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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.

Peaceful queen succession in the naked mole rat

NOMIS Researcher(s)

Published in

April 15, 2026

The eusocial naked mole rat exhibits extreme reproductive skew, with a single queen monopolizing breeding through behavioral dominance. When the queen is removed or dies, reproductive suppression is lifted, leading to aggression and intracolony conflict. While this may be advantageous under stable conditions, reliance on a single breeder may create vulnerabilities during environmental stress. Here, we report a longitudinal study of a captive colony identifying a mechanistically distinct, nonviolent mode of queen succession. Elevated colony density impaired pup survival but did not alleviate reproductive suppression or trigger aggression. In contrast, relocating the colony to a new facility caused a prolonged pause in the queen’s reproduction, without social disturbance. During this period, her daughters sequentially emerged as additional breeders, resulting in a period of peaceful plural breeding before one daughter ultimately assumed the primary reproductive status. Thus, reproductive ascension can be socially tolerated when queen reproduction declines, expanding the mechanistic framework of naked mole rat eusociality to include peaceful, fertility-based succession.

Research field(s)
Biomedical Research, Ecology, Evolutionary Biology

DOI
10.1126/sciadv.aef4157

Lifelong behavioral screen reveals an architecture of vertebrate aging

NOMIS Researcher(s)

Published in

March 12, 2026

Mapping behavior of individual vertebrate animals across lifespan could provide an unprecedented view into the lifelong process of aging. We created a platform for high-resolution continuous behavioral tracking of the African killifish across natural lifespan from adolescence to death. We found that animals follow distinct individual aging trajectories. The behaviors of long-lived animals differed markedly from those of short-lived animals, even relatively early in life, and were linked to organ-specific transcriptomic shifts. Machine-learning models accurately inferred age and even forecasted an individual’s future lifespan, given only behavior at a young age. Finally, we found that animals progressed through adulthood in a sequence of stable and stereotyped behavioral stages with abrupt transitions, revealing precise structure for an architecture of aging.

Research field(s)
Developmental Biology, Biology

DOI
10.1126/science.aea9795

The chemical habitability of Earth and rocky planets prescribed by core formation

NOMIS Researcher(s)

Published in

February 9, 2026

A crucial factor governing the habitability of exoplanets is the availability of bioessential elements such as nitrogen (N) and phosphorous (P), which foster prebiotic chemistry and sustain life after its emergence. However, concentrations of P and N in planetary mantles vary, owing to initial availability and oxidation conditions during planet formation, and thus their characterization and availability in planetary environments are challenging. Here we use a core-formation model to show that moderate oxygen fugacity during core formation is the key parameter to the availability of these two elements, with the existence of a narrow ‘chemical Goldilocks zone’ that allows both P and N to be present with the right abundances in the mantle. Earth falls within this zone, whereas planets with more reducing/oxidizing conditions will sequester P/N into the core, hindering their availability for life. Future observations refining estimates of the oxygen fugacity prevalent during exoplanet core formation will be crucial to properly evaluate exoplanetary habitability and correctly interpret possible biosignatures.

Research field(s)
Biological Physics, Chemical Physics

DOI
10.1038/s41550-026-02775-z

Estimating the causal effects of cognitive effort and policy information on party cue influence

NOMIS Researcher(s)

Published in

February 4, 2026

Party cues can influence public opinion, but the extent to which they do so varies dramatically from context to context. Why? The long-standing theory that party cues function as “heuristics” provides an answer, predicting that variation in exposure to policy information, a propensity for effortful thinking, or both causally affects the influence of party cues. However, this prediction has escaped decisive empirical testing to date, leaving in its wake a string of mixed results. Here we characterize the challenges that limit previous tests, and report on two large-scale experiments designed to overcome them. We find that exposure to policy information causally attenuates the influence of party cues, but engagement in effortful thinking per se does not. Our results advance understanding of the “when” and “why” of party cue influence; clarify a number of previously ambiguous findings; and have broad theoretical, methodological, and normative implications for understanding the influence of party cues.

Research field(s)
Psychology & Cognitive Sciences

DOI
10.1111/pops.70116

Cellular survivorship bias as a mechanistic driver of muscle stem cell aging

NOMIS Researcher(s)

Published in

January 29, 2026

Aging is characterized by a decline in the ability of tissue repair and regeneration after injury. In skeletal muscle, this decline is largely driven by impaired function of muscle stem cells (MuSCs) to efficiently contribute to muscle regeneration. We uncovered a cause of this aging-associated dysfunction: a cellular survivorship bias that prioritizes stem cell persistence at the expense of functionality. With age, MuSCs increased expression of a tumor suppressor, N-myc down-regulated gene 1 (NDRG1), which, by suppressing the mammalian target of rapamycin (mTOR) pathway, increased their long-term survival potential but at the cost of their ability to promptly activate and contribute to muscle regeneration. This delayed muscle regeneration with age may result from a trade-off that favors long-term stem cell survival over immediate regenerative capacity.

