Skip to main content
SpringerLink
Log in

Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure. Mesothelial cell loss is an initiating event for peritoneal fibrosis. We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E, driving downstream inflammatory responses, including the activation of macrophages. Moreover, pyroptosis is associated with elevated vascular endothelial growth factor A and C, two key factors in vascular angiogenesis and lymphatic vessel formation. GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure. Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action, and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy. Mechanistically, melatonin treatment maintains mitochondrial integrity in mesothelial cells, meanwhile activating mTOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate. These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress. Thus, Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alscher, D.M., Biegger, D., Mettang, T., van der Kuip, H., Kuhlmann, U., and Fritz, P. (2003). Apoptosis of mesothelial cells caused by unphysiological characteristics of peritoneal dialysis fluids. Artif Organs 27, 1035–1040.

    Article  CAS  PubMed  Google Scholar 

  • Boulanger, E., Wautier, M.P., Gane, P., Mariette, C., Devuyst, O., and Wautier, J.L. (2004). The triggering of human peritoneal mesothelial cell apoptosis and oncosis by glucose and glycoxydation products. Nephrol Dial Transplant 19, 2208–2216.

    Article  CAS  PubMed  Google Scholar 

  • Cao, Y., Li, Q., Zhou, A., Ke, Z., Chen, S., Li, M., Gong, Z., Wang, Z., and Wu, X. (2021). Notoginsenoside R1 reverses abnormal autophagy in hippocampal neurons of mice with sleep deprivation through melatonin receptor 1A. Front Pharmacol 12, 719313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cecon, E., Oishi, A., and Jockers, R. (2018). Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 175, 3263–3280.

    Article  CAS  PubMed  Google Scholar 

  • Cheng, R., Zheng, X., Wang, Y., Ma, X., Liu, X., Xu, W., Wang, M., Gao, Y., Xing, X., Zhou, C., et al. (2022). Modification of alternative splicing in bovine somatic cell nuclear transfer embryos using engineered CRISPR-Cas13d. Sci China Life Sci 65, 2257–2268.

    Article  CAS  PubMed  Google Scholar 

  • Cox, J., Matic, I., Hilger, M., Nagaraj, N., Selbach, M., Olsen, J.V., and Mann, M. (2009). A practical guide to the MaxQuant computational platform for SILAC-based quantitative proteomics. Nat Protoc 4, 698–705.

    Article  CAS  PubMed  Google Scholar 

  • Davies, S.J., Phillips, L., Naish, P.F., and Russell, G.I. (2001). Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 12, 1046–1051.

    Article  CAS  PubMed  Google Scholar 

  • del Peso, G., Jiménez-Heffernan, J.A., Bajo, M.A., Aroeira, L.S., Aguilera, A., Fernández-Perpén, A., Cirugeda, A., Castro, M.J., de Gracia, R., Sánchez-Villanueva, R., et al. (2008). Epithelial-to-mesenchymal transition of mesothelial cells is an early event during peritoneal dialysis and is associated with high peritoneal transport. Kidney Int 73, S26–S33.

    Article  Google Scholar 

  • Frampton, J.E., and Plosker, G.L. (2003). Icodextrin: a review of its use in peritoneal dialysis. Drugs 63, 2079–2105.

    Article  CAS  PubMed  Google Scholar 

  • Goossen, K., Becker, M., Marshall, M.R., Bühn, S., Breuing, J., Firanek, C.A., Hess, S., Nariai, H., Sloand, J.A., Yao, Q., et al. (2020). Icodextrin versus glucose solutions for the once-daily long dwell in peritoneal dialysis: an enriched systematic review and meta-analysis of randomized controlled trials. Am J Kidney Dis 75, 830–846.

    Article  CAS  PubMed  Google Scholar 

  • Gotloib, L., Wajsbrot, V., Cuperman, Y., and Shostak, A. (2004). Acute oxidative stress induces peritoneal hyperpermeability, mesothelial loss, and fibrosis. J Lab Clin Med 143, 31–40.

