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Research is the vital expression of humankind’s most important qualities: curiosity and imagination.

Explorers, inventors, pioneers—dedicated researchers on the frontiers of science and the humanities.

Insight, when it comes, changes everything.

Publications

The NOMIS community of researchers and partners is instrumental in driving interdisciplinary collaboration, generating insights and ultimately advancing our understanding of the world. A key component of these efforts is knowledge sharing. Comprising a unique offering of engaging scientific lectures, insightful films about our awardees’ research, and a comprehensive publication database, NOMIS Insights are designed to facilitate the sharing of knowledge. They showcase the groundbreaking findings and innovative perspectives born from NOMIS-supported research endeavors, embodying our dedication to enabling scientific progress.

Our NOMIS Insight database provides a comprehensive source of all publications resulting from NOMIS-supported research projects.

Reprogramming neuroblastoma by diet-enhanced polyamine depletion

NOMIS Researcher(s)

Published in

September 24, 2025

Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.

Research field(s)
Biochemistry & Molecular Biology, Developmental Biology, Genetics & Heredity, Pediatrics

DOI
10.1038/s41586-025-09564-0

Culture-independent meta-pangenomics enabled by long-read metagenomics reveals associations with pediatric undernutrition

NOMIS Researcher(s)

Published in

September 9, 2025

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44–64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species predictive of linear growth. Pangenome analyses revealed microbial genetic associations with linear growth, while genome instability correlated with declining length-for-age Z score (LAZ). This resource demonstrates the power of comparing cMAGs with health trajectories and establishes a new standard for microbiome association studies.

Research field(s)
Bioinformatics, Microbiology, Pediatrics

DOI
10.1016/j.cell.2025.08.020

Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes

NOMIS Researcher(s)

Published in

September 4, 2025

Base editors create precise genomic edits by directing nucleobase deamination or removal without inducing double-stranded DNA breaks. However, a vast chemical space of other DNA modifications remains to be explored for genome editing. Here we harness the bacterial antiphage toxin DarT2 to append ADP-ribosyl moieties to DNA, unlocking distinct editing outcomes in bacteria versus eukaryotes. Fusing an attenuated DarT2 to a Cas9 nickase, we program site-specific ADP-ribosylation of thymines within a target DNA sequence. In tested bacteria, targeting drives homologous recombination, offering flexible and scar-free genome editing without base replacement or counterselection. In tested yeast, plant and human cells, targeting drives substitution of the modified thymine to adenine or a mixture of adenine and cytosine with limited insertions or deletions, offering edits inaccessible to current base editors. Altogether, our approach, called append editing, leverages the addition of chemical moieties to DNA to expand current modalities for precision gene editing.

Research field(s)
Biotechnology, Biochemistry & Molecular Biology, Genetics & Heredity, Microbiology

DOI
10.1038/s41587-025-02802-w

The actin cortex acts as a mechanical memory of morphology in confined migrating cells

NOMIS Researcher(s)

Published in

August 25, 2025

Cell migration in narrow microenvironments occurs in numerous physiological processes. It involves successive cycles of confinement and release that drive important morphological changes. However, it remains unclear whether migrating cells can retain a memory of their past morphological states that could potentially facilitate their navigation through confined spaces. We demonstrate that local geometry governs a switch between two cell morphologies, thereby facilitating cell passage through long and narrow gaps. We combined cell migration assays on standardized microsystems with biophysical modelling and biochemical perturbations to show that migrating cells have a long-term memory of past confinement events. The morphological cell states correlate across transitions through actin cortex remodelling. These findings indicate that mechanical memory in migrating cells plays an active role in their migratory potential in confined environments.

Research field(s)
Biomedical Engineering, Biochemistry & Molecular Biology, Biophysics

DOI
10.1038/s41567-025-02980-z

A male-essential miRNA is key for avian sex chromosome dosage compensation

NOMIS Researcher(s)

Published in

July 16, 2025

Birds have a sex chromosome system in which females are heterogametic (ZW) and males are homogametic (ZZ)1. The differentiation of avian sex chromosomes from ancestral autosomes entails the loss of most genes from the W chromosome during evolution1,2. However, the extent to which mechanisms evolved that counterbalance this substantial reduction in female gene dosage remains unclear. Here we report functional in vivo and evolutionary analyses of a Z-linked microRNA (miR-2954) with strong male-biased expression, previously proposed to mediate avian sex chromosome dosage compensation3. We knocked out miR-2954 in chicken, which resulted in early embryonic lethality in homozygous knockout males, probably driven by specific upregulation of dosage-sensitive Z-linked target genes. Evolutionary gene expression analyses further revealed that these dosage-sensitive target genes underwent both transcriptional and translational upregulation on the single Z in female birds. Altogether, this work unveils a scenario in which evolutionary pressures following W gene loss drove transcriptional and translational upregulation of dosage-sensitive Z-linked genes in females but also their transcriptional upregulation in males. The resulting excess of transcripts in males, resulting from the combined activity of two upregulated dosage-sensitive Z gene copies, was in turn offset by the emergence of a highly targeted miR-2954-mediated transcript degradation mechanism during avian evolution. This study uncovered a unique sex chromosome dosage compensation system in birds, in which a microRNA has become essential for male survival.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Developmental Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.1038/s41586-025-09256-9

