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Theresia Gutmann*#, David Kuster*, Anthony Hyman#
SARS-CoV-2 nucleocapsid protein directly prevents cGAS-DNA recognition through competitive binding.
Proc Natl Acad Sci U.S.A., 122(26) Art. No. doi: 10.1073/pnas.2426204122 (2025)
Open Access PubMed Source   

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.
@article{Gutmann9017,
author={Theresia Gutmann, David Kuster, Anthony Hyman},
title={SARS-CoV-2 nucleocapsid protein directly prevents cGAS-DNA recognition through competitive binding.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={122},
issue ={26},
pages={1--1},
year=2025
}

Yaqing Zhang#, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony Hyman, Andres Jäschke#
Single-step discovery of high-affinity RNA ligands by UltraSelex.
Nat Chem Biol, 21(7) 1118-1126 (2025)
PubMed Source Full Text   

Aptamers, nucleic acid ligands targeting specific molecules, have emerged as drug candidates, sensors, imaging tools and nanotechnology building blocks. The predominant method for their discovery, systematic evolution of ligands by exponential enrichment, while successful, is laborious, time-consuming and often results in candidates enriched for unintended criteria. Here we present UltraSelex, a noniterative method that combines biochemical partitioning, high-throughput sequencing and computational signal-to-background rank modeling for discovering RNA aptamers in about 1 day. UltraSelex identified high-affinity RNA aptamers capable of binding a fluorogenic silicon rhodamine dye and two protein targets, the SARS-CoV-2 RNA-dependent RNA polymerase and HIV reverse transcriptase, enabling live-cell RNA imaging and efficient enzyme inhibition, respectively. From the ranked sequences, minimal aptamer motifs could be easily inferred. UltraSelex provides a rapid route to reveal new drug candidates and diagnostic tools.
@article{Zhang8945,
author={Yaqing Zhang, Yuan Jiang, David Kuster, Qiwei Ye, Wenhao Huang, Simon Fürbacher, Jingye Zhang, Pia Doll, Wenjun Lin, Siwei Dong, Hui Wang, Zhipeng Tang, David Ibberson, Klemens Wild, Irmgard Sinning, Anthony Hyman, Andres Jäschke},
title={Single-step discovery of high-affinity RNA ligands by UltraSelex.},
journal ={Nature chemical biology},
volume={21},
issue ={7},
pages={1118--1126},
year=2025
}

Yu Meng, Szabolcs Horvát, Carl D. Modes, Pierre A. Haas
Impossible ecologies: Interaction networks and stability of coexistence in ecological communities.
Cell Syst, Art. No. doi: 10.1016/j.cels.2025.101297 (2025)
Open Access PubMed Source   

Does an ecological community allow stable species coexistence? Identifying the general effects of competitive, mutualistic, and predator-prey interactions on stability remains a central problem of systems ecology because established approaches cannot account for the full network arrangement of these interactions. Here, we therefore analyze all interaction networks of N≤5 species with Lotka-Volterra dynamics by combining exact results and numerical exploration. We find that a very small subset of these networks is "impossible ecologies," in which stable coexistence is non-trivially impossible. We prove that the possibility of stable coexistence is determined by similarly rare "irreducible ecologies." Statistical sampling shows that this probability varies over orders of magnitude even in ecologies that differ only in the network arrangement of identical interactions. Thus, our approach reveals that the full network structure of interactions can influence stability of coexistence more than the established effect of interaction-type proportions. A record of this paper's transparent peer review process is included in the supplemental information.
@article{Meng9018,
author={Yu Meng, Szabolcs Horvát, Carl D. Modes, Pierre A. Haas},
title={Impossible ecologies: Interaction networks and stability of coexistence in ecological communities.},
journal ={Cell systems},
volume={},
pages={null--null},
year=2025
}

Woorin Kim#, Nicola Schmidt, Matthias Jost, Elijah Mbandi Mkala, Sylke Winkler, Guangwan Hu, Tony Heitkam#, Stefan Wanke#
Diverging repeatomes in holoparasitic Hydnoraceae uncover a playground of genome evolution.
New Phytol, Art. No. doi: 10.1111/nph.70280 (2025)
Open Access PubMed Source   

