bims-cutpro Biomed News
on Cullin targeted protein degradation
Issue of 2026–02–15
thirteen papers selected by
James M. Krieger, Francis Crick Institute
  1. Role of CIRP in Glioma Progression: Inhibition of Ferroptosis via UBR5-Mediated ACSL4 Degradation.
  2. Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1.
  3. Negative regulation of the NF-κB pathway by the ubiquitin ligase Nedd4-1(NE).
  4. E3 ubiquitin ligase DTX3L promotes breast cancer progression by enhancing PKCα ubiquitination and inhibiting the p38 MAPK signaling pathway.
  5. A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.
  6. OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway.
  7. Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression.
  8. Hundreds of plant F-box proteins in search of function.
  9. A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.
  10. Isolated absence epilepsy associated with a de novo FBXW7 missense variant in the F-box domain.
  11. Discovery of KRAS-G12D degraders via exploration of various E3 ligases.
  12. CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis.
  13. The Autophagy Receptor NDP52 Recruits the E3 Ligase ASB2 to Mediate NOX4 Degradation, Suppressing Cardiomyocyte Ferroptosis and Ameliorating Heart Failure.
  1. Exp Cell Res. 2026 Feb 11. pii: S0014-4827(26)00059-5. [Epub ahead of print] 114942
    Role of CIRP in Glioma Progression: Inhibition of Ferroptosis via UBR5-Mediated ACSL4 Degradation.
    Zhiyin Pang, Xingwang Zu, Ying Yang, Pingping Yan, Huicong Wang, Junjie Liu, Jinmin Hao.
      Glioma represents the most aggressive form of primary brain tumor, characterized by restricted therapeutic strategies and unfavorable survival rates. Accumulating studies indicate that ferroptosis is critically involved in the advancement of glioma. Although cold-inducible RNA-binding protein (CIRP), an RNA chaperone protein, upregulated in various malignancies, has not been thoroughly investigated in glioma. This research revealed that CIRP is a significantly upregulated gene in glioma patients, with high expression correlating with worse prognosis. Through functional experiments, we demonstrated that CIRP enhances proliferative, migratory, and invasive capacities of glioma cells. Notably, we discovered that CIRP enhanced GBM cell resistance to ferroptosis, as evidenced by reduced intracellular iron levels, decreased lipid peroxidation, and elevated antioxidant capacity. Mechanistic studies revealed that CIRP facilitated the interaction between the E3 ubiquitin ligase UBR5 and ACSL4, leading to increased ubiquitination and subsequent proteasomal degradation of ACSL4. In summary, our findings indicate that CIRP advances glioma progression via inhibiting ferroptosis through the promotion of UBR5-mediated ACSL4 degradation.
    Keywords:  ACSL4; CIRP; Ferroptosis; Glioma; UBR5
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114942
  2. Acta Pharm Sin B. 2026 Feb;16(2): 979-993
    Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1.
    Taoling Zeng, Tingting Jiang, Baoding Zhang, Ting Zhang, Wanjun Dai, Xun Yin, Yunzhan Li, Zhuoran Yu, Caiming Wu, Yaying Wu, Ximin Chi, Xianming Deng, Hong-Rui Wang.
      K-RAS mutations represent a most prevalent oncogenic alteration in human cancers. Despite tremendous efforts, it remains a big challenge to develop strategies that specifically target the oncogenic K-RAS mutants. Here, taking advantage of our previous finding that NEDD4-1 is an E3 ubiquitin ligase for wild-type RAS proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-RAS mutants including K-RASG12V, and significantly inhibit proliferation and tumor development of K-RAS mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.
    Keywords:  Anticancer drug; Bifunctional compound; Degradation; K-RAS; NEDD4-1; Oncogenic mutants; Small-molecule degrader; Ubiquitination
    DOI:  https://doi.org/10.1016/j.apsb.2025.07.031
  3. Commun Biol. 2026 Feb 07.
    Negative regulation of the NF-κB pathway by the ubiquitin ligase Nedd4-1(NE).
