bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–04–12
seventeen papers selected by
Xiao Qin, University of Oxford
  1. Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression.
  2. Tumour trap: engineered enhancer sequences enlisted to kill cancer cells.
  3. Multiomics and deep learning dissect regulatory syntax in human development.
  4. Temporal AI model predicts drivers of cell state trajectories across human aging.
  5. Tumor-immune trajectory context connects static tissue architecture to clinical outcomes.
  6. CRISPR-Cas-based live cell imaging of genome dynamics.
  7. High-content genetic screens identify RNA-based mechanisms to target immune evasion.
  8. Metabolomics across scales: from single cells to population studies.
  9. Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
  10. Benchmarking tools for deciphering cellular crosstalk in spatially-resolved transcriptomics.
  11. LGR5: from stem cell marker to therapeutic target.
  12. Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.
  13. Protocol for generating and characterizing Matrigel-free prostate cancer patient-derived organoids.
  14. A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation.
  15. Fine Structural Features of Complex InDels and NHEJ Repair at Naturally Occurring Damage Sites in Normal Human Colon Crypts.
  16. STAPLE: automating spatial transcriptomics analysis and AI interpretation.
  17. Regulating the dormancy of cancer stem cells: a novel approach to preventing cancer relapse.
  1. Cell Death Dis. 2026 Apr 10.
    Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression.
    Lili Li, Taekyu Ha, Jing-Xin Feng, Michael DiPrima, Dunrui Wang, Parthav Jailwala, Thomas Meyer, Justin Lack, Hidetaka Ohnuki, Giovanna Tosato.
      Despite therapeutic advances, metastatic colorectal cancer remains a therapeutic challenge as most patients will develop resistance to therapy and will progress. Epigenetic mechanisms are implicated in enabling the acquisition of new phenotypic traits as drivers of colorectal cancer progression, rather than new genetic mutations or expansion of existing mutant clones. It remains unclear, however, which epigenetic mechanisms sustain colorectal cancer plasticity, how they are induced, and how this plasticity generates subclonal diversity that drives the aggressive cancer phenotype. Here we identify the integrated stress response as an inducer of colorectal cancer cell plasticity, subclonal diversity, and tumor progression in the stress-surviving cells. Combined analysis of chromatin accessibility and gene transcription profiling in these cells found the emergence of an endogenous interferon response as a key phenotypic trait associated with subclonal colorectal cancer cell diversity, treatment resistance and heightened aggressiveness. We unveil a new experimental approach to successfully prevent treatment-resistant colorectal cancer progression by combining epigenetic modulators with a cereblon-dependent degrader of GSPT1, a regulator of protein synthesis, to normalize chromatin accessibility and induce colorectal cancer cell death. Collectively, our study identifies the integrated stress response as an inducer of epigenetic and transcriptional plasticity in colorectal cancer cells and highlights a successful approach to therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41419-026-08720-2
  2. Nature. 2026 Apr 08.
    Tumour trap: engineered enhancer sequences enlisted to kill cancer cells.
    Shi Wing Yeung, Ralf Jauch.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-00812-5
  3. Nature. 2026 Apr 08.
    Multiomics and deep learning dissect regulatory syntax in human development.
    Betty B Liu, Selin Jessa, Samuel H Kim, Yan Ting Ng, Soon Il Higashino, Georgi K Marinov, Derek C Chen, Benjamin E Parks, Li Li, Tri C Nguyen, Austin T Wang, Sean K Wang, Meng How Tan, Serena Y Tan, Michael Kosicki, Len A Pennacchio, Eyal Ben-David, Anca M Pasca, Anshul Kundaje, Kyle K H Farh, William J Greenleaf.
      Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression1. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities2. Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify 'hard' syntactic rules requiring precise motif spacing and orientation, 'soft' rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.
    DOI:  https://doi.org/10.1038/s41586-026-10326-9
  4. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715396. [Epub ahead of print]
    Temporal AI model predicts drivers of cell state trajectories across human aging.
