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Gain-of-function PPM1D mutations attenuate ischemic stroke

Cell Death & Differentiation volume 32, pages 2146–2159 (2025)Cite this article

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Abstract

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d−/−) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d−/− mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke.

Gain-of-function PPM1D mutations attenuate ischemic cerebral injury. Whole-genome sequencing data of 10,241 ischemic stroke patients from the Third Chinese National Stroke Registry (CNSR-III) identified eight patients with gain-of-function mutations in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene (17q23.2). These mutation carriers displayed improved peripheral inflammation, decreased fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Ppm1d-deficient (Ppm1d−/−) mice exhibited exacerbated stroke outcomes, characterized by enlarged infarct volumes, disrupted cerebrovascular architecture, and enhanced neuro-inflammation. Mechanistically, Ppm1d deficiency induced the disturbance of endothelial fatty acid metabolism involving the PPARα pathway. Through integrated computational modeling, virtual screening, and in vitro validation, T2755 was identified as a small molecule PPM1D stabilizer. Pharmacological PPM1D stabilization with T2755 significantly attenuated ischemic brain injury in murine models.

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Fig. 1: Genetic landscape and identification of PPM1D variants in ischemic stroke patients.
Fig. 2: Ppm1d deficiency exacerbates ischemic brain injury in mice.
Fig. 3: Spatial transcriptomics reveals unique Ppm1d-associated molecular patterns affecting cerebrovascular function in stroke mice.
Fig. 4: Ppm1d deficiency impairs exogenous fatty acid β-oxidation in CD31+ endothelial cells.
Fig. 5: The interaction between PPM1D and PPARα.
Fig. 6: Small-molecule compounds targeting PPM1D attenuate neuro-deficits and ischemic stroke injury.

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Data availability

All data generated and analyzed during this study are included in this published article or its supplementary information files, with additional data available from the corresponding author upon reasonable request. The raw and processed spatial transcriptomics data generated in this study have been deposited in the Gene Expression Omnibus public repository under accession number GSE295060.

References

  1. Feigin VL, Nguyen G, Cercy K, Johnson CO, Alam T, Parmar PG, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med. 2018;379:2429–37.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Li P, Stetler RA, Leak RK, Shi Y, Li Y, Yu W, et al. Oxidative stress and DNA damage after cerebral ischemia: Potential therapeutic targets to repair the genome and improve stroke recovery. Neuropharmacology. 2018;134:208–17.

    Article  CAS  PubMed  Google Scholar 

  3. Barinaga M. Stroke-damaged neurons may commit cellular suicide. Science. 1998;281:1302–3.

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, et al. A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science. 2016;354:aad6872.

  5. Douarre C, Mergui X, Sidibe A, Gomez D, Alberti P, Mailliet P, et al. DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase. Nucleic Acids Res. 2013;41:3588–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Uyanik B, Grigorash BB, Goloudina AR, Demidov ON. DNA damage-induced phosphatase Wip1 in regulation of hematopoiesis, immune system and inflammation. Cell Death Discov. 2017;3:17018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu G, Hu X, Sun B, Yang T, Shi J, Zhang L, et al. Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1. Blood. 2013;121:519–29.

    Article  CAS  PubMed  Google Scholar 

  8. Sun B, Hu X, Liu G, Ma B, Xu Y, Yang T, et al. Phosphatase Wip1 negatively regulates neutrophil migration and inflammation. J Immunol. 2014;192:1184–95.

    Article  CAS  PubMed  Google Scholar 

  9. Yi W, Hu X, Chen Z, Liu L, Tian Y, Chen H, et al. Phosphatase Wip1 controls antigen-independent B-cell development in a p53-dependent manner. Blood. 2015;126:620–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang P, Su H, Zhang L, Chen H, Hu X, Yang F, et al. Phosphatase wild-type p53-induced phosphatase 1 controls the development of TH9 cells and allergic airway inflammation. J Allergy Clin Immunol. 2018;141:2168–81.

    Article  CAS  PubMed  Google Scholar 

  11. Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014;124:3263–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Andrysik Z, Sullivan KD, Kieft JS, Espinosa JM. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the integrated stress response. Nat Commun. 2022;13:7400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Le Guezennec X, Brichkina A, Huang YF, Kostromina E, Han W, Bulavin DV. Wip1-dependent regulation of autophagy, obesity, and atherosclerosis. Cell Metab. 2012;16:68–80.

