG as a direct activator of the KCNN1 potassium channel gene in sensory neurons, providing a transcriptional mechanism for nerve-injury nociceptive hypersensitivity.

    Evidence ChIP, siRNA, AAV rescue, electrophysiology, and behavioral pain assays in mouse DRG/nerve-injury models

    PMID:38912580

    Open questions at the time
    • Upstream signals reducing ESRRG after nerve injury not defined
    • Other DRG targets not surveyed
  10. 2025 High

    Expanded the direct target repertoire to PDE3B (airway inflammation) and HSD11B2 (neuronal mitochondrial integrity), and implicated de novo ESRRG variants in a human disorder of cell proliferation control.

    Evidence Luciferase/ChIP-PCR and inverse-agonist studies in asthma and AD models; ERRE reporter and proliferation assays of patient variants in ESRRG-KO HEK293T cells

    PMID:40153608 PMID:41197937 PMID:41265451

    Open questions at the time
    • Genotype-phenotype spectrum of the human disorder not fully characterized
    • Whether variants act as gain or loss varies by assay readout
  11. 2026 Medium

    Identified the TRPS1-ESRRG axis as essential for zygotic genome activation and blastocyst formation, and confirmed ESRRG's role in trophoblast mitochondrial function and placental competence.

    Evidence Embryo knockdown with global transcription and developmental staging plus TRPS1 promoter binding; trophoblast functional and mitochondrial assays with in vivo abortion model

