bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024–01–21
twenty papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Post-translational regulation of the mTORC1 pathway: A switch that regulates metabolism-related gene expression.
  2. Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome.
  3. mTORC1 in energy expenditure: consequences for obesity.
  4. The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
  5. Cooperative function of oncogenic MAPK signaling and the loss of Pten for melanoma migration through the formation of lamellipodia.
  6. PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation.
  7. Disentanglement of single-cell data with biolord.
  8. Live cell imaging of signaling networks using a conventional microscope.
  9. Making the connection: How membrane contact sites have changed our view of organelle biology.
  10. Compact CRISPR genetic screens enabled by improved guide RNA library cloning.
  11. Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity.
  12. Keeping translational research grounded in human biology.
  13. The diversification of methods for studying cell-cell interactions and communication.
  14. Telomere dynamics in human pluripotent stem cells.
  15. Mentoring the next generation of cell biologists.
  16. Modes and motifs in multicellular communication.
  17. ERK-mediated curvature feedback regulates branching morphogenesis in lung epithelial tissue.
  18. In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies.
  19. NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting.
  20. Bringing computation to biology by bridging the last mile.
  1. Biochim Biophys Acta Gene Regul Mech. 2024 Jan 17. pii: S1874-9399(24)00001-4. [Epub ahead of print] 195005
    Post-translational regulation of the mTORC1 pathway: A switch that regulates metabolism-related gene expression.
    Yitao Wang, Tobias Engel, Xinchen Teng.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a kinase complex that plays a crucial role in coordinating cell growth in response to various signals, including amino acids, growth factors, oxygen, and ATP. Activation of mTORC1 promotes cell growth and anabolism, while its suppression leads to catabolism and inhibition of cell growth, enabling cells to withstand nutrient scarcity and stress. Dysregulation of mTORC1 activity is associated with numerous diseases, such as cancer, metabolic disorders, and neurodegenerative conditions. This review focuses on how post-translational modifications, particularly phosphorylation and ubiquitination, modulate mTORC1 signaling pathway and their consequential implications for pathogenesis. Understanding the impact of phosphorylation and ubiquitination on the mTORC1 signaling pathway provides valuable insights into the regulation of cellular growth and potential therapeutic targets for related diseases.
    Keywords:  Phosphorylation; Transcription factor; Ubiquitination; mTOR; mTORC1 signaling pathway
    DOI:  https://doi.org/10.1016/j.bbagrm.2024.195005
  2. Cell Rep Med. 2024 Jan 09. pii: S2666-3791(23)00613-4. [Epub ahead of print] 101384
    Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome.
    Darren Liu, Lamis Yehia, Andrew Dhawan, Ying Ni, Charis Eng.
      Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.
    Keywords:  Cowden syndrome; PTEN; PTEN hamartoma tumor syndrome; breast cancer; cell-free DNA; cfDNA; fragmentomics; second primary malignant neoplasm; thyroid cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101384
  3. Nat Rev Endocrinol. 2024 Jan 15.
    mTORC1 in energy expenditure: consequences for obesity.
    Camille Allard, Cristina Miralpeix, Antonio J López-Gambero, Daniela Cota.
      In eukaryotic cells, the mammalian target of rapamycin complex 1 (sometimes referred to as the mechanistic target of rapamycin complex 1; mTORC1) orchestrates cellular metabolism in response to environmental energy availability. As a result, at the organismal level, mTORC1 signalling regulates the intake, storage and use of energy by acting as a hub for the actions of nutrients and hormones, such as leptin and insulin, in different cell types. It is therefore unsurprising that deregulated mTORC1 signalling is associated with obesity. Strategies that increase energy expenditure offer therapeutic promise for the treatment of obesity. Here we review current evidence illustrating the critical role of mTORC1 signalling in the regulation of energy expenditure and adaptive thermogenesis through its various effects in neuronal circuits, adipose tissue and skeletal muscle. Understanding how mTORC1 signalling in one organ and cell type affects responses in other organs and cell types could be key to developing better, safer treatments targeting this pathway in obesity.
    DOI:  https://doi.org/10.1038/s41574-023-00934-0
  4. PLoS Biol. 2024 Jan;22(1): e3002406
    The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
    Mona Nazemi, Bian Yanes, Montserrat Llanses Martinez, Heather J Walker, Khoa Pham, Mark O Collins, Frederic Bard, Elena Rainero.
      Breast tumours are embedded in a collagen I-rich extracellular matrix (ECM) network, where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism.
    DOI:  https://doi.org/10.1371/journal.pbio.3002406
  5. Sci Rep. 2024 01 17. 14(1): 1525
    Cooperative function of oncogenic MAPK signaling and the loss of Pten for melanoma migration through the formation of lamellipodia.