    Avinash Persaud, George Kefalas, Alina Shteiman, Amulya Priya, Huazhu Liang, Roman A Melnyk, Audrey Astori, Brian Raught, Daniela Rotin.
      The NF-κB pathway plays a critical role in mediating the innate immune response downstream of activated immune receptors such as the TNFαR. Activation of this pathway is induced by several ubiquitin ligases (e.g., cIAP, TRAFs, NEMO, β-TrCP, KPC1), including Nedd4-1. Nedd4-1 comprises a C2-WW(4)-HECT domain architecture. We recently characterized a primate-specific splice isoform of Nedd4-1, Nedd4-1(NE), in which the C2 domain is replaced by a large N-terminally Extended (NE) region. Using miniTurbo BioID, we identified here several components of the NF-κB pathway in complex with Nedd4-1(NE) (but not with the canonical Nedd4-1), including IKKα/β and p105-NF-κB1. We further show that (i) Nedd4-1(NE) ubiquitinates and promotes degradation of IKKβ, therefore inhibiting phosphorylation and promoting stability of its substrate, the inhibitory IκBα; (ii) active Nedd4-1(NE) binds and destabilizes NF-κB1, an interaction that is dependent upon Nedd4-1(NE)-mediated KPC1 ubiquitination. Furthermore, KPC1 promotes translocation of NF-κB1 to late endosomal membranes, where Nedd4-1(NE) resides, to facilitate the Nedd4-1(NE): NF-κB1 interaction. Consequently, Nedd4-1(NE)-mediated regulation of both IKKβ and NF-κB1 suppresses NF-κB1 nuclear translocation and activation of its target genes; and (iii) Nedd4-1(NE) (but not canonical Nedd4-1) mRNA expression is increased upon prolonged TNFα treatment of cells. This work uncovered an E3 ubiquitin ligase that suppresses the NF-κB1 pathway to ensure termination of this pro-inflammatory signaling pathway in primates via a negative feedback mechanism; Such an additional layer of immune regulation has important implications for understanding inflammatory homeostasis and its dysregulation in human disease.
    DOI:  https://doi.org/10.1038/s42003-026-09634-7
  4. Int J Biol Macromol. 2026 Feb 10. pii: S0141-8130(26)00787-7. [Epub ahead of print] 150861
    E3 ubiquitin ligase DTX3L promotes breast cancer progression by enhancing PKCα ubiquitination and inhibiting the p38 MAPK signaling pathway.
    Xiaoxiao Zhang, Yunkuan Song, Chenxu Shi, Dehai Yu, Sijie Li.
      E3 ubiquitin ligases are increasingly recognized for their critical role in tumor progression. While DTX3L, a member of the Deltex ligase family, has been linked to several cancers, its exact role in breast cancer (BC) was not well understood. Here, we report that high DTX3L expression in BC is associated with poor patient outcomes. Experimentally, DTX3L promoted BC cell proliferation, migration, and invasion, as well as tumor growth in vivo. Transcriptomic profiling after DTX3L knockdown showed significant enrichment of altered genes in the mitogen-activated protein kinase (MAPK) pathway. Accordingly, we found that DTX3L regulates p38 MAPK phosphorylation. Further investigation revealed that DTX3L binds protein kinase C alpha(PKCα) through its RING domain, targeting PKCα for K48-linked ubiquitination and proteasomal degradation. This process attenuates p38 MAPK phosphorylation, which in turn drives BC progression. Together, our work defines a key signaling axis-DTX3L-PKCα-p38 MAPK-in BC progression and provide important insights for the diagnosis and treatment of this disease.
    Keywords:  Breast cancer; DTX3L; PKCα; UPS; p38 MAPK
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150861
  5. Molecules. 2026 Jan 28. pii: 459. [Epub ahead of print]31(3):
    A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.