Atlas of amnion development during the first trimester of human pregnancy

NOMIS Researcher(s)

Published in

July 14, 2025

The amnion is a critical extra-embryonic structure that supports foetal development, yet its ontogeny remains poorly defined. Here, using single-cell transcriptomics, we identified major cell types and subtypes in the human amnion across the first trimester of pregnancy, broadly categorized into epithelial, mesenchymal and macrophage lineages. We uncovered epithelial–mesenchymal and epithelial–immune transitions, highlighting dynamic remodelling during early pregnancy. Our results further revealed key intercellular communication pathways, including BMP4 signalling from mesenchymal to epithelial cells and TGF-β signalling from macrophages to mesenchymal cells, suggesting coordinated interactions that drive amnion morphogenesis. In addition, integrative comparisons across humans, non-human primates and in vitro stem cell-based models reveal that stem cell-based models recapitulate various stages of amnion development, emphasizing the need for careful selection of model systems to accurately recapitulate in vivo amnion formation. Collectively, our findings provide a detailed view of amnion cellular composition and interactions, advancing our understanding of its developmental role and regenerative potential.

Research field(s)
Molecular Biology, Developmental Biology, Microbiology

DOI
10.1038/s41556-025-01696-9

A foundation model to predict and capture human cognition

NOMIS Researcher(s)

Published in

July 2, 2025

Establishing a unified theory of cognition has been an important goal in psychology1,2. A first step towards such a theory is to create a computational model that can predict human behaviour in a wide range of settings. Here we introduce Centaur, a computational model that can predict and simulate human behaviour in any experiment expressible in natural language. We derived Centaur by fine-tuning a state-of-the-art language model on a large-scale dataset called Psych-101. Psych-101 has an unprecedented scale, covering trial-by-trial data from more than 60,000 participants performing in excess of 10,000,000 choices in 160 experiments. Centaur not only captures the behaviour of held-out participants better than existing cognitive models, but it also generalizes to previously unseen cover stories, structural task modifications and entirely new domains. Furthermore, the model’s internal representations become more aligned with human neural activity after fine-tuning. Taken together, our results demonstrate that it is possible to discover computational models that capture human behaviour across a wide range of domains. We believe that such models provide tremendous potential for guiding the development of cognitive theories, and we present a case study to demonstrate this.

Research field(s)
Information & Communication Technologies, Psychology & Cognitive Sciences, Psychology & Cognitive Sciences, Behavioral Science & Comparative Psychology

DOI
10.1038/s41586-025-09215-4

Capturing the complexity of human strategic decision-making with machine learning

NOMIS Researcher(s)

Published in

June 25, 2025

Strategic decision-making is a crucial component of human interaction. Here we conduct a large-scale study of strategic decision-making in the context of initial play in two-player matrix games, analysing over 90,000 human decisions across more than 2,400 procedurally generated games that span a much wider space than previous datasets. We show that a deep neural network trained on this dataset predicts human choices with greater accuracy than leading theories of strategic behaviour, revealing systematic variation unexplained by existing models. By modifying this network, we develop an interpretable behavioural model that uncovers key insights: individuals’ abilities to respond optimally and reason about others’ actions are highly context dependent, influenced by the complexity of the game matrices. Our findings illustrate the potential of machine learning as a tool for generating new theoretical insights into complex human behaviours.

Research field(s)
Information & Communication Technologies, Psychology & Cognitive Sciences

DOI
10.1038/s41562-025-02230-5

SARS-CoV-2 nucleocapsid protein directly prevents cGAS–DNA recognition through competitive binding

NOMIS Researcher(s)

Published in

June 23, 2025
A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA—leaked from mitochondria or nuclei during infection—remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid–sensing pathways.

Research field(s)
Biological Physics, Biochemistry & Molecular Biology, Virology, Immunology

DOI
10.1073/pnas.2426204122

Succinate undermines FOXP3 stability and disrupts Treg cell function

NOMIS Researcher(s)

Published in

June 2, 2025

Increased levels of succinate in individuals with inflammatory bowel disease suppress succinylation of the transcription factor FOXP3, leading to its increased ubiquitination and degradation in intestinal regulatory T cells. This process exacerbates colon inflammation and contributes to disease progression.

