دورية أكاديمية
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
| العنوان: | Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells. |
|---|---|
| المؤلفون: | Sanmarco LM; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Rone JM; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Polonio CM; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Fernandez Lahore G; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Giovannoni F; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Ferrara K; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Gutierrez-Vazquez C; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Li N; Synlogic Therapeutics, Cambridge, MA, USA., Sokolovska A; Synlogic Therapeutics, Cambridge, MA, USA., Plasencia A; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Faust Akl C; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Nanda P; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Heck ES; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Li Z; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Lee HG; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Chao CC; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Rejano-Gordillo CM; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Fonseca-Castro PH; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Illouz T; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Linnerbauer M; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Kenison JE; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Barilla RM; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Farrenkopf D; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Stevens NA; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Piester G; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Chung EN; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Dailey L; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kuchroo VK; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Hava D; Synlogic Therapeutics, Cambridge, MA, USA., Wheeler MA; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Clish C; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nowarski R; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.; Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA., Balsa E; Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma de Madrid, Madrid, Spain., Lora JM; Synlogic Therapeutics, Cambridge, MA, USA., Quintana FJ; Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu. |
| المصدر: | Nature [Nature] 2023 Aug; Vol. 620 (7975), pp. 881-889. Date of Electronic Publication: 2023 Aug 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Autoimmune Diseases*/immunology , Autoimmune Diseases*/metabolism , Autoimmune Diseases*/prevention & control , Central Nervous System*/cytology , Central Nervous System*/immunology , Central Nervous System*/pathology , Dendritic Cells*/immunology , Dendritic Cells*/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit*/chemistry , Hypoxia-Inducible Factor 1, alpha Subunit*/genetics , Hypoxia-Inducible Factor 1, alpha Subunit*/metabolism , Lactic Acid*/metabolism, Humans ; Autoimmunity ; Probiotics/therapeutic use ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/immunology ; Feedback, Physiological ; Lactase/genetics ; Lactase/metabolism ; Single-Cell Analysis |
| مستخلص: | Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells 1,2 . Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders 3,4 , and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation. (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) |
| التعليقات: | Update of: bioRxiv. 2023 Mar 21;:. (PMID: 36993446) Comment in: Nat Rev Immunol. 2023 Oct;23(10):615. (PMID: 37667054) |
| References: | Anderson, D. A.III, Dutertre, C. A., Ginhoux, F. & Murphy, K. M. Genetic models of human and mouse dendritic cell development and function. Nat. Rev. Immunol. 21, 101–115 (2021). (PMID: 3290829910.1038/s41577-020-00413-x) Cabeza-Cabrerizo, M., Cardoso, A., Minutti, C. M., Pereira da Costa, M. & Reis, E. S. C. Dendritic cells revisited. Annu. Rev. Immunol. 39, 131–166 (2021). (PMID: 3348164310.1146/annurev-immunol-061020-053707) Nasser, J. et al. Genome-wide enhancer maps link risk variants to disease genes. Nature 593, 238–243 (2021). (PMID: 33828297915326510.1038/s41586-021-03446-x) Saevarsdottir, S. et al. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease. Nature 584, 619–623 (2020). (PMID: 3258135910.1038/s41586-020-2436-0) Dixon, K. O. et al. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature 595, 101–106 (2021). (PMID: 34108686862769410.1038/s41586-021-03626-9) Ferris, S. T. et al. cDC1 prime and are licensed by CD4 + T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020). (PMID: 32788723746975510.1038/s41586-020-2611-3) Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017). Du, X. et al. Hippo/Mst signalling couples metabolic state and immune function of CD8α + dendritic cells. Nature 558, 141–145 (2018). (PMID: 29849151629220410.1038/s41586-018-0177-0) Campbell, C. et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature 581, 475–479 (2020). (PMID: 32461639754072110.1038/s41586-020-2193-0) Suez, J., Zmora, N., Segal, E. & Elinav, E. The pros, cons, and many unknowns of probiotics. Nat. Med. 25, 716–729 (2019). (PMID: 3106153910.1038/s41591-019-0439-x) Buffington, S. A. et al. Dissecting the contribution of host genetics and the microbiome in complex behaviors. Cell 184, 1740–1756 (2021). (PMID: 33705688899674510.1016/j.cell.2021.02.009) Canale, F. P. et al. Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature 598, 662–666 (2021). (PMID: 3461604410.1038/s41586-021-04003-2) Scott, B. M. et al. Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease. Nat. Med. 27, 1212–1222 (2021). (PMID: 3418383710.1038/s41591-021-01390-x) Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). (PMID: 25043024430184510.1038/nature13490) Benoun, J. M. et al. Optimal protection against Salmonella infection requires noncirculating memory. Proc. Natl Acad. Sci. USA 115, 10416–10421 (2018). (PMID: 30254173618714210.1073/pnas.1808339115) Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). (PMID: 23535595403168610.1038/nature11986) Safran, M. et al. Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc. Natl Acad. Sci. USA 103, 105–110 (2006). (PMID: 1637350210.1073/pnas.0509459103) Bosshart, P. D., Kalbermatter, D., Bonetti, S. & Fotiadis, D. Mechanistic basis of L-lactate transport in the SLC16 solute carrier family. Nat. Commun. 10, 2649 (2019). (PMID: 31201333657303410.1038/s41467-019-10566-6) Brown, T. P. et al. The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene 39, 3292–3304 (2020). (PMID: 3207139610.1038/s41388-020-1216-5) Levitt, M. D. & Levitt, D. G. Quantitative evaluation of D-lactate pathophysiology: new insights into the mechanisms involved and the many areas in need of further investigation. Clin. Exp. Gastroenterol. 13, 321–337 (2020). (PMID: 32982363749009010.2147/CEG.S260600) Colgan, S. P., Furuta, G. T. & Taylor, C. T. Hypoxia and innate immunity: keeping up with the HIFsters. Annu. Rev. Immunol. 38, 341–363 (2020). (PMID: 31961750792452810.1146/annurev-immunol-100819-121537) Tello, D. et al. Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting complex I activity. Cell Metab. 14, 768–779 (2011). Mogilenko, D. A. et al. Metabolic and innate immune cues merge into a specific inflammatory response via the UPR. Cell 177, 1201–1216 (2019). (PMID: 3103100510.1016/j.cell.2019.03.018) Martinez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020). (PMID: 31900386694198010.1038/s41467-019-13668-3) Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010). (PMID: 20351694311370610.1038/ni.1857) Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015). (PMID: 26073941458013510.1016/j.cell.2015.05.025) Puurunen, M. K. et al. Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study. Nat. Metab. 3, 1125–1132 (2021). (PMID: 3429492310.1038/s42255-021-00430-7) Kurtz, C. B. et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci. Transl. Med. 11, eaau7975 (2019). (PMID: 3065132410.1126/scitranslmed.aau7975) Castano-Cerezo, S. et al. An insight into the role of phosphotransacetylase (pta) and the acetate/acetyl-CoA node in Escherichia coli. Microb. Cell Fact. 8, 54 (2009). (PMID: 19852855277466810.1186/1475-2859-8-54) Enjalbert, B., Millard, P., Dinclaux, M., Portais, J. C. & Letisse, F. Acetate fluxes in Escherichia coli are determined by the thermodynamic control of the Pta–AckA pathway. Sci. Rep. 7, 42135 (2017). (PMID: 28186174530148710.1038/srep42135) Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011). (PMID: 2203132510.1038/nature10554) Hiltensperger, M. et al. Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity. Nat. Immunol. 22, 880–892 (2021). (PMID: 34099917761109710.1038/s41590-021-00948-8) Schnell, A. et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell 184, 6281–6298 (2021). (PMID: 34875227890067610.1016/j.cell.2021.11.018) Tomura, M. et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice. Proc. Natl Acad. Sci. USA 105, 10871–10876 (2008). (PMID: 18663225250479710.1073/pnas.0802278105) D’Ignazio, L., Bandarra, D. & Rocha, S. NF-κB and HIF crosstalk in immune responses. FEBS J. 283, 413–424 (2016). (PMID: 2651340510.1111/febs.13578) O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016). (PMID: 27396447500191010.1038/nri.2016.70) Aste-Amezaga, M., Ma, X., Sartori, A. & Trinchieri, G. Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J. Immunol. 160, 5936–5944 (1998). (PMID: 963750710.4049/jimmunol.160.12.5936) Mascanfroni, I. D. et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14, 1054–1063 (2013). (PMID: 23995234396400510.1038/ni.2695) Lawless, S. J. et al. Glucose represses dendritic cell-induced T cell responses. Nat. Commun. 