    Yutaka Yasuta, Ryuya Kaminaka, Shutaro Nagai, Shuto Mouri, Katsuya Ishida, Akihiro Tanaka, Yue Zhou, Hiroaki Sakurai, Satoru Yokoyama.
      The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAFV600E or GNA11Q209L, and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAFV600E or NRASQ61R background, but not with the GNA11Q209L background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAFV600E induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.
    DOI:  https://doi.org/10.1038/s41598-024-52020-8
  6. bioRxiv. 2023 Dec 27. pii: 2023.12.27.573428. [Epub ahead of print]
    PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation.
    Maria B Campaña, Madison R Perkins, Maxwell C McCabe, Andrew Neumann, Eric D Larson, Katherine A Fantauzzo.
      The platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases allows cells to communicate with one another by binding to growth factors at the plasma membrane and activating intracellular signaling pathways to elicit responses such as migration, proliferation, survival and differentiation. The PDGFR family consists of two receptors, PDGFRα and PDGFRβ, that dimerize to form PDGFRα homodimers, PDGFRα/β heterodimers and PDGFRβ homodimers. Here, we overcame prior technical limitations in visualizing and purifying PDGFRα/β heterodimers by generating a cell line stably expressing C-terminal fusions of PDGFRα and PDGFRβ with bimolecular fluorescence complementation fragments corresponding to the N-terminal and C-terminal regions of the Venus fluorescent protein, respectively. We found that these receptors heterodimerize relatively quickly in response to PDGF-BB ligand treatment, with a peak of receptor autophosphorylation following 5 minutes of ligand stimulation. Moreover, we demonstrated that PDGFRα/β heterodimers are rapidly internalized into early endosomes, particularly signaling endosomes, where they dwell for extended lengths of time. We showed that PDGFRα/β heterodimer activation does not induce downstream phosphorylation of ERK1/2 and significantly inhibits cell proliferation. Further, we characterized the PDGFR dimer-specific interactome and identified MYO1D as a novel protein that preferentially binds PDGFRα/β heterodimers. We demonstrated that knockdown of MYO1D leads to retention of PDGFRα/β heterodimers at the plasma membrane, resulting in increased phosphorylation of ERK1/2 and increased cell proliferation. Collectively, our findings impart valuable insight into the molecular mechanisms by which specificity is introduced downstream of PDGFR activation to differentially propagate signaling and generate distinct cellular responses.
    One-sentence summary: PDGFRα/β heterodimer binding to MYO1D contributes to rapid internalization of the dimerized receptors, thereby negatively affecting downstream ERK1/2 signaling and cellular proliferation.
    DOI:  https://doi.org/10.1101/2023.12.27.573428
  7. Nat Biotechnol. 2024 Jan 15.
    Disentanglement of single-cell data with biolord.
    Zoe Piran, Niv Cohen, Yedid Hoshen, Mor Nitzan.
      Biolord is a deep generative method for disentangling single-cell multi-omic data to known and unknown attributes, including spatial, temporal and disease states, used to reveal the decoupled biological signatures over diverse single-cell modalities and biological systems. By virtually shifting cells across states, biolord generates experimentally inaccessible samples, outperforming state-of-the-art methods in predictions of cellular response to unseen drugs and genetic perturbations. Biolord is available at https://github.com/nitzanlab/biolord .
    DOI:  https://doi.org/10.1038/s41587-023-02079-x
  8. Nat Biotechnol. 2024 Jan;42(1): 31
    Live cell imaging of signaling networks using a conventional microscope.
    Anahita Bishop.
      
    DOI:  https://doi.org/10.1038/s41587-023-02116-9
  9. Cell. 2024 Jan 18. pii: S0092-8674(23)01328-4. [Epub ahead of print]187(2): 257-270
    Making the connection: How membrane contact sites have changed our view of organelle biology.
    G K Voeltz, E M Sawyer, G Hajnóczky, W A Prinz.
      The view of organelles and how they operate together has changed dramatically over the last two decades. The textbook view of organelles was that they operated largely independently and were connected by vesicular trafficking and the diffusion of signals through the cytoplasm. We now know that all organelles make functional close contacts with one another, often called membrane contact sites. The study of these sites has moved to center stage in cell biology as it has become clear that they play critical roles in healthy and developing cells and during cell stress and disease states. Contact sites have important roles in intracellular signaling, lipid metabolism, motor-protein-mediated membrane dynamics, organelle division, and organelle biogenesis. Here, we summarize the major conceptual changes that have occurred in cell biology as we have come to appreciate how contact sites integrate the activities of organelles.
    DOI:  https://doi.org/10.1016/j.cell.2023.11.040
  10. Genome Biol. 2024 Jan 19. 25(1): 25
    Compact CRISPR genetic screens enabled by improved guide RNA library cloning.
