健康肌肉是健康体魄的必要保证,但是50%以上老年人患有肌肉衰减综合症。肌肉衰减导致老年人虚弱、还会引发肥胖、糖尿病等代谢综合症。据统计,中国有1.1亿人患代谢综合症。干细胞再生与代谢研究组以肌肉组织和多种动物为模型,研究肌肉再生和衰老过程中的干细胞代谢。我们的实验室建立和优化了人胚胎干细胞定向诱导分化为单层成肌细胞,从而扩展人成肌细胞,应用于成肌细胞转移治疗和高通量药物筛选。我们的研究显示,在肌肉衰减综合征患者人群中,高水平的炎症因子与肌萎缩风险增加相关,而代谢激素与肌萎缩风险降低相关。强化生活方式干预可以显著改善肌肉减少症患者的肌肉质量,减少炎症,恢复代谢激素水平。 我们的愿景是将肌肉干细胞生物学的最新进展、代谢组学与深度测序的最新技术相结合,以探索如何通过调节代谢系统来调节干细胞的自我更新。这一研究方向对于治疗老龄化人口的退行性代谢性疾病,如肌肉衰减综合症和2型糖尿病,具有重要的意义。 代谢在干细胞与组织再生中已知的一些调控机制 | 研究内容和目标: 本课题组致力于肌肉衰老与再生的机制研究。利用骨骼肌等组织做研究模型,我们开展了一系列的干细胞代谢组学分析工作,探讨如何利用代谢原理来调控细胞命运:(1)研究干细胞代谢如何在组织再生中影响干细胞分化,我们用小分子诱导人类多能干细胞定向分化为肌肉肌纤维。(2)研究衰老过程中肌肉衰减综合征发生的机制。我们用人类多能干细胞诱导分化的骨骼肌肌肌纤维来模拟人类肌肉萎缩,研究不同的促炎细胞因子和其他生长因子在老年人肌肉衰减综合征发展过程中的作用机制,以及强化生活方式干预后与肌萎缩相关的循环因子改善健康状况的分子和代谢机制。(3)干细胞如何通过代谢调控以维持组织的自我平衡,以及研究如何利用干细胞代谢的原理来治疗老龄人群及癌症恶病质患者的肌肉衰减综合征等疾病。我们致力于用干细胞代谢和再生医学提高老龄人群的生活质量,以应对老龄化对中国社会的冲击。 代表性发表论文: - Le, M. T., Teh, C.*, Shyh-Chang, N.*, Xie, H., Zhou, B., Korzh, V., Lodish, H. F., and Lim, B. (2009). MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 23, 862–76.
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- Zhu, H.*, Shyh-Chang, N.*, Segre, A. V., Shinoda, G., Shah, S. P., Einhorn, W. S., Takeuchi, A., Engreitz, J. M., Hagan, J. P., Kharas, M. G., Urbach, A., Thornton, J. E., Triboulet, R., Gregory, R. I., DIAGRAM Consortium, MAGIC Investigators, Altshuler, D., and Daley GQ. (2011). The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81-94.
- Le, M. T.*, Shyh-Chang, N.*, Khaw, S. L., Chin, L., Teh, C., Tay, J., O'Day, E., Korzh, V., Yang, H., Lal, A., Lieberman, J., Lodish, H. F., and Lim, B. (2011). Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs. PLoS Genetics 7, e1002242.
- Shyh-Chang, N., Zheng, Y., Locasale, J. W. and Cantley, L. C. (2011). Human pluripotent stem cells decouple respiration from energy production. EMBO Journal 30, 4851-4852.
- Zhang, W. C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B. S., Sun, L. L., Tai, B. C., Nga, M. E., Bhakoo, K. K., Jayapal, S. R., Nichane, M., Yu, Q., Ahmed, D. A., Tan, C., Sing, W. P., Tam, J., Thirugananam, A., Noghabi, M. S., Pang, Y. H., Ang, H. S., Mitchell, W., Robson, P., Kaldis, P., Soo, R. A., Swarup, S., Lim, E. H., and Lim, B. (2012). Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259-72.