    Yifan Zhang, Linlin Li, Jiajia Xu, Chunchen Che, Jiaqing Jia, Haohao Lu, Qidong You, Xiaoli Xu.
      Molecular glue degraders (MGDs) constitute a class of innovative therapeutic agents within the field of targeted protein degradation (TPD). In contrast to proteolysis-targeting chimeras (PROTACs), MGDs induce protein degradation by stabilizing the interaction between an E3 ubiquitin ligase and a target protein. They typically exhibit favorable drug-like characteristics, including lower molecular weight and enhanced bioavailability. Although their discovery was historically serendipitous, recent advances in high-throughput screening, bioinformatics, and artificial intelligence are enabling more systematic identification and optimization. To date, three MGD-based drugs have been approved for clinical use, with numerous candidates under active investigation. This review comprehensively traces the technological progression of MGDs from serendipitous discovery to the current era of rational design. We systematically introduce and critically evaluate strategies for discovering MGDs, accompanied by illustrative examples. Concurrently, we discuss the major challenges hindering the broader application of MGDs and propose potential approaches to address these issues. Finally, we outline prospective research directions in the field. This review aims to provide a holistic framework for understanding the past, present, and future of molecular glue degraders, underscoring their significant potential to reshape the landscape of drug discovery.
    Keywords:  drug discovery methods; molecular glue degraders; targeted protein degradation
    DOI:  https://doi.org/10.3390/molecules31030459
  6. bioRxiv. 2026 Jan 26. pii: 2026.01.23.701155. [Epub ahead of print]
    OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway.
    Muhammad Usama Tariq, Namratha Sheshadri, Jianliang Shen, Jaeyong Jung, Rongrong Li, Kevin Lu, Junrong Yan, Mark C Koch, Giuseppe Caso, Hassan Sajjad, Brinda Vallat, Stephen K Burley, Yi Sun, Tong Liu, Hong Li, Christian Hinrichs, Francesco Bertoni, Richard Z Lin, Jun Wang, Y Lynn Wang, Jean Vacher, Ping Xie, Wei-Xing Zong.
      Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a membrane-integral glycosylated protein known for regulating lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a critical tumor suppressor in B-cell malignancies. In humans, OSTM1 is frequently deleted or downregulated across a wide range of B-cell malignancies. In mice, B-cell-specific monoallelic or biallelic Ostm1 ablation cooperates with Cdkn2a loss to drive lymphomagenesis with near 100% penetrance. Mechanistically, we reveal that a cytosolic, non-glycosylated fraction of OSTM1 functions as an E3 ligase that targets phosphodiesterase 3B (PDE3B) for proteasomal degradation. Because PDE3B catalyzes the conversion of cAMP to AMP and thereby negatively regulating the cAMP-dependent PKA/CREB/CREBBP tumor suppressive pathway, the loss of OSTM1 leads to PDE3B stabilization and enhanced cell transformation. Our findings establish OSTM1 as a pivotal E3 ligase that prevents B-cell lymphomagenesis through the regulation of the cAMP/PKA/CREB pathway.
    DOI:  https://doi.org/10.64898/2026.01.23.701155
  7. Acta Pharm Sin B. 2026 Feb;16(2): 913-929
    Blocking TRIM47-mediated HNF4α degradation suppresses hepatocellular carcinoma progression.
    Huanyu Hong, Mengchao Xiao, Hui Qian, Siqi Tan, Sihan Wu, Fang Liu, Xialu Hong, Shuqing Liu, Chenhong Ding, Keqi Wang, Weifen Xie, Xin Zhang.