Research field(s)
Molecular Biology

DOI
10.1126/science.ads9175

Dietary methionine mitigates immune-mediated damage by enhancing renal clearance of cytokines

NOMIS Researcher(s)

Published in

January 22, 2026

The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using Yersinia pseudotuberculosis infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite S-adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death.

Research field(s)
Biochemistry & Molecular Biology, Immunology

DOI
10.1016/j.cmet.2025.12.011

Disease tolerance and infection pathogenesis age-related tradeoffs in mice

NOMIS Researcher(s)

Published in

January 14, 2026

Disease tolerance is a defence strategy essential for survival of infections, limiting physiological damage without killing the pathogen1,2. The disease course and pathology an infection may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Because successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defence strategy would change with age. Animals infected with a 50% lethal dose  (LD50) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance1,3 and can be used to define tolerance mechanisms. Here, using a polymicrobial sepsis model, we found that, despite having the same LD50, aged and young susceptible mice showed distinct disease courses. In young survivors, cardiac Foxo1 and its downstream effector Trim63 (MuRF1) protected from sepsis-induced cardiac remodelling, multi-organ injury and mortality. Conversely, in aged hosts, Foxo1 and Trim63 acted as drivers of sepsis pathogenesis and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and indicate that disease tolerance genes show antagonistic pleiotropy.

Research field(s)
Biochemistry & Molecular Biology, Geriatrics, Immunology

DOI
10.1038/s41586-025-09923-x

FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry

NOMIS Researcher(s)

Published in

January 13, 2026

FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4+ T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Treg and Tconv cells to identify cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS−) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS− CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.

Research field(s)
Biochemistry & Molecular Biology, Immunology

DOI
10.1016/j.immuni.2025.10.020

Geometry-driven asymmetric cell divisions pattern cell cycles and zygotic genome activation in the zebrafish embryo

NOMIS Researcher(s)

Published in

January 5, 2026

Early embryo geometry is one of the most invariant species-specific traits, yet its role in ensuring developmental reproducibility and robustness remains underexplored. Here we show that in zebrafish, the geometry of the fertilized egg—specifically its curvature and volume—serves as a critical initial condition triggering a cascade of events that influence development. The embryo geometry guides patterned asymmetric cell divisions in the blastoderm, generating radial gradients of cell volume and nucleocytoplasmic ratio. These gradients generate mitotic phase waves, with the nucleocytoplasmic ratio determining individual cell cycle periods independently of other cells. We demonstrate that reducing cell autonomy reshapes these waves, emphasizing the instructive role of geometry-derived volume patterns in setting the intrinsic period of the cell cycle oscillator. In addition to organizing cell cycles, early embryo geometry spatially patterns zygotic genome activation at the midblastula transition, a key step in establishing embryonic autonomy. Disrupting the embryo shape alters the zygotic genome activation pattern and causes ectopic germ layer specification, underscoring the developmental significance of geometry. Together, our findings reveal a symmetry-breaking function of early embryo geometry in coordinating cell cycle and transcriptional patterning.

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

DOI
10.1038/s41567-025-03122-1

Fertilization triggers early proteomic symmetry breaking in mammalian embryos

NOMIS Researcher(s)

Published in

December 3, 2025

While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins—many involved in protein degradation and transport—dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.

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

DOI
10.1016/j.cell.2025.11.006

A novel tamoxifen-inducible Mct8-CreERT2 mouse model for targeted studies of Mct8-expressing cells and thyroid hormone transport and function

NOMIS Researcher(s)

Published in

November 28, 2025

Deficiency of the Monocarboxylate Transporter 8 (MCT8) severely impairs thyroid hormone (TH) transport into the brain, disrupting brain development as well as peripheral TH homeostasis. Studies assessing MCT8 expression patterns and tissue-specific pathologies induced by local TH-deficiency are often inconclusive due to unreliable antibody staining and the lack of functional tools to specifically target MCT8-expressing cells. For this purpose, we generated non-inducible Mct8-Cre and tamoxifen-inducible Mct8-CreERT2 mice. Mct8-Cre;Sun1-sfGFP mice demonstrated ubiquitous Sun1-sfGFP expression, due to early recombination driven by Mct8 gene expression at the stage of trophoblast implantation. Tamoxifen injection in 6-week-old Mct8-CreERT2 mice induced reporter expression specifically in Mct8-expressing cells in the brain and peripherally in liver, kidney, and thyroid, without leaky reporter expression in vehicle controls. Using vDISCO tissue clearing and 3D-imaging of GFP-nanobody-boosted mice, we further identified the sublingual salivary gland and the prostate as prominent Mct8-expressing organs. Nuclei from Mct8-expressing cells in the brain could selectively be enriched using fluorescence-activated nuclei sorting on Mct8-CreERT2;Sun1-sfGFP mice and characterized as choroid plexus cells and tanycytes. Our new inducible Mct8-CreERT2 line provides researchers with a tool to reliably mark, enrich, and characterize Mct8-expressing cells and to genetically modify genes specifically in these cells to study thyroid hormone transport and function.