- Shinoda, G., Shyh-Chang, N., de Soysa, T. Y., Zhu, H., Seligson, M. T., Shah, S. P., Abo-Sido, N., Yabuuchi, A., Hagan, J. P., Gregory, R. I., Asara, J. M., Cantley, L. C., Moss, E. G., and Daley, G. Q. (2013). Fetal deficiency of Lin28 programs life-long aberrations in growth and glucose metabolism. Stem Cells. doi: 10.1002/stem.1423.
- Shyh-Chang, N., Locasale, J. W., Lyssiotis, C. A., Zheng, Y., Teo, R. Y., Ratanasirintrawoot, S., Zhang, J., Onder, T., Unternaehrer, J. J., Zhu, H., Asara, J. M., Daley, G. Q., and Cantley, L. C. (2013). Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222-226.
- Shyh-Chang, N., Daley, G. Q., and Cantley, L. C. (2013). Stem cell metabolism during tissue development and aging. Development 12, 2535-47.
- Shyh-Chang, N. and Daley, G. Q. (2013). Lin28: Primal regulator of growth and metabolism in stem cells. Cell Stem Cell 12, 395-406.
- Shyh-Chang, N., Zhu, H., de Soysa, T. Y., Shinoda, G., Seligson, M. T., Tsanov, K. T., Nguyen L., Asara, J. M., Cantley, L. C., and Daley, G. Q. (2013). Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155, 778-92.
- Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC. (2013). Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. DOI: 10.1038/nature12040.
- Shyh-Chang, N. and Daley, G. Q. (2015). Metabolic switches linked to pluripotency and embryonic stem cell differentiation. Cell Metabolism 21, 349-50
- Khaw, S. L., Min-Wen, C., Koh, C. G., Lim, B., and Shyh-Chang, N. (2015). Oocyte factors suppress mitochondrial polynucleotide phosphorylase to remodel the metabolome and enhance reprogramming. Cell Reports 12(7), 1080-8.
- Wu, L.*, Nguyen L. H.*, Zhou, K., de Soysa, T. Y., Li, L., Miller, J. B., Tian, J., Locker, J., Zhang, S., Shinoda, G., Seligson, M. T., Zeitels, L. R., Acharya, A., Wang, S. C., Mendell, J. T., He, X., Nishino, J., Morrison, S. J., Siegwart, D. J., Daley, G. Q., Shyh-Chang, N., Zhu, H. (2015). Precise let-7 expression levels balance organ regeneration against tumor suppression. eLife 10.7554
- Liu TM, Lee EH, Lim B, Shyh-Chang, N. (2015). Balancing Stem Cell Self-renewal and Differentiation with PLZF. Stem Cells doi: 10.1002/stem.2270.
- Jun-Hao ET, Gupta RR, Shyh-Chang, N. (2016). Lin28 and let-7 in the metabolic physiology of aging. Trends Endocrinol. Metab. S1043-2760(15)00251-9. doi: 10.1016/j.tem.2015.12.006.
- Min-Wen JC, Jun-Hao ET, Shyh-Chang, N. (2016). Stem cell mitochondria during aging. Seminars in Cell and Developmental Biology. doi:10.1016/j.semcdb.2016.02.005.
- Tan, J.L., Fogley, R.D., Flynn, R.A., Ablain, J., Yang, S., Saint-André, V., Fan, Z.P., Do, B.T., Laga, A.C., Fujinaga, K., Santoriello, C., Greer, C.B., Kim, Y.J., Clohessy, J.G., Bothmer, A., Pandell, N., Avagyan, S., Brogie, J.E., van Rooijen, E., Hagedorn, E.J., Shyh-Chang, N., White, R.M., Price, D.H., Pandolfi, P.P., Peterlin, B.M., Zhou, Y., Kim, T.H., Asara, J.M., Chang, H.Y., Young, R.A., Zon, L.I. (2016). Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma. Molecular Cell. 62(1), 34-46.