    Seok-Jin Heo, Lauren D Enriquez, Scot Federman, Amy Y Chang, Rachel Mace, Kaivalya Shevade, Phuong Nguyen, Adam J Litterman, Shawn Shafer, Laralynne Przybyla, Eric D Chow.
      CRISPR genome editing approaches theoretically enable researchers to define the function of each human gene in specific cell types, but challenges remain to efficiently perform genetic perturbations in relevant models. In this work, we develop a library cloning protocol that increases sgRNA uniformity and greatly reduces bias in existing genome-wide libraries. We demonstrate that our libraries can achieve equivalent or better statistical power compared to previously reported screens using an order of magnitude fewer cells. This improved cloning protocol enables genome-scale CRISPR screens in technically challenging cell models and screen formats.
    Keywords:  CRISPR screening; Guide library; Library cloning; Primary cell CRISPR screening; iPSC-derived CRISPR screening
    DOI:  https://doi.org/10.1186/s13059-023-03132-3
  11. Elife. 2024 Jan 19. pii: e85214. [Epub ahead of print]13
    Organelle proteomic profiling reveals lysosomal heterogeneity in association with longevity.
    Yong Yu, Shihong M Gao, Youchen Guan, Pei-Wen Hu, Qinghao Zhang, Jiaming Liu, Bentian Jing, Qian Zhao, David M Sabatini, Monther Abu-Remaileh, Sung Yun Jung, Meng C Wang.
      Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk and organism longevity.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.85214
  12. J Clin Invest. 2024 Jan 16. pii: e178332. [Epub ahead of print]134(2):
    Keeping translational research grounded in human biology.
    Saptarsi M Haldar.
      
    DOI:  https://doi.org/10.1172/JCI178332
  13. Nat Rev Genet. 2024 Jan 18.
    The diversification of methods for studying cell-cell interactions and communication.
    Erick Armingol, Hratch M Baghdassarian, Nathan E Lewis.
      No cell lives in a vacuum, and the molecular interactions between cells define most phenotypes. Transcriptomics provides rich information to infer cell-cell interactions and communication, thus accelerating the discovery of the roles of cells within their communities. Such research relies heavily on algorithms that infer which cells are interacting and the ligands and receptors involved. Specific pressures on different research niches are driving the evolution of next-generation computational tools, enabling new conceptual opportunities and technological advances. More sophisticated algorithms now account for the heterogeneity and spatial organization of cells, multiple ligand types and intracellular signalling events, and enable the use of larger and more complex datasets, including single-cell and spatial transcriptomics. Similarly, new high-throughput experimental methods are increasing the number and resolution of interactions that can be analysed simultaneously. Here, we explore recent progress in cell-cell interaction research and highlight the diversification of the next generation of tools, which have yielded a rich ecosystem of tools for different applications and are enabling invaluable discoveries.
    DOI:  https://doi.org/10.1038/s41576-023-00685-8
  14. Cell Cycle. 2024 Jan 14. 1-17
    Telomere dynamics in human pluripotent stem cells.
    Buyun Ma, Paula Martínez, Raúl Sánchez-Vázquez, Maria A Blasco.
      Pluripotent stem cells (PSCs) are a promising source of stem cells for regenerative therapies. Stem cell function depends on telomere maintenance mechanisms that provide them with the proliferative capacity and genome stability necessary to multiply and regenerate tissues. We show here that established human embryonic stem cells (hESCs) have stable telomere length that is dependent on telomerase but not on alternative mechanisms based on homologous recombination pathways. Here, we show that human-induced pluripotent stem cells (hiPSCs) reprogrammed from somatic cells show progressive telomere lengthening until reaching a length similar to ESCs. hiPSCs also acquire telomeric chromatin marks of ESCs including decreased abundance of tri-methylated histone H3K9 and H4K20 and HP1 heterochromatic marks, as well as of the shelterin component TRF2. These chromatin features are accompanied with increased abundance of telomere transcripts or TERRAs. We also found that telomeres of both hESCs and hiPSCs are well protected from DNA damage during telomere elongation and once full telomere length is achieved, and exhibit stable genomes. Collectively, this study highlights that hiPSCs acquire ESC features during reprogramming and reveals the telomere biology in human pluripotent stem cells (hPSCs).
    Keywords:  Telomerase; Telomeres; hESCs; hiPSCs
    DOI:  https://doi.org/10.1080/15384101.2023.2285551
  15. Nat Cell Biol. 2024 Jan;26(1): 15-18
    Mentoring the next generation of cell biologists.
    Derek A Applewhite, Needhi Bhalla, Nina Cabezas-Wallscheid, Neta Erez, Mengfeng Li, Jose M Polo, Tomohiko Taguchi, Abdou Rachid Thiam, Xiaochen Wang.