    Article  PubMed  Google Scholar 

  14. Arends CM, Liman TG, Strzelecka PM, Kufner A, Löwe P, Huo S, et al. Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke. Blood. 2023;141:787–99.

    Article  CAS  PubMed  Google Scholar 

  15. Yan F, Cheng X, Zhao M, Gong S, Han Y, Ding L, et al. Loss of Wip1 aggravates brain injury after ischaemia/reperfusion by overactivating microglia. Stroke Vasc Neurol. 2021;6:344–51.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wang Y, Jing J, Meng X, Pan Y, Wang Y, Zhao X, et al. The Third China National Stroke Registry (CNSR-III) for patients with acute ischaemic stroke or transient ischaemic attack: design, rationale and baseline patient characteristics. Stroke Vasc Neurol. 2019;4:158–64.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Cheng S, Xu Z, Bian S, Chen X, Shi Y, Li Y, et al. The STROMICS genome study: deep whole-genome sequencing and analysis of 10K Chinese patients with ischemic stroke reveal complex genetic and phenotypic interplay. Cell Discov. 2023;9:75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cheng S, Xu Z, Liu Y, Lin J, Jiang Y, Wang Y, et al. Whole genome sequencing of 10K patients with acute ischaemic stroke or transient ischaemic attack: design, methods and baseline patient characteristics. Stroke Vasc Neurol. 2021;6:291–7.

    Article  PubMed  Google Scholar 

  19. Li Q, Wang K. InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines. Am J Hum Genet. 2017;100:267–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Feng Y, Li Y, Zhang Y, Zhang BH, Zhao H, Zhao X, et al. miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling. J Neuroinflamm. 2021;18:133.

    Article  CAS  Google Scholar 

  21. Jin WN, Gonzales R, Feng Y, Wood K, Chai Z, Dong JF, et al. Brain ischemia induces diversified neuroantigen-specific T-cell responses that exacerbate brain injury. Stroke. 2018;49:1471–8.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Liu Q, Jin WN, Liu Y, Shi K, Sun H, Zhang F, et al. Brain ischemia suppresses immunity in the periphery and brain via different neurogenic innervations. Immunity. 2017;46:474–87.

    Article  CAS  PubMed  Google Scholar 

  23. Jin WN, Shi SX, Li Z, Li M, Wood K, Gonzales RJ, et al. Depletion of microglia exacerbates postischemic inflammation and brain injury. J Cereb Blood Flow Metab. 2017;37:2224–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zou M, Feng Y, Xiu Y, Li Y, Zhang Y, Fan J, et al. Pertussis toxin-induced inflammatory response exacerbates intracerebral haemorrhage and ischaemic stroke in mice. Stroke Vasc Neurol. 2022;7:29–37.

    Article  PubMed  Google Scholar 

  25. Yang CS, Guo A, Li Y, Shi K, Shi FD, Li M. Dl-3-n-butylphthalide reduces neurovascular inflammation and ischemic brain injury in mice. Aging Dis. 2019;10:964–76.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang Z, Li Y, Jiang S, Shi FD, Shi K, Jin WN. Targeting CCL5 signaling attenuates neuroinflammation after seizure. CNS Neurosci Ther. 2023;29:317–30.

    Article  CAS  PubMed  Google Scholar 

  27. Li Y, Zou C, Chen C, Li S, Zhu Z, Fan Q, et al. Myeloid-derived MIF drives RIPK1-mediated cerebromicrovascular endothelial cell death to exacerbate ischemic brain injury. Proc Natl Acad Sci USA. 2023;120:e2219091120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wan T, Zhu W, Zhao Y, Zhang X, Ye R, Zuo M, et al. Astrocytic phagocytosis contributes to demyelination after focal cortical ischemia in mice. Nat Commun. 2022;13:1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Iijima T, Mies G, Hossmann KA. Repeated negative DC deflections in rat cortex following middle cerebral artery occlusion are abolished by MK-801: effect on volume of ischemic injury. J Cereb Blood Flow Metab. 1992;12:727–33.

    Article  CAS  PubMed  Google Scholar 

  30. Chen B, Cheng Q, Yang K, Lyden PD. Thrombin mediates severe neurovascular injury during ischemia. Stroke. 2010;41:2348–52.

    Article  CAS  PubMed  Google Scholar 

  31. Pinard E, Nallet H, MacKenzie ET, Seylaz J, Roussel S. Penumbral microcirculatory changes associated with peri-infarct depolarizations in the rat. Stroke. 2002;33:606–12.