- Fukawa, T., Yan-Jiang, B.C., Min-Wen, J.C., Jun-Hao, E.T., Huang, D., Qian, C.N., Ong, P., Li, Z., Mohan, R.E., Wang, R.R., Kanayama, H., Lai, J.H., Chua, C., Ong, H.S., Tan, K.K., Ho, Y.S., Tan, I.B., Teh, B.T., Shyh-Chang, N. (2016). Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nature Medicine. 22(6), 666-71.(cover story)
- Loh KM, Chen A, Koh PW, Deng TZ, Sinha R, Tsai JM, Barkal AA, Shen KY, Jain R, Morganti RM, Shyh-Chang N, Fernhoff NB, George BM, Wernig G, Salomon REA, Chen Z, Vogel H, Epstein JA, Kundaje A, Talbot WS, Beachy PA, Ang LT, Weissman IL. (2016). Mapping the Pairwise Choices Leading from Pluripotency to Human Bone, Heart, and Other Mesoderm Cell Types. Cell. 166, 451-467.
- Zhang J, Ratanasirintrawoot S, Chandrasekaran S, Wu Z, Ficarro SB, Yu C, Ross CA, Cacchiarelli D, Xia Q, Seligson M, Shinoda G, Xie W, Cahan P, Wang L, Ng SC, Tintara S, Trapnell C, Onder T, Loh YH, Mikkelsen T, Sliz P, Teitell MA, Asara JM, Marto JA, Li H, Collins JJ, Daley GQ. (2016). LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell Stem Cell. DOI: 10.1016/j.stem.2016.05.009.
- Zhang WC, Chin TM, Yang H, Nga ME, Lunny DP, Lim EK, Sun LL, Pang YH, Leow YN, Malusay SR, Lim PX, Lee JZ, Tan BJ, Shyh-Chang N, Lim EH, Lim WT, Tan DS, Tan EH, Tai BC, Soo RA, Tam WL, Lim B. (2016) Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression. Nat Commun. DOI: 10.1038/ncomms11702.
- Lee HJ, Jedrychowski MP, Vinayagam A, Wu N, Shyh-Chang N, Hu Y, Min-Wen C, Moore JK, Asara JM, Lyssiotis CA, Perrimon N, Gygi SP, Cantley LC, Kirschner MW. (2017). Proteomic and metabolomic characterization of a mammalian cellular transition from quiescence to proliferation. Cell Rep. 20(3), 721-736.
- Liu TM, Shyh-Chang N. (2017). SIRT2 and glycolytic enzyme acetylation in pluripotent stem cells. Nat Cell Biol. 19(5), 412-414.
- Andriani Y#, Chua JM#, Chua BY, Phang IY, Shyh-Chang N*, Tan WS*. (2017). Polyurethane acrylates as effective substrates for sustained in vitro culture of human myotubes. Acta Biomater. 57, 115-126.
- Shyh-Chang N and Huck-Hui Ng. (2017). The Metabolic Programming of Stem Cells. Genes Dev. 31(4), 336-346.
- Min-Wen JC, Yan-Jiang BC, Mishra S, Dai X, Magae J, Shyh-Chang N, Kumar AP, Sethi G. (2017). Molecular Targets of Ascochlorin and Its Derivatives for Cancer Therapy. Adv Protein Chem Struct Biol. 108, 199-225.
- Shyh-Chang N. (2017). Metabolic Changes During Cancer Cachexia Pathogenesis. Adv Exp Med Biol. 1026, 233-249.
- Usman WM, Pham TC, Kwok YY, Vu LT, Ma V, Peng B, Chan YS, Wei L, Chin SM, Azad A, He AB, Leung AYH, Yang M, Shyh-Chang N, Cho WC, Shi J, Le MTN. (2018). Efficient RNA drug delivery using red blood cell extracellular vesicles. Nat Commun. 9, 2359.