The transition from an autotrophic to a heterotrophic lifestyle is associated with numerous genomic changes. These often involve large genomic alterations, potentially driven by repetitive DNAs. Despite their recognized role in shaping plant genomes, the contribution of repetitive DNAs to parasitic plant genome evolution remains largely unexplored. This study presents the first analysis of repetitive DNAs in Hydnoraceae genomes, a plant family whose members are holoparasitic. Repetitive DNAs were identified and annotated de novo. Abundant transposable elements and 35S ribosomal DNA in the Hydnora visseri genome were reconstructed in silico. Their patterns of abundance and presence-absence were individually and comparatively analyzed. Both Hydnoraceae genera, Hydnora and Prosopanche, exhibit distinct repeatome profiles which challenge our current understanding of repeatome and rDNA evolution. The Hydnora genomes are dominated by long terminal repeat retrotransposons, while the Prosopanche genomes vary greatly in their repeat composition: Prosopanche bonacinae with a highly abundant single DNA transposon and Prosopanche panguanensis with over 15% 5S rDNA, compared to ≤ 0.1% in the Hydnora genomes. The repeat profiles align with the phylogeny, geographical distribution, and host shifts of the Hydnoraceae, indicating a potential role of repetitive DNAs in shaping Hydnoraceae genomes to adapt to the parasitic lifestyle.
@article{Kim9014,
author={Woorin Kim, Nicola Schmidt, Matthias Jost, Elijah Mbandi Mkala, Sylke Winkler, Guangwan Hu, Tony Heitkam, Stefan Wanke},
title={Diverging repeatomes in holoparasitic Hydnoraceae uncover a playground of genome evolution.},
journal ={New phytologist, The},
volume={},
pages={1--1},
year=2025
}

Shiheng Zhao, Pierre A. Haas
Mechanics of Poking a Cyst.
Phys Rev Lett, 134(22) Art. No. 228402 (2025)
Open Access Source   

Indentation tests are classical tools to determine material properties. For biological samples such as cysts of cells, however, the observed force-displacement relation cannot be expected to follow predictions for simple materials. Here, by solving the Pogorelov problem of a point force indenting an elastic shell for a purely nonlinear material, we discover that complex material behavior can even give rise to new scaling exponents in this force-displacement relation. In finite-element simulations, we show that these exponents are surprisingly robust, persisting even for thick shells indented with a sphere. By scaling arguments, we generalize our results to pressurized and prestressed shells, uncovering additional new scaling exponents. We find these predicted scaling exponents in the force-displacement relation observed in cyst indentation experiments. Our results thus form the basis for inferring the mechanisms that set the mechanical properties of these biological materials.
@article{Zhao9019,
author={Shiheng Zhao, Pierre A. Haas},
title={Mechanics of Poking a Cyst.},
journal ={Physical review letters},
volume={134},
issue ={22},
pages={null--null},
year=2025
}

Matthias Höllerhage*, Linghan Duan*, Oscar Wing Ho Chua, Claudia Moebius, Svenja H Bothe, Kristina Losse, Rebecca Kotzur, Kristina Lau, Franziska Hopfner, Franziska Richter, Christian Wahl-Schott, Marc Bickle, Günter U Höglinger
A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson's disease cell model.
Transl Neurodegener, 14(1) Art. No. 27 (2025)
Open Access PubMed Source   

Alpha-synuclein (αSyn) is a major player in the pathophysiology of synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. To date, there is no disease-modifying therapy available for these synucleinopathies. Furthermore, the intracellular mechanisms by which αSyn confers toxicity are not yet fully understood. Therefore, it is of utmost importance to investigate the pathophysiology of αSyn-induced toxicity in order to identify novel molecular targets for the development of disease-modifying therapies.
@article{Höllerhage9010,
author={Matthias Höllerhage, Linghan Duan, Oscar Wing Ho Chua, Claudia Moebius, Svenja H Bothe, Kristina Losse, Rebecca Kotzur, Kristina Lau, Franziska Hopfner, Franziska Richter, Christian Wahl-Schott, Marc Bickle, Günter U Höglinger},
title={A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson's disease cell model.},
journal ={Translational neurodegeneration},
volume={14},
issue ={1},
pages={null--null},
year=2025
}

Meri Abgaryan*, Xinning Cui*, Nandu Gopan, Gabriel della Maggiora, Artur Yakimovich, Ivo F. Sbalzarini
Regularized Gradient Statistics Improve Generative Deep Learning Models of Super Resolution Microscopy.
Small Methods, Art. No. doi: 10.1002/smtd.202401900 (2025)
Open Access Source   