    Article  CAS  PubMed  Google Scholar 

  • Hardeland, R., Cardinali, D.P., Srinivasan, V., Spence, D.W., Brown, G.M., and Pandi-Perumal, S.R. (2011). Melatonin—A pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93, 350–384.

    Article  CAS  PubMed  Google Scholar 

  • Himmelfarb, J., Vanholder, R., Mehrotra, R., and Tonelli, M. (2020). The current and future landscape of dialysis. Nat Rev Nephrol 16, 573–585.

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang, R., Xu, Y., Lu, X., Tang, X., Lin, J., Cui, K., Yu, S., Shi, Y., Ye, D., Liu, Y., et al. (2021). Melatonin protects inner retinal neurons of newborn mice after hypoxiaischemia. J Pineal Res 71, e12716.

    Article  CAS  PubMed  Google Scholar 

  • Hung, K.Y., Liu, S.Y., Yang, T.C., Liao, T.L., and Kao, S.H. (2014). High-dialysate-glucose-induced oxidative stress and mitochondrial-mediated apoptosis in human peritoneal mesothelial cells. Oxid Med Cell Longev 2014, 1–12.

    Article  Google Scholar 

  • Ito, T., and Yorioka, N. (2008). Peritoneal damage by peritoneal dialysis solutions. Clin Exp Nephrol 12, 243–249.

    Article  PubMed  Google Scholar 

  • Jiang, N., Zhang, Z., Shao, X., Jing, R., Wang, C., Fang, W., Mou, S., and Ni, Z. (2020). Blockade of thrombospondin-1 ameliorates high glucose-induced peritoneal fibrosis through downregulation of TGF-β1/Smad3 signaling pathway. J Cell Physiol 235, 364–379.

    Article  CAS  PubMed  Google Scholar 

  • Kariya, T., Nishimura, H., Mizuno, M., Suzuki, Y., Matsukawa, Y., Sakata, F., Maruyama, S., Takei, Y., and Ito, Y. (2018). TGF-β1-VEGF-A pathway induces neoangiogenesis with peritoneal fibrosis in patients undergoing peritoneal dialysis. Am J Physiol Renal Physiol 314, F167–F180.

    Article  PubMed  Google Scholar 

  • Kilic, U., Caglayan, A.B., Beker, M.C., Gunal, M.Y., Caglayan, B., Yalcin, E., Kelestemur, T., Gundogdu, R.Z., Yulug, B., Yilmaz, B., et al. (2017). Particular phosphorylation of PI3K/Akt on Thr308 via PDK-1 and PTEN mediates melatonin’s neuroprotective activity after focal cerebral ischemia in mice. Redox Biol 12, 657–665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinashi, H., Ito, Y., Sun, T., Katsuno, T., and Takei, Y. (2018). Roles of the TGF-β-VEGF-C pathway in fibrosis-related lymphangiogenesis. Int J Mol Sci 19, 2487.

    Article  PubMed  PubMed Central  Google Scholar 

  • Krediet, R.T., and Struijk, D.G. (2013). Peritoneal changes in patients on long-term peritoneal dialysis. Nat Rev Nephrol 9, 419–429.

    Article  CAS  PubMed  Google Scholar 

  • Lanoix, D., Lacasse, A.A., Reiter, R.J., and Vaillancourt, C. (2012). Melatonin: the smart killer: the human trophoblast as a model. Mol Cell Endocrinol 348, 1–11.

    Article  PubMed  Google Scholar 

  • Lerner, A.B., Case, J.D., and Takahashi, Y. (1960). Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands. J Biol Chem 235, 1992–1997.