- Zhang X, Liu Z, Liu X, Wang S, Zhang Y, He X, Sun S, Ma S, Shyh-Chang N, Liu F, Wang Q, Wang X, Liu L, Zhang W, Song M, Liu GH, Qu J. (2019). Telomere-dependent and telomere-independent roles of RAP1 in regulating human stem cell homeostasis. Protein Cell. doi: 10.1007/s13238-019-0610-7
- Chua MJ, Yildirim ED, Tan JE, Chua YB, Low SC, Ding SLS, Li CW, Jiang Z, Teh BT, Yu K, Shyh-Chang N. (2019). Assessment of different strategies for scalable production and proliferation of human myoblasts. Cell Prolif. e12602. doi: 10.1111/cpr.12602.
- Li CW*, Yu K#, Shyh-Chang N#, Li GX, Jiang LJ, Yu SL, Xu LY, Liu RJ, Guo ZJ, Xie HY, Li RR, Ying J, Li K, Li DJ. (2019). Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention. J Cachexia Sarcopenia Muscle. doi: 10.1002/jcsm.12417.
- Jiang Z, Guang L, Li L, Shyh-Chang N#. (2019). Putting stem cells on a low-fat diet switches their pluripotent state. Cell Stem Cell, doi: 10.1016/j.stem.2019.06.002.
- Xu YJ, Liu PP, Ng SC, Teng ZQ, Liu CM. (2019). Regulatory Networks between Polycomb Complexes and Non-coding RNAs in Central Nervous System. J Mol Cell Biol, doi: 10.1093/jmcb/mjz058.
- Liu T, Shyh-Chang N#. (2019). Oncofetal SALL4-driven tumorigenesis is highly dependent on oxidative phosphorylation, revealing therapeutic opportunities. Gastroenterology, doi: 10.1053/j.gastro.2019.09.044.
- Xu C, Ooi WF, Qamra A, Tan J, Chua BY, Ho SWT, Das K, Adam Isa ZF, Li Z, Yao X, Yan T, Xing M, Huang KK, Lin JS, Nandi T, Tay ST, Lee MH, Tan ALK, Ong X, Ashktorab H, Smoot D, Li S, Ng SC, Teh BT, Tan P. (2020). HNF4α pathway mapping identifies wild-type IDH1 as a targetable metabolic node in gastric cancer. Gut, doi: 10.1136/gutjnl-2018-318025.
- Liu TM, Yildirim ED, Li P, Fang HT, Denslin V, Kumar V, Loh YH, Lee EH, Cool SM, Teh BT, Hui JH, Lim B, Shyh-Chang N#. (2020). Ascorbate and iron are required for the specification and long-term self-renewal of human skeletal mesenchymal stromal cells. Stem Cell Reports, doi: 10.1016/j.stemcr.2020.01.002.
- Wu J, Song D, Li Z, Guo B, Xiao Y, Liu W, Liang L, Feng C, Gao T, Chen Y, Li Y, Wang Z, Wen J, Yang S, Liu P, Wang L, Wang Y, Peng L, Stacey GN, Hu Z, Feng G, Li W, Huo Y, Jin R, Shyh-Chang N, Zhou Q, Wang L, Hu B, Dai H, Hao J. Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell Res. 2020 Sep;30(9):794-809.
- Yao Z, Chen Y, Cao W, Shyh-Chang N#. Chromatin-modifying drugs and metabolites in cell fate control. Cell Prolif. 2020 Nov;53(11):e12898.
- Xiaoxiao Wang, Yunlong Xiang, Yang Yu, Ran Wang, Yu Zhang, Qianhua Xu, Hao Sun, Zhen-Ao Zhao, Xiangxiang Jiang , Xiaoqing Wang, Xukun Lu, Dandan Qin, Yujun Quan, Jiaqi Zhang, Ng Shyh-Chang, Hongmei Wang, Naihe Jing, Wei Xie, Lei Li. Formative pluripotent stem cells show features of epiblast cells poised for gastrulation. Cell Res. 2021 Feb 19. doi: 10.1038/s41422-021-00477-x.