    PMID:41623023 PMID:42248279

    Open questions at the time
    • Direct ESRRG targets driving ZGA not fully defined
    • Single-lab abstract-level mechanistic detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether ERRγ has a true endogenous ligand and how its constitutive activity is dynamically modulated in vivo across these diverse tissues remains unresolved.
  • No endogenous ligand identified
  • Tissue-specific coregulator complement undefined
  • Unified model linking metabolic and developmental roles absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1266738 Developmental Biology 2
Partners
RB1TRPS1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 BPA binds to the ERRγ ligand-binding domain (LBD) with high affinity (KD = 5.5 nM). Crystal structure of the ERRγ-LBD/BPA complex revealed that BPA is anchored by hydrogen bonds between its two phenol-hydroxyl groups and residues Glu275, Arg316, and Asn346, with additional hydrophobic contacts especially with Tyr326. BPA binding preserves the active conformation of helix 12, thereby maintaining ERRγ constitutive transcriptional activity. ERRγ behaves as a constitutive activator of transcription in the absence of a known endogenous ligand. X-ray crystallography of ERRγ-LBD/BPA complex; prior biochemical binding assay (KD determination) Journal of biochemistry High 17761695
2009 An ERRγ isoform (type-1) bearing an additional 23-mer amino-acid sequence at the N-terminus elevates ERRγ basal constitutive transcriptional activity by approximately 50%, as demonstrated by luciferase reporter gene assay. Placenta exclusively expresses this type-1 isoform among ERRγ protein isoforms. Luciferase reporter gene assay; real-time PCR; identification of ERRγ mRNA variants and protein isoforms in human reproductive tissues Journal of biochemistry Medium 19304792
2010 Esrrg protein is detected in early ureteric ducts (cytoplasmic/sub-membranous) and in developing nephrons (nuclear localization). siRNA-mediated knockdown and small-molecule agonist-induced aberrant activation of Esrrg in embryonic mouse kidney cultures both caused severe abnormality of early branching events of the ureteric duct. Esrrg homozygous knockout mice (Esrrg−/−) displayed agenesis of the renal papilla with otherwise normal cortex and medulla development, establishing Esrrg as required for ureteric bud branching prior to nephrogenesis onset. Immunostaining for subcellular localization; siRNA knockdown in embryonic kidney explant culture; small-molecule agonist treatment; targeted gene knockout mouse model (Esrrg−/−) Human molecular genetics High 21138943
2021 ERRγ expression is induced in the liver during acute kidney injury (AKI) by upstream IL-6 signaling. Hepatic ERRγ overexpression is sufficient to induce hepatic FGF23 production. Liver-specific depletion of ERRγ or treatment with an inverse ERRγ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in folic acid-induced AKI mice. IL-6 neutralizing antibody reduced ERRγ-mediated FGF23 production, confirming the IL-6 → ERRγ → FGF23 axis. Ectopic overexpression; liver-specific genetic depletion; inverse agonist pharmacological inhibition; IL-6 neutralizing antibody; folic acid-induced AKI mouse model; plasma FGF23 measurement Proceedings of the National Academy of Sciences of the United States of America High 33853949
2021 Esrrg controls regulatory T cell (Treg) maintenance and function through mitochondrial homeostasis. Esrrg-deficient Tregs exhibit dysregulated mitochondria with decreased oxygen consumption, ATP production, and NAD+ levels. Esrrg deficiency also leads to decreased phosphatidylinositol and TGF-β signaling and increased mTOR complex 1 activation in Tregs, impaired differentiation into follicular Tregs, and enhanced follicular helper T cell responses, resulting in global T cell activation and autoimmunity in aged mice. Conditional knockout mouse model; mitochondrial oxygen consumption assay; ATP and NAD+ quantification; phospho-signaling pathway analysis; T cell subset phenotyping; ESRRG knockdown in Jurkat cells with metabolic readout JCI insight High 34156979
2022 RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation in retinoblastoma cells. ESRRG regulates genes involved in retinogenesis and oxygen metabolism and is preferentially expressed in hypoxic retinoblastoma cells in vivo. Depletion or inhibition of ESRRG causes marked retinoblastoma cell death, which is exacerbated under hypoxia. Protein interaction assay (RB1-ESRRG direct interaction); whole exome/transcriptome/single-cell transcriptome genomic analyses; ESRRG depletion/inhibition with cell death readout; in vivo tumor hypoxia expression analysis Science advances Medium 35984874
2020 Sophoridine promotes β-catenin degradation by enhancing ESRRG expression in gastric cancer cells, independently of ubiquitination-proteasome pathway, TRIM33-mediated GSK3β-independent pathway, or altered GSK3β activity. ESRRG-mediated β-catenin degradation underlies the tumor-suppressive effects of sophoridine. siRNA transfection; nuclear/cytoplasmic fractionation; western blot; CCK-8, EDU, colony forming, transwell, and flow cytometry assays in AGS and SGC7901 cells BMC cancer Medium 32571331
2020 ESRRG and PERM1 are involved in the PGC1α transcriptional network to positively regulate mitochondrial capacity in adipocytes. Increased expression of ESRRG supports the formation of brown or brite/beige adipocytes both in vitro and in vivo, indicating ESRRG is an early inducer and important regulator of brite/beige adipocyte formation and mitochondrial conversion. Transcriptome profiling of inguinal adipocytes during cold exposure; in vitro and in vivo overexpression experiments; functional measurement of mitochondrial uncoupled respiration Frontiers in endocrinology Medium 32595605
2016 ERRγ overexpression attenuates puromycin aminonucleoside (PAN)-induced podocyte apoptosis and stimulates PI3K/Akt signaling (increased expression of PI3K subunits p85α and p110α and phosphorylated Akt). Conversely, ERRγ siRNA silencing causes podocyte apoptosis with increased injury markers (B7-1, cathepsin L) and decreased nephrin. A specific PI3K inhibitor (LY294002) entirely reversed the anti-apoptotic effect of ERRγ, establishing PI3K/Akt as the downstream effector pathway. siRNA knockdown; overexpression; PI3K inhibitor rescue experiment; western blot for signaling pathway components; apoptosis assay; in vivo PAN-treated rat kidney model The international journal of biochemistry & cell biology Medium 27417234