    Javier Gόmez Ortega, Rangarajan D Nadadur, Akira Kunitomi, Steven Kothen-Hill, Julian U G Wagner, Sarp D Kurtoglu, Bumjoon Kim, Madigan M Reid, Thomas Lu, Kaho Washizu, Lukas Zanders, Han Chen, Yujie Zhang, Sarah Ancheta, Sara Lichtarge, William A Johnson, Chris Thompson, Dereck M Phan, Alexis J Combes, Andrew C Yang, Neha Tadimeti, Stefanie Dimmeler, Shinya Yamanaka, Michael Alexanian, Christina V Theodoris.
      Foundational AI models have recently shown promise for predicting the impact of perturbations on cell states. However, current models typically consider only one cell state at a time, limiting their ability to learn how cellular responses unfold over time, particularly across long trajectories such as diseases of aging. Here, we develop a temporal AI model, MaxToki, trained on nearly 1 trillion gene tokens including cell state trajectories across the human lifespan to generate cell states across long timelapses of human aging. MaxToki generalized to unseen trajectories through in-context learning and predicted novel age-modulating targets that were experimentally verified to influence age-related gene programs and functional decline in vivo. MaxToki represents a promising strategy for temporal modeling to accelerate the discovery of interventions for programming therapeutic cellular trajectories.
    DOI:  https://doi.org/10.64898/2026.03.30.715396
  5. bioRxiv. 2026 Apr 02. pii: 2026.03.26.714521. [Epub ahead of print]
    Tumor-immune trajectory context connects static tissue architecture to clinical outcomes.
    Eric M Cramer, Randy Heiland, Heber Lima da Rocha, Daniel R Bergman, Joe W Gray, Gordon B Mills, Elana J Fertig, Paul Macklin, Laura M Heiser, Young Hwan Chang.
      Multiplexed tissue imaging (MTI) has revealed recurrent tumor microenvironment (TME) architectures with prognostic value, yet these measurements are inherently static, obscuring dynamic changes in the TME that govern therapeutic response. Here, we introduce a trajectory-centric framework that reconstructs continuous TME dynamics by integrating agent-based mathematical modeling and simulation with state space analysis. This approach yields a mechanistically constrained reference landscape built entirely from in silico simulation, and onto which static patient biospecimens can be projected and mapped onto simulated TME trajectories. Systematic simulation of tumor-immune interactions in triple-negative breast cancer identifies six metastable TME states connected by transition pathways spanning immune control to immune escape. Mapping MTI data from two independent patient cohorts, including longitudinal samples from a randomized immunotherapy trial, validates this landscape by positioning individual biospecimens along inferred TME trajectories rather than in static states. We show that treatment-phase TME states, but not pre-treatment configurations, robustly predict immunotherapy response, and identical terminal states can arise from distinct trajectory histories corresponding to immune failure or resolved inflammation. Thus, this framework enables mechanistic simulations to define a reference dynamical landscape that serves as a coordinate system for interpreting static clinical spatial data, providing a principled basis for evaluating consistency, predictiveness, and clinical relevance across independent patient cohorts. Altogether, this study advances spatial tumor profiling from static state classification of human tissues to dynamic trajectory inference, establishing a quantitative framework for trajectory-informed, state-guided, and temporally adaptive immunotherapy strategies.
    DOI:  https://doi.org/10.64898/2026.03.26.714521
  6. Nat Rev Genet. 2026 Apr 08.
    CRISPR-Cas-based live cell imaging of genome dynamics.
    Yanyu Zhu, W E Moerner, Lei S Qi.
      The 3D architecture and dynamics of the genome are crucial for regulation of genome stability, transcription and cellular function. CRISPR-based live imaging technologies have enabled real-time visualization of specific genomic loci and transcripts in living cells. These tools harness customized guide RNAs and nuclease-deactivated Cas effectors to achieve precise genomic targeting, and recent methodological advances provide the 3D spatiotemporal resolution required to decipher real-time chromatin communication. These methods are elucidating the biophysical properties of chromatin, linking dynamic enhancer-promoter interactions directly to transcription, and revealing the role of 3D genome dynamics in basic cellular processes and disease. Here, we summarize the development of CRISPR-based live-cell imaging techniques, highlight the complementary 3D microscopy and analysis methods compatible with these methods, and offer perspectives on their applications to uncover fundamental principles that govern genome dynamics and function.