Research field(s)
Developmental Biology, Genetics & Heredity

DOI
10.1007/s11248-025-00471-8

Experimental Manipulations of Albedo and Mortality of Upper Canopy Leaves in a Tropical Forest Diverge From Earth System Model Results

NOMIS Researcher(s)

Published in

November 25, 2025

How tropical forest leaves respond to climate change has important implications for the global carbon cycle and biodiversity. Climate change could impact the energy balance properties of tropical forest canopies through (a) long-term trait changes and (b) abrupt disruptions/damage to leaf/photosynthetic machinery. We assessed the radiative and evaporative impacts of two recently proposed impacts of climate change on tropical forest canopies: (a) long-term leaf darkening and (b) leaf death through high temperature extremes. We darkened leaves to absorb 138 Wm−2 more energy in the upper canopy of a seasonally dry tropical moist forest in Panama. 20% of this extra energy went toward heating leaves by ∼4°C, 3% went toward warming the air, and 77% went toward evaporative cooling. This leaf warming led to the appearance of necrosis across 9 ± 5% of the leaf area on certain species. In contrast, brightening leaves decreased energy absorbed by an average of 58 Wm−2, which mainly reduced evaporation (88%) with only 12% reducing leaf temperatures (and no change in sensible heat flux). This asymmetrical result suggests leaves may be close to hydraulic limitations to support transpirational cooling toward the end of the dry season. Similar albedo increases in a model (CLM 4.0) did not diverge between brightening and darkening leaves and generally showed sensible heat flux to dominate although there were strong geographic trends. Heat death in leaves generally heated nearby leaves (by an average of ∼1.35°C) and air temperature (by 0.5°C) but less than hypothesized because leaf albedo increased. Overall, our canopy top experiments question important potential climate feedbacks but need further study.

Research field(s)
Ecology, Plant Biology & Botany, Environmental Sciences

DOI
10.1029/2024jg008495

Circadian regulator REV-ERBα is a master regulator of tumor lineage plasticity and an effective therapeutic target

NOMIS Researcher(s)

Published in

November 13, 2025

Epigenetic and transcriptional dysregulation plays a fundamental role in tumor lineage plasticity (LP). However, the underlying mechanisms, especially for the initial events of LP development, are still poorly understood. Here, we report that in progression of prostate cancer from adenocarcinoma to treatment-induced neuroendocrine prostate cancer (t-NEPC), anti-androgen receptor (AR) signaling inhibitors (ARSIs) reprogram the function of circadian regulator/nuclear receptor REV-ERBα by switching its target gene programs from kinase signaling and metabolic programs to programs of LP, which includes neurogenesis, stem cell, and epithelial–mesenchymal transition as well as over fifteen LP drivers including POU3F2/BRN2, ASCL1, FOXA2, ONECUT2, and MYCN. Unexpectedly, REV-ERBα facilitates the chromatin occupancy of BRN2, ASCL1, and FOXA1 in their activation of LP programs, thus functioning as a master regulator of ARSI-induced LP driver network. Mechanistically, REV-ERBα induces chromatin accessibility and H3K27ac modification at promoters of LP genes through its recruitment of BRD4 and p300. Overexpression of REV-ERBα alone is sufficient to induce LP and neuroendocrine phenotype and confers resistance to ARSI in adenocarcinoma cells. Loss of REV-ERBα potently inhibits NEPC cell growth and abolishes the expression of LP drivers and gene programs. Pharmacological inhibition of REV-ERBα exhibits high potency in blocking the growth of NEPC tumors including patient-derived xenografts. Our findings reveal that therapy-induced LP development entails a coordinated induction of a network of LP drivers and that REV-ERBα is an unexpected master regulator of the network and a promising therapeutic target for treatment of advanced prostate cancer such as NEPC.

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

DOI
10.1073/pnas.2513468122

Signal discrimination in the psychotic phenotype: increased sensory precision and reduced decision threshold associated with psychotic-like experiences

NOMIS Researcher(s)

Published in

November 12, 2025

Background

Psychotic-like experiences may reflect disrupted signal discrimination, whereby individuals overinterpret noisy sensory input as meaningful. Drawing on predictive coding accounts, we investigated whether increased sensory precision and reduced data-gathering relate to psychotic-like experiences in a signal discrimination task.