    Article  CAS  PubMed  Google Scholar 

  • Lin, J., Cheng, A., Cheng, K., Deng, Q., Zhang, S., Lan, Z., Wang, W., and Chen, J. (2020a). New insights into the mechanisms of pyroptosis and implications for diabetic kidney disease. Int J Mol Sci 21, 7057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin, P.H., Tung, Y.T., Chen, H.Y., Chiang, Y.F., Hong, H.C., Huang, K.C., Hsu, S.P., Huang, T.C., and Hsia, S.M. (2020b). Melatonin activates cell death programs for the suppression of uterine leiomyoma cell proliferation. J Pineal Res 68, e12620.

    Article  CAS  PubMed  Google Scholar 

  • Marchant, V., Tejera-Muñoz, A., Marquez-Expósito, L., Rayego-Mateos, S., Rodrigues-Diez, R.R., Tejedor, L., Santos-Sanchez, L., Egido, J., Ortiz, A., Valdivielso, J.M., et al. (2020). IL-17A as a potential therapeutic target for patients on peritoneal dialysis. Biomolecules 10, 1361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margetts, P.J., Kolb, M., Galt, T., Hoff, C.M., Shockley, T.R., and Gauldie, J. (2001). Gene transfer of transforming growth factor-β1 to the rat peritoneum: effects on membrane function. J Am Soc Nephrol 12, 2029–2039.

    Article  CAS  PubMed  Google Scholar 

  • Margetts, P.J., Kolb, M., Yu, L., Hoff, C.M., Holmes, C.J., Anthony, D.C., and Gauldie, J. (2002). Inflammatory cytokines, angiogenesis, and fibrosis in the rat peritoneum. Am J Pathol 160, 2285–2294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mollaoglu, H., Topal, T., Ozler, M., Uysal, B., Reiter, R.J., Korkmaz, A., and Oter, S. (2007). Antioxidant effects of melatonin in rats during chronic exposure to hyperbaric oxygen. J Pineal Res 42, 50–54.

    Article  CAS  PubMed  Google Scholar 

  • Niu, Y., Zhou, W., Nie, Z., Shin, K., and Cui, X. (2020). Melatonin enhances mitochondrial biogenesis and protects against rotenone-induced mitochondrial deficiency in early porcine embryos. J Pineal Res 68, e12627.

    Article  CAS  PubMed  Google Scholar 

  • O’Brien, M.D., and Webster, S.D. (2007). The construction and preliminary validation of the internet behaviours and attitudes questionnaire (IBAQ). Sex Abuse 19, 237–256.

    Article  PubMed  Google Scholar 

  • Qin, H., Chen, Y., Mao, J., Cheng, K., Sun, D., Dong, M., Wang, L., Wang, L., and Ye, M. (2019). Proteomics analysis of site-specific glycoforms by a virtual multistage mass spectrometry method. Anal Chim Acta 1070, 60–68.

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez, C., Mayo, J.C., Sainz, R.M., Antolin, I., Herrera, F., Martin, V., and Reiter, R.J. (2004). Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36, 1–9.

    Article  CAS  PubMed  Google Scholar 

  • Santamaría, B., Ucero, A.C., Benito-Martin, A., Vicent, M.J., Orzáez, M., Celdrán, A., Selgas, R., Ruíz-Ortega, M., and Ortiz, A. (2015). Biocompatibility reduces inflammation-induced apoptosis in mesothelial cells exposed to peritoneal dialysis fluid. Blood Purif 39, 200–209.

    Article  PubMed  Google Scholar 

  • Stazi, M., Negro, S., Megighian, A., D’Este, G., Solimena, M., Jockers, R., Lista, F., Montecucco, C., and Rigoni, M. (2021). Melatonin promotes regeneration of injured motor axons via MT1 receptors. J Pineal Res 70, e12695.

    Article  CAS  PubMed  Google Scholar 

  • Táranu, T., Florea, L., Păduraru, D., Georgescu, S.O., Frãncu, L.L., and Stan, C.I. (2014). Morphological changes of the peritoneal membrane in patients with long-term dialysis. Rom J Morphol Embryol 55, 927–932.