    Article  PubMed  Google Scholar 

  32. Xu D, Zhang F, Wang Y, Sun Y, Xu Z. Microcephaly-associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex. Cell Rep. 2014;6:104–16.

    Article  CAS  PubMed  Google Scholar 

  33. Kukekov XuZ, Greene NV. LA. POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 2003;22:252–61.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jin WN, Ducruet AF, Liu Q, Shi SX, Waters M, Zou M, et al. Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia. FASEB J. 2018;32:2757–67.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Altelaar AF, Munoz J, Heck AJ. Next-generation proteomics: towards an integrative view of proteome dynamics. Nat Rev Genet. 2013;14:35–48.

    Article  CAS  PubMed  Google Scholar 

  36. Li X, Wang W, Chen J. Recent progress in mass spectrometry proteomics for biomedical research. Sci China Life Sci. 2017;60:1093–113.

    Article  CAS  PubMed  Google Scholar 

  37. Tsaban T, Varga JK, Avraham O, Ben-Aharon Z, Khramushin A, Schueler-Furman O. Harnessing protein folding neural networks for peptide-protein docking. Nat Commun. 2022;13:176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang C, Xu H, Yang D, Xie Y, Xiong M, Fan Y, et al. A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury. Nat Commun. 2023;14:4261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Moumbock AFA, Li J, Tran HTT, Hinkelmann R, Lamy E, Jessen HJ, et al. ePharmaLib: a versatile library of e-pharmacophores to address small-molecule (poly-)pharmacology. J Chem Inf Model. 2021;61:3659–66.

    Article  CAS  PubMed  Google Scholar 

  40. Sivaslioglu A, Goktas Z. A comprehensive review on the impact of hesperidin and its aglycone hesperetin on metabolic dysfunction-associated steatotic liver disease and other liver disorders. Nutr Res Rev. 2023;9:eabq0712.

  41. Wdowiak K, Walkowiak J, Pietrzak R, Bazan-Woźniak A, Cielecka-Piontek J. Bioavailability of hesperidin and its aglycone hesperetin-compounds found in citrus fruits as a parameter conditioning the pro-health potential (neuroprotective and antidiabetic activity)-mini-review. nutrients. 2022;14.

  42. Jiang S, Li X, Li Y, Chang Z, Yuan M, Zhang Y, et al. APOE from patient-derived astrocytic extracellular vesicles alleviates neuromyelitis optica spectrum disorder in a mouse model. Sci Transl Med. 2024;16:eadg5116.

    Article  CAS  PubMed  Google Scholar 

  43. Shi SX, Xiu Y, Li Y, Yuan M, Shi K, Liu Q, et al. CD4+T cells aggravate hemorrhagic brain injury. Sci Adv. 2023;9:eabq0712:1-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burocziova M, Burdova K, Martinikova AS, Kasparek P, Kleiblova P, Danielsen SA, et al. Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon. Cell Death Dis. 2019;10:818.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, et al. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. Nat Commun. 2022;13:604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2013;493:406–10.

    Article  CAS  PubMed  Google Scholar 

  47. Han L, Shen WJ, Bittner S, Kraemer FB, Azhar S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-α. Future Cardiol. 2017;13:259–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol. 2021;18:809–23.

    Article  CAS  PubMed  Google Scholar 

  49. Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006;116:571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Semenkovich CF. Fatty acid metabolism and vascular disease. Trends Cardiovasc Med. 2004;14:72–6.

    Article  CAS  PubMed  Google Scholar 

  51. Auguściak-Duma A, Lesiak M, Stępień K, Gutmajster E, Sieroń AL. mRNA Expression of thrombospondin 1, 2 and 3 from proximal to distal in human abdominal aortic aneurysm - preliminary report. Acta Biochim Pol. 2021;68:745–50.

    PubMed  Google Scholar 

  52. Lin CG, Chen CC, Leu SJ, Grzeszkiewicz TM, Lau LF. Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing. J Biol Chem. 2005;280:8229–37.

    Article  CAS  PubMed  Google Scholar 

  53. Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, et al. CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem. 2003;278:24200–8.

    Article  CAS  PubMed  Google Scholar 

  54. Spinelli CC, Carrizzo A, Ferrario A, Villa F, Damato A, Ambrosio M, et al. LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+/PKC-alpha-dependent mechanism. Cardiovasc Res. 2017;113:795–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hyslop NP, Liu Y, Yatkin S, Trzepla K. Application of the U.S. EPA procedure for determining method detection limits to EDXRF measurement of filter-based aerosol samples. J Air Waste Manag Assoc. 2022;72:905–13.