    DOI:  https://doi.org/10.1038/s41576-026-00949-z
  7. Nat Genet. 2026 Apr 09.
    High-content genetic screens identify RNA-based mechanisms to target immune evasion.
      
    DOI:  https://doi.org/10.1038/s41588-026-02563-5
  8. Nature. 2026 04;652(8109): 313-320
    Metabolomics across scales: from single cells to population studies.
    Theodore Alexandrov, Nicola Zamboni.
      Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.
    DOI:  https://doi.org/10.1038/s41586-026-10277-1
  9. Cell. 2026 Apr 03. pii: S0092-8674(26)00272-2. [Epub ahead of print]
    Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
    Clemens Hinterleitner, Hailey V Goldberg, Domhnall McHugh, Valentin J A Barthet, Aveline Filliol, Scott W Lowe.
      Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.
    DOI:  https://doi.org/10.1016/j.cell.2026.03.005
  10. Genome Biol. 2026 Apr 08.
    Benchmarking tools for deciphering cellular crosstalk in spatially-resolved transcriptomics.
    Li-Ting Ku, Vincent Bernard, Jimin Min, Ying Yuan, Eugene Jon Koay, Anirban Maitra, Liang Li, Ziyi Li.
       BACKGROUND: Cell-cell communication via ligand-receptor signaling is a fundamental mechanism shaping multicellular organization and functional heterogeneity within tissue microenvironments. Recent advances in spatial transcriptomics (ST) have enabled unprecedented opportunities to systematically infer such interactions under the native spatial context. While prior studies have summarized or compared existing cell-cell interaction (CCI) inference methods, comprehensive benchmarking of tools specifically developed for ST applications remains limited.
    RESULTS: Here, we present a comprehensive evaluation of nine computational CCI inference methods on a series of realistic simulation settings and nine real ST datasets from three independent studies, spanning Visium, Stereo-seq, and Xenium platforms. Method performance was assessed based on ligand-receptor prediction accuracy, spatial coherence of interactions, biological relevance via pathway enrichment, and computational efficiency.
    CONCLUSIONS: Our results demonstrate substantial variability in tool performance across spatial resolutions, tissue contexts, and platforms, offering practical guidance for tool selection. This study also highlights key challenges in applying existing tools to real ST data and provides insights to inform future advances in spatially resolved cell-cell interaction analysis.
    DOI:  https://doi.org/10.1186/s13059-026-04063-5
  11. Trends Cancer. 2026 Apr 06. pii: S2405-8033(26)00037-3. [Epub ahead of print]
    LGR5: from stem cell marker to therapeutic target.
    Peyton C High, Maya G Cappellino, Tiffani A Blackburn, Kendra S Carmon.
      Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is an established marker of normal and cancer stemlike cells. LGR5 has been implicated in promoting cancer cell plasticity that drives tumorigenesis, metastasis, and therapeutic resistance. LGR5 rapidly and constitutively internalizes and potentiates Wnt (Wingless/Int-1)/β-catenin and adhesion signaling pathways, though its precise mechanisms and interacting partners remain unresolved. An improved understanding of LGR5 signaling may provide invaluable insight into its intricate and important functions in cancer progression. Moreover, several LGR5-targeting therapies, including peptibody- and antibody-drug conjugates and bispecific antibodies, are showing promising efficacy and tolerability in colorectal cancer and other tumor types. This review discusses the cancer-related functions of LGR5 and explores the preclinical and clinical approaches to therapeutically target this enigmatic protein.
    Keywords:  LGR5; Wnt/β-catenin signaling; antibody–drug conjugate; bispecific antibody; cancer cell plasticity; colorectal cancer
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.006
  12. bioRxiv. 2026 Apr 05. pii: 2026.04.02.715982. [Epub ahead of print]
    Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.