It is shown that regularizing the signal gradient statistics during training of deep-learning models of super-resolution fluorescence microscopy improves the generated images. Specifically, regularizing the images in the training data set is proposed to have gradient and Laplacian statistics closer to those expected for natural-scene images. The BioSR data set of matched pairs of diffraction-limited and super-resolution images is used to evaluate the proposed regularization in a state-of-the-art generative deep-learning model of super-resolution microscopy, the Conditional Variational Diffusion Model (CVDM). Since the proposed regularization is applied as a preprocessing step to the training data, it can be used in conjunction with any supervised machine-learning model. However, its utility is limited to images for which the prior is appropriate, which in the BioSR data set are the images of filamentous structures. The quality and generalization power of CVDM trained with and without the proposed regularization are compared, showing that the new prior yields images with clearer visual detail and better small-scale structure.
@article{Abgaryan9008,
author={Meri Abgaryan, Xinning Cui, Nandu Gopan, Gabriel della Maggiora, Artur Yakimovich, Ivo F. Sbalzarini},
title={Regularized Gradient Statistics Improve Generative Deep Learning Models of Super Resolution Microscopy.},
journal ={Small methods},
volume={},
pages={1--1},
year=2025
}

Gonen Golani#, Manas Seal, Mrityunjoy Kar, Anthony Hyman, Daniella Goldfarb, Samuel Safran#
Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS).
Communications Physics, 8(1) Art. No. 226 (2025)
Open Access Source   

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.
@article{Golani9013,
author={Gonen Golani, Manas Seal, Mrityunjoy Kar, Anthony Hyman, Daniella Goldfarb, Samuel Safran},
title={Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS).},
journal ={Communications Physics},
volume={8},
issue ={1},
pages={null--null},
year=2025
}

Justina Stark#, Rohit Krishnan Harish, Ivo F. Sbalzarini, Michael Brand#
Morphogen gradients are regulated by porous media characteristics of the developing tissue.
Development, Art. No. doi: 10.1242/dev.204312 (2025)
Open Access PubMed Source   

Long-range morphogen gradients have been proposed to form by morphogen diffusion from a localized source to distributed sinks in the target tissue. The role of the complex tissue geometry in this process is, however, less well understood and has not been explicitly resolved in existing models. Here, we numerically reconstruct pore-scale 3D geometries of zebrafish epiboly from light-sheet microscopy volumes. In these high-resolution 3D geometries, we simulate Fgf8a gradient formation in the tortuous extracellular space. Our simulations show that when realistic embryo geometries are considered, a source-diffusion-degradation mechanism with additional binding to extracellular matrix polymers is sufficient to explain self-organized emergence and robust maintenance of Fgf8a gradients. The predicted normalized gradient is robust against changes in source and sink rates but sensitive to changes in the pore connectivity of the extracellular space, with lower connectivity leading to steeper and shorter gradients. This demonstrates the importance of considering realistic geometries when studying morphogen gradients.
@article{Stark9009,
author={Justina Stark, Rohit Krishnan Harish, Ivo F. Sbalzarini, Michael Brand},
title={Morphogen gradients are regulated by porous media characteristics of the developing tissue.},
journal ={Development (Cambridge, England)},
volume={},
pages={1--1},
year=2025
}

Kaitlyn M Abshire, Louise Dagher, Francisca Espinoza, Arushi Gupta, James E Hammond, Alexandra T Lion, Fjodor Merkuri, Yuchuan Miao, Jakke Neiro, Maya Pahima, Chaitra Prabhakara, Ekasit K Sonpho, Ruth Styfhals, Marc Trani Bustos, Frederic Zimmer
Embryology 2024: a summer like no other.
Development, 152(11) Art. No. doi:10.1242/dev.204908 (2025)
PubMed Source  

@article{Abshire9007,
author={Kaitlyn M Abshire, Louise Dagher, Francisca Espinoza, Arushi Gupta, James E Hammond, Alexandra T Lion, Fjodor Merkuri, Yuchuan Miao, Jakke Neiro, Maya Pahima, Chaitra Prabhakara, Ekasit K Sonpho, Ruth Styfhals, Marc Trani Bustos, Frederic Zimmer},
title={Embryology 2024: a summer like no other.},
journal ={Development (Cambridge, England)},
volume={152},
issue ={11},
pages={1--1},
year=2025
}
* joint first authors, # joint corresponding authors