      
    DOI:  https://doi.org/10.1038/s41556-023-01278-7
  16. Cell Syst. 2024 Jan 17. pii: S2405-4712(23)00361-7. [Epub ahead of print]15(1): 1-3
    Modes and motifs in multicellular communication.
    Anna C Kögler, Patrick Müller.
      Signaling pathways feature multiple interacting ligand and receptor variants, which are thought to act in a combinatorial manner to elicit different cellular responses. Transcriptome analyses now suggest that many signaling pathways use their components in combinations that are surprisingly often shared between otherwise dissimilar cell states.
    DOI:  https://doi.org/10.1016/j.cels.2023.12.007
  17. Curr Biol. 2024 Jan 09. pii: S0960-9822(23)01749-9. [Epub ahead of print]
    ERK-mediated curvature feedback regulates branching morphogenesis in lung epithelial tissue.
    Tsuyoshi Hirashima, Michiyuki Matsuda.
      Intricate branching patterns emerge in internal organs due to the recurrent occurrence of simple deformations in epithelial tissues. During murine lung development, epithelial cells in distal tips of the single tube require fibroblast growth factor (FGF) signals emanating from their surrounding mesenchyme to form repetitive tip bifurcations. However, it remains unknown how the cells employ FGF signaling to convert their behaviors to achieve the recursive branching processes. Here, we show a mechano-chemical regulatory system underlying lung branching morphogenesis, orchestrated by extracellular signal-regulated kinase (ERK) as a downstream driver of FGF signaling. We found that tissue-scale curvature regulated ERK activity in the lung epithelium using two-photon live cell imaging and mechanical perturbations. ERK activation occurs specifically in epithelial tissues exhibiting positive curvature, regardless of whether the change in curvature was attributable to morphogenesis or perturbations. Moreover, ERK activation accelerates actin polymerization preferentially at the apical side of cells, mechanically contributing to the extension of the apical membrane, culminating in a reduction of epithelial tissue curvature. These results indicate the existence of a negative feedback loop between tissue curvature and ERK activity that transcends spatial scales. Our mathematical model confirms that this regulatory mechanism is sufficient to generate the recursive branching processes. Taken together, we propose that ERK orchestrates a curvature feedback loop pivotal to the self-organized patterning of tissues.
    Keywords:  ERK; FRET biosensor; curvature; live-cell imaging; lung development; mathematical model; mechano-chemical feedback; mechanobiology; self-organization; tissue morphogenesis
    DOI:  https://doi.org/10.1016/j.cub.2023.12.049
  18. iScience. 2024 Jan 19. 27(1): 108711
    In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies.
    Nancy E Sealover, Patricia T Theard, Jacob M Hughes, Amanda J Linke, Brianna R Daley, Robert L Kortum.
      Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an in situ resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs. We additionally modeled resistance to targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.
    Keywords:  Biochemistry; Biochemistry methods; Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108711
  19. Commun Biol. 2024 Jan 19. 7(1): 112
    NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting.
    Swati Sharma, Marcelo Ehrlich, Manqi Zhang, Gerard C Blobe, Yoav I Henis.
      Endothelial cells express neuropilin 1 (NRP1), endoglin (ENG) and vascular endothelial growth factor receptor 2 (VEGFR2), which regulate VEGF-A-mediated vascular development and angiogenesis. However, the link between complex formation among these receptors with VEGF-A-induced signaling and biology is yet unclear. Here, we quantify surface receptor interactions by IgG-mediated immobilization of one receptor, and fluorescence recovery after photobleaching (FRAP) measurements of the mobility of another coexpressed receptor. We observe stable ENG/NRP1, ENG/VEGFR2, and NRP1/VEGFR2 complexes, which are enhanced by VEGF-A. ENG augments NRP1/VEGFR2 interactions, suggesting formation of tripartite complexes bridged by ENG. Effects on signaling are measured in murine embryonic endothelial cells expressing (MEEC+/+) or lacking (MEEC-/-) ENG, along with NRP1 and/or ENG overexpression or knockdown. We find that optimal VEGF-A-mediated phosphorylation of VEGFR2 and Erk1/2 requires ENG and NRP1. ENG or NRP1 increase VEGF-A-induced sprouting, becoming optimal in cells expressing all three receptors, and both processes are inhibited by a MEK1/2 inhibitor. We propose a model where the maximal potency of VEGF-A involves a tripartite complex where ENG bridges VEGFR2 and NRP1, providing an attractive therapeutic target for modulation of VEGF-A signaling and biological responses.
    DOI:  https://doi.org/10.1038/s42003-024-05798-2
  20. Nat Cell Biol. 2024 Jan;26(1): 5-7
    Bringing computation to biology by bridging the last mile.
    Anne E Carpenter, Shantanu Singh.
      
    DOI:  https://doi.org/10.1038/s41556-023-01286-7
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