      Previous studies have highlighted the downregulation of hepatocyte nuclear factor 4alpha (HNF4α) as a critical event in the pathogenesis of HCC. However, the mechanism of its degradation in HCC remains unclear. Tripartite motif 47 (TRIM47), a typical E3 ubiquitin ligase of the TRIM family, has been implicated in various tumors, yet its specific role in HCC progression is not fully elucidated. In this study, HNF4α was identified as a potential target of TRIM47 by using co-immunoprecipitation (Co-IP) combined with mass spectrometry analysis. TRIM47 facilitates the degradation of HNF4α by mediating K48-linked ubiquitination at lysine 470. Abrogation of HNF4α ubiquitination attenuated the promoting effect of TRIM47 on HCC malignancy. Molecular docking studies and Co-IP experiments revealed that K342, W349, and E353 of HNF4α, along with K534 and K600 of TRIM47, are crucial for their interaction. A small molecule, CZ-2401, was selected as a potent inhibitor of the TRIM47-HNF4α interaction through virtual screening and pharmacological activity validation. CZ-2401 effectively stabilizes HNF4α protein in HCC cells and ameliorates TRIM47-driven HCC progression in vivo. Taken together, our research elucidates that targeting TRIM47-HNF4α interaction is a potential therapeutic strategy for HCC, and identifies CZ-2401 as a potent inhibitor of HNF4α degradation and a promising candidate for HCC therapy.
    Keywords:  CZ-2401; HNF4α; Hepatocellular carcinoma; Protein–protein interactions; Small molecule; TRIM47; Ubiquitination; Virtual screening
    DOI:  https://doi.org/10.1016/j.apsb.2025.10.045
  8. J Exp Bot. 2026 Feb 12. pii: erag074. [Epub ahead of print]
    Hundreds of plant F-box proteins in search of function.
    Vishal Varshney, Thomas Potuschak, Shunping Yan, Sandra Noir, Pascal Genschik.
      F-box proteins (FBPs), the substrate-recognition subunits of SCF (SKP1-Cullin1-F-box) E3 ubiquitin ligases, are pivotal regulators of protein turnover and play central roles in shaping cellular signaling dynamics. In plants, the repertoire of FBP-encoding genes has undergone remarkable expansion, giving rise to one of the largest and most functionally diverse protein families in the plant kingdom. This diversification underpins an extensive regulatory capacity, enabling FBPs to modulate processes such as hormone perception, developmental patterning, circadian rhythm, and responses to a wide spectrum of biotic and abiotic stresses. Here, we synthesize recent advances that illuminate the molecular mechanisms governing FBP activity, including insights into substrate recognition and their potential applications.
    Keywords:  F-box proteins; degron; hormone; proteostasis; stress; ubiquitin
    DOI:  https://doi.org/10.1093/jxb/erag074
  9. bioRxiv. 2026 Jan 29. pii: 2026.01.28.702105. [Epub ahead of print]
    A HaloTag-4R-Tau Pulse-Chase Sensor Reveals Neddylation Inhibition Promotes Degradation of Tau in iNeurons.
    Qiang Xiao, Zi Gao, Seth Allen, Danny Garza, Richard I Morimoto, Jeffery W Kelly.
      Tau accumulation is a central driver of neurodegenerative diseases, yet strategies to promote its clearance remain limited. We developed a HaloTag-4R-Tau sensor in human iPSC-derived neurons (iNeurons) that enables sensitive monitoring the kinetics of both lysosomal partitioning and overall cellular turnover of tau. Using this sensor, we screened a small collection of small-molecule modulators of proteostasis network function and identified Neddylation inhibition by Pevonedistat as a robust promoter of soluble tau degradation. Mechanistic analysis including proteomic profiling revealed that Neddylation inhibition hastens HaloTag-Tau clearance via compensatory activation of a proteasome-dependent pathway(s) as well as the autophagy-lysosome pathway. Our findings establish a powerful tool for probing tau homeostasis and highlight Neddylation inhibition as a potential therapeutic approach for enhancing both proteasome and lysosome-mediated tau clearance in tauopathies.
    DOI:  https://doi.org/10.64898/2026.01.28.702105
  10. Epilepsia Open. 2026 Feb 13.
    Isolated absence epilepsy associated with a de novo FBXW7 missense variant in the F-box domain.