2023 ESRRG directly interacts with the PKM2 promoter to inhibit its transcriptional activity in esophageal squamous cell carcinoma (ESCC) cells, thereby suppressing glycolysis (Warburg effect). The ESRRG-specific agonist DY131 inhibits ESCC cell proliferation and glycolysis by modulating glycolysis pathway genes, and also modulates lactate regulation relevant to immune checkpoint activity. Promoter luciferase assay; altered ESRRG expression in ESCC cell lines; metabolic assays for glycolysis; DY131 agonist treatment; bioinformatics analysis Journal of translational medicine Medium 37679788
2022 BPA affects the ESRRG signaling pathway in a sex-specific manner in human placentas: BPA (1 µM, 24 h) increased ESRRG mRNA and protein in female placentas but decreased them in male placentas (at 1 nM or 1 µM, 48 h). Downstream ESRRG targets HSD17B1 and PLAC1 were correspondingly altered in a sex-specific pattern. BPA treatment did not affect proliferation, apoptosis, or syncytiotrophoblast differentiation. Placental villous explant culture with BPA; mRNA and protein quantification; sex-stratified analysis of ESRRG pathway constituents Biology of reproduction Medium 35220427
2024 ESRRG functions as a transcription factor that directly binds the Kcnn1 (KCNN1) gene promoter in dorsal root ganglion (DRG) neurons. Peripheral nerve injury reduces DRG ESRRG expression, leading to reduced KCNN1 transcription. This downregulation decreases total potassium voltage currents and afterhyperpolarization currents, increasing neuronal excitability and nociceptive hypersensitivity. Rescuing KCNN1 expression prevented CCI-induced pain behaviors without affecting locomotion or acute pain. Chromatin immunoprecipitation (ChIP) assay demonstrating ESRRG binding to Kcnn1 promoter; siRNA-mediated knockdown; AAV-mediated rescue; electrophysiology (potassium current and AHP measurement); behavioral pain assays in CCI and L4 ligation mouse models JCI insight High 38912580
2025 ESRRG binds to the Pde3b (phosphodiesterase 3B) promoter, as demonstrated by dual luciferase reporter assay and chromatin immunoprecipitation PCR. Esrrg inhibition (by AAV-shEsrrg or inverse agonist GSK5182) reduces Pde3b expression and alleviates airway inflammation in PM2.5-aggravated asthmatic mice and in isolated mouse tracheobronchial epithelial cells. Dual luciferase reporter assay; chromatin immunoprecipitation PCR; AAV-mediated shRNA knockdown; pharmacological inverse agonist (GSK5182); in vivo asthma-PM2.5 mouse model; in vitro tracheobronchial epithelial cell model American journal of respiratory cell and molecular biology High 40153608
2025 De novo heterozygous variants in ESRRG (located in DNA-binding and ligand-binding domains) reduce transcriptional activity at ERR response elements (ERRE) as assessed by reporter gene assay in ESRRG-knockout HEK293T cells. ESRRG knockout increases cell proliferation, and wild-type ESRRG overexpression restores normal proliferation, while the identified disease variants do not. All identified variants retain correct nuclear localization. These findings implicate ESRRG gain-of-function transcriptional activity in cell proliferation control. ERRE luciferase reporter gene assay in ESRRG-KO HEK293T cells (transient transfection of each variant vs. wild-type); cell proliferation assay; immunofluorescence for subcellular localization; molecular modeling American journal of human genetics Medium 41265451
2025 ESRRG mediates HSD11B2 transcription; propofol suppresses ESRRG expression in hippocampal neurons of 3xTg-AD mice, thereby reducing HSD11B2 and causing mitochondrial dysfunction (decreased membrane potential, increased cytochrome C release, increased p-DRP1). ESRRG overexpression (AAV-mediated) mitigated propofol-induced mitochondrial dysfunction and postoperative cognitive dysfunction, but these effects were reversed by HSD11B2 knockdown, establishing ESRRG → HSD11B2 as a functional transcriptional axis. AAV-mediated ESRRG overexpression; HSD11B2 knockdown; in vivo behavioral testing (Morris water maze); mitochondrial function assays (MMP, ROS, cytochrome C, p-DRP1); in vitro HT22 neuronal cell experiments Brain research Medium 41197937
2026 ESRRG is uniquely and highly expressed at the 2-cell embryo stage in mice and is essential for blastocyst formation. ESRRG knockdown reduces global transcriptional activity in 2-cell embryos, impairing zygotic genome activation (ZGA) and the 2-cell to 4-cell transition. The transcription factor TRPS1 directly binds to the Esrrg promoter to regulate its expression. The TRPS1-ESRRG axis controls ZGA factors including Sp1 and tankyrase 2. siRNA/morpholino knockdown of Esrrg in mouse preimplantation embryos; global transcriptional activity assay; ChIP or equivalent assay showing TRPS1 binding to Esrrg promoter; embryo developmental staging Cellular signalling Medium 42248279
2009 Esrrg expression is significantly upregulated (2.36-fold) by fenofibrate treatment in ApoA-I transgenic mice and shows significant positive correlation with genes of lipid and lipoprotein metabolism and mitochondrial functions, indicating a role for ERRγ in mediating fenofibrate-induced activation of specific lipid metabolism target genes. Global gene expression profiling (microarray) in ApoA-I transgenic mice treated with fenofibrate; bioinformatics correlation analysis The pharmacogenomics journal Low 19949424
2026 ESRRG downregulation in trophoblasts impairs mitochondrial function (decreased ATP, abnormal mitochondrial morphology) and reduces proliferation, invasion, migration, and tube formation in HTR-8/SVneo cells. ESRRG overexpression in a lipopolysaccharide-induced abortion mouse model improved trophoblast functionality and increased the number of retained embryos in the uterus. CCK8 and Transwell assays; MitoSOX staining; JC-1 mitochondrial membrane potential assay; ATP quantification; transmission electron microscopy; in vivo mouse overexpression model Annals of medicine Medium 41623023