    Lauren Riede, Alexander Borowiec, Saptarshi Mallick, Sohini Mallick, Jayati Chakrabarti, Curtis A Thorne, Kelvin W Pond.
      Colonic stem cells reside in a microenvironment enriched in epidermal growth factor, which is essential for their survival and can activate both PI3K-AKT and MAPK-ERK pathways. This predicts co-activation of both pathways within the growth factor-high stem cell compartment at the base of crypts. However, in patient-derived human colonic organoids and normal human tissue, stem cells maintain robust AKT activity while suppressing ERK signaling despite active EGFR engagement. As stem cells differentiate, they activate pulsatile ERK signaling, which is essential for migration, survival, and maintenance of barrier function. We show that AKT-dependent phosphorylation of RAF-1 at serine 259 establishes a post-receptor checkpoint that maintains ERK temporal dynamics in stem cells. Acute activation of ERK in stem cells triggers rapid global differentiation. Disruption of the ERK checkpoint via mutation of serine 259 leads to sustained AKT and ERK co-activation in stem cells. Unlike ERK/AKT coactivation driven by apoptosis, co-activation in the stem cell compartment results in the emergence of a neoplastic, architecturally disorganized cell population dominating the cell fate profile. Incredibly, introducing brief ERK pulses through AKT inhibition or ERK activation triggers re-differentiation of neoplastic cells. Consistent with duration-dependent MAPK encoding principles, these data demonstrate that regardless of baseline signaling amplitude, that ERK signaling dynamics are epistatic to total kinase signaling load in human colonic stem cells.
    SIGNIFICANCE: Stem cells must balance self-renewal and differentiation while remaining responsive to continuous mitogenic stimulation to preserve tissue homeostasis. When self-renewal is impaired, wound healing and barrier integrity decline, whereas loss of proper differentiation drives tumorigenesis. Our findings demonstrate that this balance in the human colon is achieved through temporal control of kinase signaling rather than modulation of ligand availability. By establishing an AKT-dependent ERK dynamics checkpoint, colonic stem cells suppress differentiation-inducing ERK pulses while maintaining growth factor responsiveness. These results identify kinase dynamics as a fundamental determinant of epithelial homeostasis and suggest that subtle alterations in these dynamics may destabilize tissue organization during regeneration or chronic inflammation. Temporal encoding of kinase activity thus represents a central organizing principle in human stem cell biology.
    DOI:  https://doi.org/10.64898/2026.04.02.715982
  13. STAR Protoc. 2026 Apr 07. pii: S2666-1667(26)00139-5. [Epub ahead of print]7(2): 104486
    Protocol for generating and characterizing Matrigel-free prostate cancer patient-derived organoids.
    Robin Dolgos, Romuald Parmentier, Jing Wang, Arnoud J Templeton, Kirsten D Mertz, Heike Pueschel, Helge Seifert, Ashkan Mortezavi, Tatjana Vlajnic, Cyrill A Rentsch, Lukas Bubendorf, Clémentine Le Magnen.
      Here, we present a protocol for the generation of prostate cancer patient-derived organoids (PCa PDOs) in Matrigel-free conditions. We describe steps for sample selection, pathological resection, and tissue dissociation. We then detail procedures for the generation, maintenance, and characterization of the PCa PDOs. Finally, we provide guidance for the processing of PDOs for single-cell RNA sequencing (scRNA-seq) analysis and using the prostate PDO single-cell atlas (PPScA) for both novice and advanced bioinformatic users. For complete details on the use and execution of this protocol, please refer to Dolgos et al.1.
    Keywords:  Bioinformatics; Cancer; Cell Biology; Molecular Biology; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2026.104486
  14. bioRxiv. 2026 Mar 11. pii: 2026.03.09.710586. [Epub ahead of print]
    A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation.