DOI
10.1038/s41590-025-02167-x

Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS)

NOMIS Researcher(s)

Published in

June 2, 2025

The observation of Liquid-Liquid Phase Separation (LLPS) in biological cells has dramatically shifted the paradigm that soluble proteins are uniformly dispersed in the cytoplasm or nucleoplasm. The LLPS region is preceded by a one-phase solution, where recent experiments have identified clusters in an aqueous solution with 102-103 proteins. Here, we theoretically consider a core-shell model with mesoscale core, surface, and bending properties of the clusters’ shell and contrast two experimental paradigms for the measured cluster size distributions of the Cytoplasmic Polyadenylation Element Binding-4 (CPEB4) and Fused in Sarcoma (FUS) proteins. The fits to the theoretical model and earlier electron paramagnetic resonance (EPR) experiments suggest that the same protein may exhibit hydrophilic, hydrophobic, and amphiphilic conformations, which act to stabilize the clusters. We find that CPEB4 clusters are much more stable compared to FUS clusters, which are less energetically favorable. This suggests that in CPEB4, LLPS consists of large-scale aggregates of clusters, while for FUS, clusters coalesce to form micron-scale LLPS domains.

Research field(s)
Biological Physics, Chemical Physics

DOI
10.1038/s42005-025-02134-w

Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates

NOMIS Researcher(s)

Published in

May 23, 2025

Cytosolic aggregation of the nuclear protein TAR DNA-binding protein 43 (TDP-43) is associated with many neurodegenerative diseases, but the triggers for TDP-43 aggregation are still debated. Here, we demonstrate that TDP-43 aggregation requires a double event. One is up-concentration in stress granules beyond a threshold, and the other is oxidative stress. These two events collectively induce intra-condensate demixing, giving rise to a dynamic TDP-43-enriched phase within stress granules, which subsequently transition into pathological aggregates. Intra-condensate demixing of TDP-43 is observed in iPS-motor neurons, a disease mouse model, and patient samples. Mechanistically, intra-condensate demixing is triggered by local unfolding of the RRM1 domain for intermolecular disulfide bond formation and by increased hydrophobic patch interactions in the C-terminal domain. By engineering TDP-43 variants resistant to intra-condensate demixing, we successfully eliminate pathological TDP-43 aggregates in cells. We suggest that up-concentration inside condensates followed by intra-condensate demixing could be a general pathway for protein aggregation.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology, Biophysics

DOI
10.1016/j.cell.2025.04.039

Robust prediction of synthetic gRNA activity and cryptic DNA repair by disentangling cellular CRISPR cleavage outcomes

NOMIS Researcher(s)

Published in

May 21, 2025

The ability to robustly predict guide RNA (gRNA) activity is a long-standing goal for CRISPR applications, as it would reduce the need to pre-screen gRNAs. Quantification of formation of short insertions and deletions (indels) after DNA cleavage by transcribed gRNAs has been typically used to measure and predict gRNA activity. We evaluate the effect of chemically synthesized Cas9 gRNAs on different cellular DNA cleavage outcomes and find that the activity of different gRNAs is largely similar and often underestimated when only indels are scored. We provide a simple linear model that reliably predicts synthetic gRNA activity across cell lines, robustly identifies inefficient gRNAs across different published datasets, and is easily accessible via online genome browser tracks. In addition, we develop a homology-directed repair efficiency prediction tool and show that unintended large-scale repair events are common for Cas9 but not for Cas12a, which may be relevant for safety in gene therapy applications.

Research field(s)
Genetics & Heredity

DOI
10.1038/s41467-025-59947-0

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS

NOMIS Researcher(s)

Published in

May 19, 2025

Mutations in FUS and TARDBP cause amyotrophic lateral sclerosis (ALS), but the precise mechanisms of selective motor neuron degeneration remain unresolved. To address if pathomechanisms are shared across mutations and related to either gain- or loss-of-function, we performed single-cell RNA sequencing across isogenic induced pluripotent stem cell-derived neuron types, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. Transcriptional changes were far more pronounced in motor neurons than interneurons. About 20% of uniquely dysregulated motor neuron transcripts were shared across FUS mutations, half from gain-of-function. Most indicated mitochondrial impairments, with attenuated pathways shared with mutant TARDBP M337V as well as C9orf72-ALS patient motor neurons. Mitochondrial motility was impaired in ALS motor axons, even with nuclear localized FUS mutants, demonstrating shared toxic gain-of-function mechanisms across FUS- and TARDBP-ALS, uncoupled from protein mislocalization. These early mitochondrial dysfunctions unique to motor neurons may affect survival and represent therapeutic targets in ALS.