    PubMed  Google Scholar 

  • Terabayashi, T., Ito, Y., Mizuno, M., Suzuki, Y., Kinashi, H., Sakata, F., Tomita, T., Iguchi, D., Tawada, M., Nishio, R., et al. (2015). Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury. Lab Invest 95, 1029–1043.

    Article  CAS  PubMed  Google Scholar 

  • Terri, M., Trionfetti, F., Montaldo, C., Cordani, M., Tripodi, M., Lopez-Cabrera, M., and Strippoli, R. (2021). Mechanisms of peritoneal fibrosis: focus on immune cells-peritoneal stroma interactions. Front Immunol 12, 607204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyanova, S., Temu, T., Sinitcyn, P., Carlson, A., Hein, M.Y., Geiger, T., Mann, M., and Cox, J. (2016). The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13, 731–740.

    Article  CAS  PubMed  Google Scholar 

  • Vanecek, J. (1998). Cellular mechanisms of melatonin action. Physiol Rev 78, 687–721.

    Article  CAS  PubMed  Google Scholar 

  • Wang, B., Lv, X., Wang, Y., Wang, Z., Liu, Q., Lu, B., Liu, Y., and Gu, F. (2021). CRISPR/Cas9-mediated mutagenesis at microhomologous regions of human mitochondrial genome. Sci China Life Sci 64, 1463–1472.

    Article  ADS  PubMed  Google Scholar 

  • Wang, Y., Gao, W., Shi, X., Ding, J., Liu, W., He, H., Wang, K., and Shao, F. (2017). Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103.

    Article  ADS  CAS  PubMed  Google Scholar 

  • Wang, Y., Zhou, L., Zhou, Y., Zhao, C., Lu, X., and Xu, G. (2020). A rapid GC method coupled with quadrupole or time of flight mass spectrometry for metabolomics analysis. J Chromatogr B 1160, 122355.

    Article  CAS  Google Scholar 

  • Williams, J.D., Craig, K.J., Topley, N., Von Ruhland, C., Fallon, M., Newman, G.R., Mackenzie, R.K., and Williams, G.T. (2002). Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 13, 470–479.

    Article  PubMed  Google Scholar 

  • Williams, J.D., Craig, K.J., Topley, N., and Williams, G.T. (2003). Peritoneal dialysis: changes to the structure of the peritoneal membrane and potential for biocompatible solutions. Kidney Int 63, S158–S161.

    Article  Google Scholar 

  • Xie, C., Wu, W., Tang, A., Luo, N., and Tan, Y. (2019). lncRNA GAS5/miR-452-5p reduces oxidative stress and pyroptosis of high-glucose-stimulated renal tubular cells. Diabetes Metab Syndr Obes 12, 2609–2617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshio, Y., Miyazaki, M., Abe, K., Nishino, T., Furusu, A., Mizuta, Y., Harada, T., Ozono, Y., Koji, T., and Kohno, S. (2004). TNP-470, an angiogenesis inhibitor, suppresses the progression of peritoneal fibrosis in mouse experimental model. Kidney Int 66, 1677–1685.

    Article  CAS  PubMed  Google Scholar 

  • Zazzeroni, L., Pasquinelli, G., Nanni, E., Cremonini, V., and Rubbi, I. (2017). Comparison of quality of life in patients undergoing hemodialysis and peritoneal dialysis: a systematic review and meta-analysis. Kidney Blood Press Res 42, 717–727.

    Article  PubMed  Google Scholar 

  • Zhang, H.M., and Zhang, Y. (2014). Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57, 131–146.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, M., Zhang, B., Wang, X., Song, J., Tong, M., Dong, Z., Xu, J., Liu, M., Jiang, Y., Wang, N., et al. (2023). LncRNA CFAR promotes cardiac fibrosis via the miR-449a-5p/LOXL3/mTOR axis. Sci China Life Sci 66, 783–799.