- Chun-Wei Li, Kang Yu#, Ng Shyh-Chang#, Guo-Xun Li, Song-Lin Yu , Hui-Jun Liu, Bo Yang, Zi-Yao Li, Yong-Jie Zhao, Long-Yu Xu, Jing Xu, Ling-Juan Jiang, Rong-Ji Liu, Xin-Yuan Zhang, Shao-Fei Li, Xiao-Wei Zhang, Hai-Yan Xie, Kang Li, Yi-Xiang Zhan, Min Cui, Hang-Bo Tao, Yao Li, Gao-Shan Liu, Ke-Min Ni, Dong-Jing Li. Sterol metabolism and protein metabolism are differentially correlated with sarcopenia in Asian men and women. Cell Prolif. 2021 Feb 20;e12989. doi: 10.1111/cpr.12989
- Ng Shyh-Chang# and Lei Li#. Stabilizing formative pluripotent states with germ cell competency. Cell Stem Cell. 2021 Mar; doi: 10.1016/j.stem.2021.02.021.
- Fan T, Wang S, Jiang Z, Ji S, Cao W, Liu W, Ji Y, Li Y, Shyh-Chang N#, Gu Q#. Controllable assembly of skeletal muscle-like bundles through 3D bioprinting. Biofabrication. 2021 Dec 1;14(1). doi: 10.1088/1758-5090/ac3aca.
- Li CW, Yu K#, Shyh-Chang N#, Jiang Z, Liu T, Ma S, Luo L, Guang L, Liang K, Ma W, Miao H, Cao W, Liu R, Jiang LJ, Yu SL, Li C, Liu HJ, Xu LY, Liu RJ, Zhang XY, Liu GS. Pathogenesis of sarcopenia and the relationship with fat mass. J Cachexia Sarcopenia Muscle. 2022 Feb 2. doi: 10.1002/jcsm.12901.
- Liu Z, Li W, Geng L, Sun L, Wang Q, Yu Y, Yan P, Liang C, Ren J, Song M, Zhao Q, Lei J, Cai Y, Li J, Yan K, Wu Z, Chu Q, Li J, Wang S, Li C, Han JJ, Hernandez-Benitez R, Shyh-Chang N, Belmonte JCI, Zhang W, Qu J, Liu GH. Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor. Cell Discov. 2022 Feb 1;8(1):6. doi: 10.1038/s41421-021-00361-3.
- Chew EGY, Lim TC, Leong MF, Liu X, Sia YY, Leong ST, Yan-Jiang BC, Stoecklin C, Borhan R, Heilmann-Heimbach S, Nothen MM, Viasnoff V, Shyh-Chang N, Wan ACA, Philpott MP, Hillmer AM. Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia. Exp Dermatol. 2022 Feb 4. doi: 10.1111/exd.14536.
- Ma S, Shyh-Chang N#. The Metabaging Cycle. Cell Prolif. 2022 Mar;55(3):e13197. doi: 10.1111/cpr.13197. Epub 2022 Feb 2.
- Song D, Shyh-Chang N#. An RNA methylation code to regulate protein translation and cell fate. Cell Prolif. 2022 May;55(5):e13224. doi: 10.1111/cpr.13224.
- Jiang Z, Zhang L, Yao Z, Cao W, Ma S, Chen Y, Guang L, Zheng Z, Li C, Yu K#, Shyh-Chang N#. Machine learning-based phenotypic screening for postmitotic growth inducers uncover vitamin D3 metabolites as small molecule ribosome agonists. Cell Prolif. 2022 May;55(5):e13214. doi: 10.1111/cpr.13214.
- Liang L, Tian Y, Feng L, Wang C, Feng G, Stacey GN, Shyh-Chang N, Wu J, Hu B, Li W, Hao J, Wang L, Wang Y. Single-cell transcriptomics reveals the cell fate transitions of human dopaminergic progenitors derived from hESCs. Stem Cell Res Ther. 2022 Aug 13;13(1):412. doi: 10.1186/s13287-022-03104-7.