Research field(s)
Molecular Biology, Neuroscience, Biochemistry & Molecular Biology

DOI
10.1038/s41467-025-59679-1

Small-molecule dissolution of stress granules by redox modulation benefits ALS models

NOMIS Researcher(s)

Published in

May 14, 2025

Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology

DOI
10.1038/s41589-025-01893-5

Realism Drives Interpersonal Reciprocity but Yields to AI-Assisted Egocentrism in a Coordination Experiment

NOMIS Researcher(s)

Published in

April 25, 2025

Virtual reality technologies that enhance realism and artificial intelligence (AI) systems that assist human behavior are increasingly interwoven in social applications. However, how these technologies might jointly influence interpersonal coordination remains unclear. We conducted an experiment with 240 participants in 120 pairs who interacted through remote-controlled robot cars in a physical space or virtual cars in a digital space, with or without autosteering assistance, using the chicken game, an established model of interpersonal coordination. We find that both realism and AI assistance help improve user performance but through opposing mechanisms. Real-world contexts enhanced communication, fostering reciprocal actions and collective benefits. In contrast, autosteering assistance diminished the need for interpersonal coordination, shifting participants’ focus towards self-interest. Notably, when combined, the egocentric effects of autosteering assistance outweighed the prosocial effects of realism. The design of HCI systems that involve social coordination will, we believe, need to take such effects into account.

Research field(s)
Information & Communication Technologies, Behavioral Science & Comparative Psychology

DOI
10.1145/3706598.3713371

Exchange anisotropies in microwave-driven singlet-triplet qubits

NOMIS Researcher(s)

Published in

April 24, 2025

Hole spin qubits are emerging as the workhorse of semiconducting quantum processors because of their large spin-orbit interaction, enabling fast, low-power, all-electric operations. However, this interaction also causes non-uniformities, resulting in site-dependent qubit energies and anisotropies. Although these anisotropies enable single-spin control, if not properly harnessed, they can hinder scalability. Here, we report on microwave-driven singlet-triplet qubits in planar germanium and use them to investigate spin anisotropies. For in-plane magnetic fields, the spins are largely anisotropic and electrically tunable, allowing access to all transitions and coherence times exceeding 3 μs are extracted. For out-of-plane fields they have an isotropic response. Even in this field direction, where the qubit lifetime is strongly affected by nuclear spins, we find 400 ns coherence times. Our work adds a valuable tool to investigate and harness the spin anisotropies, applicable to two-dimensional devices, facilitating the path towards scalable quantum processors.

Research field(s)
Quantum, Microwave, Qubits

DOI
10.1038/s41467-025-58969-y

Binary climate data visuals amplify perceived impact of climate change

NOMIS Researcher(s)

Published in

April 17, 2025

For much of the global population, climate change appears as a slow, gradual shift in daily weather. This leads many to perceive its impacts as minor and results in apathy (the ‘boiling frog’ effect). How can we convey the urgency of the crisis when its impacts appear so subtle? Here, through a series of large-scale cognitive experiments (N = 799), we find that presenting people with binary climate data (for example, lake freeze history) significantly increases the perceived impact of climate change (Cohen’s d = 0.40, 95% confidence interval 0.26–0.54) compared with continuous data (for example, mean temperature). Computational modelling and follow-up experiments (N = 398) suggest that binary data enhance perceived impact by creating an ‘illusion’ of sudden shifts. Crucially, our approach does not involve selective data presentation but rather compares different datasets that reflect equivalent trends in climate change over time. These findings, robustly replicated across multiple experiments, provide a cognitive basis for the ‘boiling frog’ effect and offer a psychologically grounded approach for policymakers and educators to improve climate change communication while maintaining scientific accuracy.

Research field(s)
Information & Communication Technologies, Psychology & Cognitive Sciences, Behavioral Science & Comparative Psychology

DOI
10.1038/s41562-025-02183-9

DNA binding and mitotic phosphorylation protect polyglutamine proteins from assembly formation

NOMIS Researcher(s)

Published in

April 15, 2025
Polyglutamine (polyQ) expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyQ tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2’s eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the “EVO patch,” and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA-binding domain, a phosphomimetic variant of this EVO patch, or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.

Research field(s)
Neuroscience, Biochemistry & Molecular Biology, Genetics & Heredity, Evolutionary Biology

DOI
10.1016/j.cell.2025.03.031

Comprehensive interrogation of synthetic lethality in the DNA damage response

NOMIS Researcher(s)

Published in

April 9, 2025

The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability1,2. Unravelling the complementary interplay between these pathways remains a challenge3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

Partnership(s)
,

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Genetics & Heredity, Oncology & Carcinogenesis

DOI
10.1038/s41586-025-08815-4

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