    Article  ADS  CAS  PubMed  Google Scholar 

  • Zhang, Q., Li, D., Dong, X., Zhang, X., Liu, J., Peng, L., Meng, B., Hua, Q., Pei, X., Zhao, L., et al. (2022). LncDACH1 promotes mitochondrial oxidative stress of cardiomyocytes by interacting with sirtuin3 and aggravates diabetic cardiomyopathy. Sci China Life Sci 65, 1198–1212.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Y., Sun, Y., Wu, Z., Xiong, X., Zhang, J., Ma, J., Xiao, S., Huang, L., and Yang, B. (2021). Subcutaneous and intramuscular fat transcriptomes show large differences in network organization and associations with adipose traits in pigs. Sci China Life Sci 64, 1732–1746.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, Q., Bajo, M.A., del Peso, G., Yu, X., and Selgas, R. (2016). Preventing peritoneal membrane fibrosis in peritoneal dialysis patients. Kidney Int 90, 515–524.

    Article  PubMed  Google Scholar 

  • Zhou, Q., Yang, M., Lan, H., and Yu, X. (2013). miR-30a negatively regulates TGF-β1-induced epithelial-mesenchymal transition and peritoneal fibrosis by targeting snai1. Am J Pathol 183, 808–819.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, B., Cheng, X., Jiang, Y., Cheng, M., Chen, L., Bao, J., and Tang, X. (2020). Silencing of KCNQ1OT1 decreases oxidative stress and pyroptosis of renal tubular epithelial cells. Diabetes Metab Syndr Obes 13, 365–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgement

This work was supported by the National Key Research and Development Program of China (2020YFC2005002), the National Natural Science Foundation of China (81970642, 81370460, 81700580, 81670668, 22222409), Key research and development grant from The Department of Science and Technology, Liaoning Province, Innovative Leading Researcher grant from the Department of Science and Technology, Dalian, and Key Laboratory of Immune, Genetic and Metabolic Kidney Diseases, Dalian, and Youth Innovation Promotion Association of CAS (2018212).

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Hongxia Ruan, Rulin Hua, Yuan Wang, Yujie Fan, Shuwen Guo, Shafiq ur Rahman, Ziwei Wang, Yuyuan Wei, Ruqiang Yuan, Lihong Chen, Youfei Guan & Feng Zheng

  2. Department of Nephrology, Second Hospital, Dalian Medical University, Dalian, 116023, China

    Xuejuan Li, Lihua Wang, Shuangyan Yu, Rongzhi Zhang, Qian Cheng, Jie Sheng, Xue Li, Xiaoyan Liu & Feng Zheng

  3. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China

    Lina Zhou, Guowang Xu & Hongqiang Qin

  4. Chongqing International Institute for Immunology, Chongqing, 401320, China

    Zihan Zheng

  5. Department of Nephrology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518101, China

    Xu Wang

  6. Wuhu Hospital and Health Science Center, East China Normal University, Shanghai, 200241, China

    Xuejuan Li, Xiaoyan Zhang, Lihong Chen, Youfei Guan & Feng Zheng

  7. Peking University First Hospital, Peking University, Beijing, 100034, China

    Jing Nie

Authors
  1. Hongxia Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuejuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lina Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zihan Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rulin Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yujie Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shuwen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lihua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shafiq ur Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ziwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yuyuan Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shuangyan Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Rongzhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Qian Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jie Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Xue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Xiaoyan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Ruqiang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Xiaoyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Lihong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Guowang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Youfei Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Jing Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Hongqiang Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Feng Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xuejuan Li, Hongqiang Qin or Feng Zheng.

Ethics declarations

The author(s) declare that they have no conflict of interest.

Supplementary figure Legends

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruan, H., Li, X., Zhou, L. et al. Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure. Sci. China Life Sci. 67, 360–378 (2024). https://doi.org/10.1007/s11427-022-2365-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-022-2365-1

Search

Navigation