8, 15620 (2017). (PMID: 28555668545998910.1038/ncomms15620) Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019). (PMID: 31645732681875510.1038/s41586-019-1678-1) Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014). (PMID: 25258083422623810.1126/science.1250684) Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021). (PMID: 33589820799068210.1038/s41586-020-03045-2) Sanmarco, L. M. et al. Identification of environmental factors that promote intestinal inflammation. Nature 611, 801–809 (2022). (PMID: 36266581989882610.1038/s41586-022-05308-6) Schiering, C. et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242–245 (2017). (PMID: 28146477530215910.1038/nature21080) Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011). (PMID: 2197602310.1038/nature10491) Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 (2019). (PMID: 30962630805263210.1038/s41593-019-0370-y) Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019). (PMID: 3071883110.1038/s41577-019-0125-8) Mascanfroni, I. D. et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat. Med. 21, 638–646 (2015). (PMID: 26005855447624610.1038/nm.3868) Kenison, J. E. et al. Tolerogenic nanoparticles suppress central nervous system inflammation. Proc. Natl Acad. Sci. USA 117, 32017–32028 (2020). (PMID: 33239445774936210.1073/pnas.2016451117) Krienke, C. et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science 371, 145–153 (2021). (PMID: 3341421510.1126/science.aay3638) Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003). (PMID: 12732654219396710.1084/jem.20021603) Sanmarco, L. M. et al. Gut-licensed IFNγ + NK cells drive LAMP1 + TRAIL + anti-inflammatory astrocytes. Nature 590, 473–479 (2021). (PMID: 33408417803991010.1038/s41586-020-03116-4) Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). (PMID: 32051591804984310.1038/s41586-020-1999-0) Eberhardt, N. et al. Deficiency of CD73 activity promotes protective cardiac immunity against Trypanosoma cruzi infection but permissive environment in visceral adipose tissue. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165592 (2020). (PMID: 3167815710.1016/j.bbadis.2019.165592) Wheeler, M. A. et al. Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176, 581–596 (2019). (PMID: 30661753644074910.1016/j.cell.2018.12.012) Leventhal, D. S. et al. Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nat. Commun. 11, 2739 (2020). (PMID: 32483165726423910.1038/s41467-020-16602-0) Trombetta, J. J. et al. Preparation of single-cell RNA-seq libraries for next generation sequencing. Curr. Protoc. Mol. Biol. 107, 4.22.1–4.22.17 (2014). (PMID: 2498485410.1002/0471142727.mb0422s107) Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016). (PMID: 2704300210.1038/nbt.3519) Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017). (PMID: 28263959560014810.1038/nmeth.4197) Zhu, A., Ibrahim, J. G. & Love, M. I. Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences. Bioinformatics 35, 2084–2092 (2019). (PMID: 3039517810.1093/bioinformatics/bty895) Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005). (PMID: 16199517123989610.1073/pnas.0506580102) Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003). (PMID: 1280845710.1038/ng1180) Illouz, T., Madar, R., Hirsh, T., Biragyn, A. & Okun, E. Induction of an effective anti-Amyloid-β humoral response in aged mice. Vaccine 39, 4817–4829 (2021). (PMID: 34294479923763810.1016/j.vaccine.2021.07.023) Illouz, T. et al. Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis. Commun. Biol. 4, 329 (2021). (PMID: 33712740795507310.1038/s42003-021-01851-6) Haralick, R. M. & Shapiro, L. G. in Computer and Robot Vision Vol. 1 (eds Haralick, R. M. & Shapiro, L. G.) 28–48 (Addison-Wesley, 1992). Motulsky, H. J., & Brown, R. E. Detecting outliers when fitting data with nonlinear regression–a new method based on robust nonlinear regression and the false discovery rate. BMC Bioinformatics 7, 123 (2006). (PMID: 16526949147269210.1186/1471-2105-7-123) |
| معلومات مُعتمدة: | R01 MH130458 United States MH NIMH NIH HHS; P30 DK040561 United States DK NIDDK NIH HHS; R01 NS102807 United States NS NINDS NIH HHS; K99 NS114111 United States NS NINDS NIH HHS; R01 AI126880 United States AI NIAID NIH HHS; F32 NS101790 United States NS NINDS NIH HHS; R01 NS129778 United States NS NINDS NIH HHS; R01 ES029136 United States ES NIEHS NIH HHS; R00 NS114111 United States NS NINDS NIH HHS |
| المشرفين على المادة: | 0 (HIF1A protein, human) 0 (Hypoxia-Inducible Factor 1, alpha Subunit) 33X04XA5AT (Lactic Acid) 0 (NDUFA4L2 protein, human) 0 (Reactive Oxygen Species) 0 (XBP1 protein, human) EC 3.2.1.108 (Lactase) |
| تواريخ الأحداث: | Date Created: 20230809 Date Completed: 20230826 Latest Revision: 20240510 |
| رمز التحديث: | 20240510 |
| مُعرف محوري في PubMed: | PMC10725186 |
| DOI: | 10.1038/s41586-023-06409-6 |
| PMID: | 37558878 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 1476-4687 |
|---|---|
| DOI: | 10.1038/s41586-023-06409-6 |