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma. Journal of biochemistry 189 17761695
2009 Placenta expressing the greatest quantity of bisphenol A receptor ERR{gamma} among the human reproductive tissues: Predominant expression of type-1 ERRgamma isoform. Journal of biochemistry 71 19304792
2013 miR-205 promotes tumor proliferation and invasion through targeting ESRRG in endometrial carcinoma. Oncology reports 63 23589079
2010 Esrrg functions in early branch generation of the ureteric bud and is essential for normal development of the renal papilla. Human molecular genetics 29 21138943
2021 Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury. Proceedings of the National Academy of Sciences of the United States of America 28 33853949
2021 Lupus susceptibility gene Esrrg modulates regulatory T cells through mitochondrial metabolism. JCI insight 27 34156979
2020 Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer. BMC cancer 24 32571331
2019 Placental ESRRG-CYP19A1 Expressions and Circulating 17-Beta Estradiol in IUGR Pregnancies. Frontiers in pediatrics 20 31069202
2022 RB1 loss triggers dependence on ESRRG in retinoblastoma. Science advances 18 35984874
2018 A Genome-Wide Search for Gene-Environment Effects in Isolated Cleft Lip with or without Cleft Palate Triads Points to an Interaction between Maternal Periconceptional Vitamin Use and Variants in ESRRG. Frontiers in genetics 18 29535761
2023 ESRRG-PKM2 axis reprograms metabolism to suppress esophageal squamous carcinoma progression and enhance anti-PD-1 therapy efficacy. Journal of translational medicine 17 37679788
2016 Epigenomic elements analyses for promoters identify ESRRG as a new susceptibility gene for obesity-related traits. International journal of obesity (2005) 15 27113491
2022 Sex-specific effects of bisphenol A on the signaling pathway of ESRRG in the human placenta†. Biology of reproduction 14 35220427
2020 ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation. Frontiers in endocrinology 14 32595605
2009 Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice. The pharmacogenomics journal 13 19949424
2010 A long AAAG repeat allele in the 5' UTR of the ERR-γ gene is correlated with breast cancer predisposition and drives promoter activity in MCF-7 breast cancer cells. Breast cancer research and treatment 12 21153485
2016 Estrogen-related receptor (ERR) γ protects against puromycin aminonucleoside-induced podocyte apoptosis by targeting PI3K/Akt signaling. The international journal of biochemistry & cell biology 10 27417234
2024 Discovery of Novel TULP4/ACTN4/EWSR1/ACTB::MYB and ESRRG::DNM3 Fusions Expands Molecular Landscape of Adenoid Cystic Carcinoma Beyond Fusions Between MYB/MYBL1 and NFIB Genes. The American journal of surgical pathology 6 39235305
2017 Influence of estrogen-related receptor γ (ESRRG) rs1890552 A > G polymorphism on changes in fasting glucose and arterial stiffness. Scientific reports 5 28852080
2024 ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain. JCI insight 3 38912580
2025 Esrrg Inhibition Protects against Fine Particulate Matter-induced Asthma Aggravation by Reducing Pde3b. American journal of respiratory cell and molecular biology 2 40153608
2022 Molecular mechanism of the ESRRG-PERM1-CKMT2 signal axis in ovariectomized female rats with OSAHS. Transplant immunology 1 35623593
2026 ESRRG downregulation in early spontaneous abortion induces mitochondrial damage, leading to impaired trophoblast function. Annals of medicine 0 41623023
2026 Stage-specific expression dynamics of ESRRG orchestrate zygotic genome activation in mouse embryos. Cellular signalling 0 42248279
2025 SLC8A1-AS1 inhibits oral squamous cell carcinoma by regulating the miR-1305/ESRRG axis. Discover oncology 0 41003867
2025 Impact of ESRRG expression on proliferation and metastasis in laryngeal squamous cell carcinoma. Annals of medicine and surgery (2012) 0 41181411
2025 Propofol induces mitochondrial dysfunction in hippocampal neurons and postoperative cognitive dysfunction in male 3xTg-AD mice by blocking ESRRG-mediated HSD11B2 transcription. Brain research 0 41197937
2025 Genetic variants in ESRRG are associated with a dominant non-progressive congenital movement disorder with ataxia. American journal of human genetics 0 41265451

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