    Anees Muhammad, Mohammad Sadegh Shams Nosrati, Alireza Dostmohammadi, Francesca Madia, Maria Margherita Mancardi, Stefania Fornarino, Luca Bosisio, Zahra Hoseini Tavassol, Mir Davood Omrani, Federico Zara, Marcello Scala.
      The FBXW7 gene encodes a substrate-recognition component of the Skp1-Cul1-F-box (SCF) E3 ubiquitin ligase complex, which targets key regulatory proteins for proteasomal degradation. Recently, loss-of-function FBXW7 variants have been associated with a novel neurodevelopmental disorder characterized by heterogeneous clinical features. Most reported pathogenic variants cluster within the WD40 domains, while variants in other regions, such as the F-box domain, remain poorly characterized. In this study, we performed trio-exome sequencing on a 3-year-old girl with Early-Onset Childhood Absence Epilepsy. We analyzed the identified FBXW7 variant using multiple in silico tools for pathogenicity prediction and structural modeling. Clinical phenotype was compared with previously reported cases. We identified a novel de novo missense variant in FBXW7, c.926G>C; p.(Arg309Pro), affecting a highly conserved residue in the F-box domain. Notably, unlike prior cases predominantly associated with WD40 domain variants and severe phenotypes, our patient exhibited a much milder clinical presentation consisting of isolated, drug-responsive absence seizures without intellectual disability. Structural modeling predicted significant impairment in protein-protein binding affinity, particularly with the SCF complex component SKP1, supporting a potentially disruptive effect of the p.(Arg309Pro) substitution on complex assembly. Overall, our findings expand the genotypic and phenotypic spectrum of FBXW7-related disorders. Variants in the F-box domain may result in milder neurological phenotypes compared to those in the WD40 domains, suggesting domain-specific effects and potentially distinct pathogenic mechanisms. PLAIN LANGUAGE SUMMARY: The FBXW7 gene helps regulate the stability of many proteins essential for brain development and function. Changes in this gene have recently been linked to neurodevelopmental disorders with epilepsy. We identified a new FBXW7 variant in a 3-year-old girl with early-onset absence epilepsy. Computer-based modeling suggests that this change weakens the protein's normal interactions. Our findings broaden the spectrum of FBXW7-related disorders and indicate that variants in different gene regions may result in variable clinical severity.
    Keywords:   FBXW7 ; F‐box; de novo; early‐onset absence epilepsy; missense variant; neurodevelopmental disorder
    DOI:  https://doi.org/10.1002/epi4.70227
  11. Eur J Med Chem. 2026 Feb 03. pii: S0223-5234(26)00080-2. [Epub ahead of print]307 118635
    Discovery of KRAS-G12D degraders via exploration of various E3 ligases.
    Hyerin Yim, Xiangyang Song, Yue Zhong, Jacqueline Hu, Yan Xiong, Jian Jin.
      PROteolysis TArgeting Chimera (PROTAC) is a promising modality for targeted protein degradation. Although 600+ E3 ligases exist in the human genome, most PROTACs exploit a very limited set of E3 ligases, primarily CRBN and VHL. In this study, we designed, synthesized and evaluated a series of KRAS-G12D degraders that recruit one of four E3 ligases (CRBN, VHL, DCAF1, or KLHDC2) using a common KRAS-G12D binder derived from the KRAS-G12D inhibitor MRTX1133. Through this structure-activity relationship (SAR) study, we discovered two potent degraders: 30 (CRBN-based) and 41 (VHL-based), both of which effectively degraded KRAS-G12D and suppressed downstream signaling. By introducing a triazole-based VHL ligand, we subsequently discovered 43, which showed improved degradation and antiproliferative activity comparable to a previously reported KRAS-G12D degrader. In contrast, KLHDC2- and DCAF1-based degraders failed to induce KRAS-G12D degradation, potentially due to suboptimal ternary complex formation or insufficient E3 ligase compatibility. These findings highlight the importance of E3 ligase selection in the development of effective KRAS-G12D degraders.