    Xian Zhang, Wilfred Wong, Hyein S Cho, Dapeng Yang, Gary Dixon, Renhe Luo, Dingyu Liu, Denis Torre, Shigeaki Umeda, Federico González, Gokce Askan, Aslihan Yavas, Jeyaram Ravichandran Damodaran, Robert W Rickert, Rajya Kappagantula, Fong Cheng Pan, Victoria G Aveson, Adrien Grimont, Julian Pulecio, Samuel J Kaplan, Heng Pan, Steven D Leach, Christine A Iacobuzio-Donahue, Rohit Chandwani, Christina S Leslie, Danwei Huangfu.
      The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.
    DOI:  https://doi.org/10.64898/2026.03.09.710586
  15. bioRxiv. 2026 Apr 03. pii: 2026.03.30.714948. [Epub ahead of print]
    Fine Structural Features of Complex InDels and NHEJ Repair at Naturally Occurring Damage Sites in Normal Human Colon Crypts.
    Yong Hwee Eddie Loh, Michael R Lieber, Timothy Okitsu, Cindy Okitsu, Jordan Wlodarczyk, Zarko Manojlovic, Chih-Lin Hsieh.
      DNA repair in biochemical and genetic experimental systems permits a precise definition of enzyme requirements and mechanistic steps. Comparing these findings to repair events at naturally occurring damage sites in multicellular organisms is essential for confirming and expanding these insights into a physiologic context. However, heterogeneity in any normal cell population increases with each cell division, and the reliable detection of replication-independent DNA damage sites and their repair has been a major barrier. Here, we examine single human colon crypts, which harbor natural cell clones, using a novel whole-genome sequencing (WGS) method to identify complex insertion-deletion (indel) in the crypt stem cells. Analysis of complex indel events likely repaired by non-homologous end joining occurring in crypt stem cells permits inferences about the in vivo repair of naturally occurring DNA damage within physiologically-relevant chromatin in normal human cells.
    DOI:  https://doi.org/10.64898/2026.03.30.714948
  16. bioRxiv. 2026 Apr 01. pii: 2026.03.30.715127. [Epub ahead of print]
    STAPLE: automating spatial transcriptomics analysis and AI interpretation.
    Demystifying Pancreatic Cancer Therapies TeamLab
      Spatial transcriptomics workflows often span separate tools for cell typing, neighborhoods, and cell-cell communication, yielding fragmented outputs that hinder scalability, interpretation, and reproducibility. STAPLE systematizes analyses across distinct methods into a modular framework, unifying data structures and cross-tool interoperability. End-to-end analyses are performed unassisted with a single invocation, fostering rigorous, reproducible spatial transcriptomics analysis. Its novel, AI-enabled reporting layer synthesizes quantitative results into summaries of biological findings, facilitating analysis interpretation.
    DOI:  https://doi.org/10.64898/2026.03.30.715127
  17. Cell Death Dis. 2026 Apr 04.
    Regulating the dormancy of cancer stem cells: a novel approach to preventing cancer relapse.
    Qian Wang, Ning Liang, Xiongchao Fang, Tao Yang, Xianli He, Gang Wang, Nan Wang.
      Dormant cancer stem cells (CSCs) are the root cause of the drug resistance and metastatic processes of malignant tumors, but an in-depth analysis of their biological mechanisms is needed. Dormant CSCs are in the G0 phase of the cell cycle and are characterized by enhanced autophagic activity, a stable genomic structure and strong plasticity. Recently, several new specific markers of dormant CSCs, such as p27, CD13, QSOX1, Survivin, GPD1 and BEX2, have been identified, which offer hope for targeted therapy. In addition, epigenetic modifications such as DNA methylation and histone modifications have been reported to regulate the transition between the quiescent and proliferative states of dormant CSCs. From a clinical perspective, keeping cancer stem cells in a dormant state is helpful for preventing tumor recurrence and metastasis. To this end, clarifying the potential mechanisms and molecular regulation of cancer stem cell dormancy is vital. Here, in this review, we examine recent significant findings regarding tumor stem cell dormancy in both experimental and human disease models, emphasizing the underlying molecular mechanisms, regulatory processes, experimental models, and prospective research directions aimed at advancing this field and enhancing clinical translation.
    DOI:  https://doi.org/10.1038/s41419-026-08707-z
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