Methods

We fitted drift-diffusion models to Random Dot Motion (RDM) task data completed by 191 participants. We estimated drift rate and decision threshold: (1) across groups differing in psychotic phenotypes, and (2) as outcomes in regression models with psychotic-like experiences as predictors. Drift rate measures evidence gain and, in this task, can be considered an approximate measure of sensory precision. We also tested whether reduced data-gathering on the beads task replicated prior associations with psychotic phenotypes.

Results

Hallucination– and delusion-like experiences were associated with increased drift rates. Hallucination-like experiences also predicted lower decision thresholds. In the beads task, psychotic-like experiences correlated with higher confidence ratings but not with reduced data-gathering.

Conclusions

Our findings indicate that psychotic-like phenomenology is linked to increased precision of signal discrimination and reduced decision thresholds. Overprecise signal discrimination and lower decision thresholds may bias perceptual inference toward false positive detections, potentially leading to anomalous experiences.

Research field(s)
Clinical Psychology, Experimental Psychology

DOI
10.1080/13546805.2025.2587020

Mind over bias: How is cognitive control related to politically motivated reasoning?

NOMIS Researcher(s)

Published in

November 11, 2025

People often favour information aligned with their ideological motives. Can our tendency for directional motivated reasoning be overcome with cognitive control? It remains contested whether cognitive control processes, such as cognitive reflection and inhibitory control, are linked to a greater tendency to engage in politically motivated reasoning, as proposed by the “motivated reflection” hypothesis, or can help people overcome it, as suggested by cognitive science research. In this pre-registered study (N = 504 UK participants rating n = 4963 news messages), we first provide evidence for motivated reasoning on multiple political and non-political topics. We then investigated the associations of the two cognitive control variables cognitive reflection and inhibitory control with motivated reasoning. We find that associations between cognitive control processes and motivated reasoning are likely small. On political topics specifically, we find that a negative association with cognitive reflection is more likely than a positive association. This finding is contrary to predictions from the popular motivated reflection hypothesis. Results for inhibitory control are inconclusive. We discuss how these findings relate to interdisciplinary literature from cognitive and political psychology.

Research field(s)
Behavioral Science & Comparative Psychology, Experimental Psychology, Social Psychology

DOI
10.1016/j.cognition.2025.106373

The new frontier in understanding human and mammalian brain development

NOMIS Researcher(s)

Published in

November 5, 2025

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

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

DOI
10.1038/s41586-025-09652-1

Investigating aerosols as a way to reconcile K2-18 b JWST MIRI and NIRISS/NIRSpec observations

NOMIS Researcher(s)

Published in

October 24, 2025

Recent JWST observations of the temperate sub-Neptune K2-18 b with NIRISS SOSS/NIRSpec G395H and MIRI LRS have yielded apparently inconsistent results: the MIRI spectra exhibit spectral features nearly twice as large as those seen at shorter wavelengths, challenging the high-metallicity, CH4-rich nonequilibrium model that fits the NIRISS/NIRSpec data. We performed a suite of atmospheric retrievals on both datasets, including free-chemistry, nonequilibrium, and aerosol models, using laboratory-derived complex refractive indices for a variety of photochemical haze analogs. Free retrievals systematically output lower metallicities than inferred by self-consistent chemical disequilibrium models, and the inclusion of absorbing aerosols, especially CH4-dominated, nitrogen-poor tholins, can further reduce the inferred metallicity by over an order of magnitude. These hazes reproduce the observed NIRISS slope through scattering and match MIRI features via C–H bending absorption near 7 μm, while yielding particle properties consistent with photochemical production in H2-rich atmospheres. Although their inclusion improves the joint fit and reduces tension between datasets, it also significantly lowers the retrieved CH4 abundance, highlighting degeneracies between metallicity, composition, and aerosol properties. Our results underscore the importance of aerosol absorption in interpreting temperate sub-Neptune spectra and motivate future JWST observations and laboratory work to break these degeneracies.

Research field(s)
Physics & Astronomy

DOI
10.1051/0004-6361/202556905

WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2

NOMIS Researcher(s)

Published in

October 9, 2025

Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775. We demonstrate that this synergy depends on ISR activation, which is induced by the off-target activity of WEE1 inhibitors. Furthermore, PROTAC-based WEE1 inhibitors and molecular glues show reduced or no ISR activation, suggesting potential strategies to minimise off-target toxicity. Our findings reveal that certain WEE1 inhibitors elicit dual toxicity via ISR activation and genotoxic stress, with ISR activation being independent of WEE1 itself or cell-cycle status. This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors.

Research field(s)
Molecular Biology, Genetics & Heredity

DOI
10.1038/s41467-025-64050-5

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

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