    Article  CAS  PubMed  Google Scholar 

  56. Zekavat SM, Viana-Huete V, Matesanz N, Jorshery SD, Zuriaga MA, Uddin MM, et al. TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease. Nat Cardiovasc Res. 2023;2:144–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhen H, Zhao L, Ling Z, Kuo L, Xue X, Feng J. Wip1 regulates blood-brain barrier function and neuro-inflammation induced by lipopolysaccharide via the sonic hedgehog signaling signaling pathway. Mol Immunol. 2018;93:31–7.

    Article  CAS  PubMed  Google Scholar 

  58. de la Riva P, Marta-Enguita J, Rodríguez-Antigüedad J, Bergareche A, de Munain AL. Understanding endothelial dysfunction and its role in ischemic stroke after the outbreak of recanalization therapies. Int J Mol Sci. 2024;25:11631–52.

  59. Li X, Zheng L, Xia Q, Liu L, Mao M, Zhou H, et al. A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1. Cell Death Differ. 2019;26:260–75.

    Article  CAS  PubMed  Google Scholar 

  60. Chen L, Peters JE, Prins B, Persyn E, Traylor M, Surendran P, et al. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke. Nat Commun. 2022;13:6143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are deeply grateful to many colleagues at the China National Clinical Research Center for Neurological Diseases for their invaluable contributions in establishing, maintaining, and conducting whole-genome analysis of The Third Chinese National Stroke Registry (CNSR-III). We thank Samuel. X. Shi for editorial assistance and Yingying Chang for artistic improvement of figures. We are grateful to Dr. L.A. Donehower from Baylor College of Medicine for the Ppm1d knockout mice. We acknowledge the assistance provided by Tianjin BioAI-global Technology Co., Ltd. in molecular modeling and virtual screening. This study was supported by the National Natural Science Foundation of China (82371324, 82371353, 82320108007); the Beijing Municipal Science and Technology Project (Z241100009024046).

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  1. These authors contributed equally: Wenyan He, Yan Li.

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  1. Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of innovative Drug and Device Research & Development for Cerebrovascular Diseases, Beijing, China

    Wenyan He, Yan Li, Junwan Fan, Yang Liu, Meng Yuan, Si Cheng, Xinying Huang, Tian Lan, Zhilin Chang, Yong Jiang, Hao Li, Xia Meng, Yilong Wang, Yongjun Wang, Fu-Dong Shi & Wei-Na Jin

  2. Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China

    Bo Yan, Zhuoran Zhang, Yuwen Xiu, Huimin Zhu & Fu-Dong Shi

  3. Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Luc Van Kaer

  4. Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

    Alexei Verkhratsky

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Contributions

W-NJ, F-DS, and YW (Yongjun Wang) formulated the concept and study design. WH, W-NJ, YL, JF, MY, BY, YX, HZ, and TL performed the experiments. YL, SC, and XH analyzed GWAS data. ZZ and ZC analyzed the spatial transcriptomics data. W-NJ, WH, HL, YJ, XM, YW (Yilong Wang), LVK, AV, and F-DS interpreted the results. F-DS, LVK, AV, YW (Yongjun Wang)，WH, and W-NJ drafted the manuscript.

Corresponding authors

Correspondence to Yongjun Wang, Fu-Dong Shi or Wei-Na Jin.

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Competing interests

LVK is a member of the scientific advisory board of Isu Abxis Co., Ltd. (Republic of Korea). The other authors declare no competing interests.

Ethical approval

The whole-genome sequencing data utilized in this study were derived from the CNSR-III cohort, with ethical approval granted by the Institutional Review Board of Beijing Tiantan Hospital (approval number: KY2015-001-01). Written informed consents were obtained from all participating patients prior to their inclusion in this study. All animal experiments were conducted in accordance with the ARRIVE (Animal Research: Reporting of in vivo Experiments) guidelines and were performed under protocols approved by the Institutional Animal Care and Use Committee of Beijing Tiantan Hospital (201902026).

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He, W., Li, Y., Fan, J. et al. Gain-of-function PPM1D mutations attenuate ischemic stroke. Cell Death Differ 32, 2146–2159 (2025). https://doi.org/10.1038/s41418-025-01523-6

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