    DOI:  https://doi.org/10.1016/j.ejmech.2026.118635
  12. Biochem Pharmacol. 2026 Feb 10. pii: S0006-2952(26)00114-0. [Epub ahead of print] 117783
    CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis.
    Dantong Sun, Jun Wang, Xue Yang, Han Shu, Yongfeng Cheng, Ying Chen, Qingqing Xia, Facai Wang, Siwei Deng, Jun Li, Xiao-Feng Li, Biao Song.
      The central role in the pathogenesis of rheumatoid arthritis (RA) is played by fibroblast-like synoviocytes (FLS), which drive disease progression through aberrant proliferation, recruitment of inflammatory cells, and subsequent degradation of cartilage and bone. Cullin 4A (CUL4A) is an important member of the Cullin family, which is a scaffolding protein for the E3 ubiquitin ligase complex. In this study, we investigated the functional significance and molecular mechanisms of CUL4A in the pathogenesis of RA. We identified elevated CUL4A expression in synovial tissues, TNFα-stimulated FLS, and peripheral blood mononuclear cells from RA patients. Furthermore, CUL4A mRNA expression levels showed a positive correlation with both clinical disease activity and inflammatory markers in RA. Knockdown of CUL4A led to a marked suppression of both cytokine production and glycolytic metabolism in FLS in vitro. RNA sequencing analysis and validation revealed the PI3K/AKT pathway as a key mediator in this process, with a significant functional interaction between CUL4A and fibroblast growth factor 2 (FGF2). Furthermore, knocking down FGF2 significantly inhibited synovial inflammation in RA FLS. In vivo experiments, knocking down CUL4A significantly reduced synovial inflammation in K/BxN serum transfer-induced arthritis (STA) mice and inhibited glycolytic metabolism. In conclusion, our findings reveal that CUL4A, via FGF2 binding, initiates PI3K/AKT pathway signaling, fostering the glycolysis process and synovial inflammation. Consequently, CUL4A holds significant promise as a target for early intervention against this pathogenic cascade.
    Keywords:  CUL4A; Fibroblast-like synoviocytes; K/BxN serum transfer-induced arthritis; Rheumatoid arthritis; Synovial inflammation
    DOI:  https://doi.org/10.1016/j.bcp.2026.117783
  13. Free Radic Biol Med. 2026 Feb 07. pii: S0891-5849(26)00111-5. [Epub ahead of print]
    The Autophagy Receptor NDP52 Recruits the E3 Ligase ASB2 to Mediate NOX4 Degradation, Suppressing Cardiomyocyte Ferroptosis and Ameliorating Heart Failure.
    Shouguo Yang, Jian Wu, Xiaoyue Song, Hong Jiang, Yunzeng Zou, Lei Zhang, Junbo Ge.
       BACKGROUND: Heart failure (HF) is characterized by cardiomyocyte loss. While ferroptosis driven by NOX4 contributes to HF, how autophagy regulates NOX4 stability remains unclear.
    METHODS: Using in vitro (isoproterenol-induced) and in vivo (TAC-induced) HF models, we combined pharmacological and genetic approaches with co-IP and molecular docking to investigate the autophagy-NOX4 axis.
    RESULTS: We identified a novel pathway wherein autophagy activation prompts the receptor NDP52 to bind NOX4 and recruit the E3 ligase ASB2, mediating K48-linked ubiquitination and autophagic degradation of NOX4. This process suppressed ferroptosis and ameliorated cardiomyocyte injury. The NOX4 inhibitor GLX351322, alone or combined with the autophagy activator metformin, conferred significant cardioprotection in vivo.
    CONCLUSION: Our findings reveal the 'autophagy-NDP52-ASB2-NOX4' axis as a crucial mechanism coupling autophagy to ferroptosis in HF, highlighting its therapeutic potential.
    Keywords:  Autophagy; Ferroptosis; Heart failure; NADPH Oxidase 4 (NOX4); NDP52/ASB2 Axis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.014
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