- Cao J, Stacey G, Shyh-Chang N, Zhao T. Developing standards to support cell technology applications. Cell Prolif. 2022 Apr;55(4):e13210. doi: 10.1111/cpr.13210.
- Wang R, Zhang P#, Wang J, Ma L, E W, Suo S, Jiang M, Li J, Chen H, Sun H, Fei L, Zhou Z, Zhou Y, Chen Y, Zhang W, Wang X, Mei Y, Sun Z, Yu C, Shao J, Fu Y, Xiao Y, Ye F, Fang X, Wu H, Guo Q, Fang X, Li X, Gao X, Wang D, Xu PF, Zeng R, Xu G, Zhu L, Wang L, Qu J, Zhang D, Ouyang H, Huang H, Chen M, Shyh-Chang N#, Liu GH#, Yuan GC#, Guo G#, Han X#. Construction of a cross-species cell landscape at single-cell level. Nucleic Acids Res. 2023 Jan 25;51(2):501-516. doi: 10.1093/nar/gkac633.
- Luo L, Ma W, Liang K, Wang Y, Su J, Liu R, Liu T, Shyh-Chang N#. Spatial metabolomics reveals skeletal myofiber subtypes. Science Advances. 2023 Feb 3;9(5):eadd0455. doi: 10.1126/sciadv.add0455.
- Ma W, Luo L, Liang K, Liu T, Su J, Wang Y, Li J, Zhou SK, Shyh-Chang N#. XAI-enabled neural network analysis of metabolite spatial distributions. Anal Bioanal Chem. 2023 Jun;415(14):2819-2830. doi: 10.1007/s00216-023-04694-8. Epub 2023 Apr 21.
- Peng B, Yang Y, Wu Z, Tan R, Pham TT, Yeo EYM, Pirisinu M, Jayasinghe MK, Pham TC, Liang K, Shyh-Chang N#, Le MTN#. Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia. Mol Ther. 2023 May 3;31(5):1418-1436. doi: 10.1016/j.ymthe.2023.03.036. Epub 2023 Apr 3.
- Luo L, Chua YB, Liu T, Liang K, Chua MJ, Ma W, Goh JW, Wang Y, Su J, Ho YS, Li CW, Liu KH, Teh BT, Yu K, Shyh-Chang N#. Muscle Injuries Induce a Prostacyclin-PPARγ/PGC1a-FAO Spike That Boosts Regeneration. Adv Sci. 2023 May 4:e2301519. doi: 10.1002/advs.202301519. Online ahead of print.
- Wang P, Liu X, Chen Y, Jun-Hao ET, Yao Z, Min-Wen JC, Yan-Jiang BC, Ma S, Ma W, Luo L, Guo L, Song D, Shyh-Chang N#. Adult progenitor rejuvenation with embryonic factors. Cell Prolif. 2023 May;56(5):e13459. doi: 10.1111/cpr.13459. Epub 2023 May 12.
- Wang P, Liu X, Yao Z, Chen Y, Luo L, Liang K, Tan JE, Chua MJ, Chua YB, Ma S, Zhang L, Ma W, Liu S, Cao W, Guo L, Guang L, Wang Y, Zhao H, Ai N, Li Y, Li C, Wang RR, Teh BT, Jiang L, Yu K, Shyh-Chang N#. Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state. Cell Res. 2023 May 15. doi: 10.1038/s41422-023-00818-y. Online ahead of print.
- Yu D, Wan H, Tong C, Guang L, Chen G, Su J, Zhang L, Wang Y, Xiao Z, Zhai J, Yan L, Ma W, Liang K, Liu T, Wang Y, Peng Z, Luo L, Yu R, Li W#, Qi H#, Wang H#, Shyh-Chang N#.(2024)A multi-tissue metabolome atlas of primate pregnancy. Cell. DOI: 10.1016/j.cell.2023.11.043
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