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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
}

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
}

Luis David Garcia Puente, Elizabeth Gross, Heather A Harrington, Matthew Johnston, Nicolette Meshkat, Mercedes Perez Millan, Anne Shiu
Absolute concentration robustness: Algebra and geometry.
J SYMB COMPUT, 128 Art. No. 102398 (2025)
Open Access Source   

Motivated by the question of how biological systems maintain homeostasis in changing environments, Shinar and Feinberg introduced in 2010 the concept of absolute concentration robustness (ACR). A biochemical system exhibits ACR in some species if the steady-state value of that species does not depend on initial conditions. Thus, a system with ACR can maintain a constant level of one species even as the initial condition changes. Despite a great deal of interest in ACR in recent years, the following basic question remains open: How can we determine quickly whether a given biochemical system has ACR? Although various approaches to this problem have been proposed, we show that they are incomplete. Accordingly, we present new methods for deciding ACR, which harness computational algebra. We illustrate our results on several biochemical signaling networks.
@article{Puente8861,
author={Luis David Garcia Puente, Elizabeth Gross, Heather A Harrington, Matthew Johnston, Nicolette Meshkat, Mercedes Perez Millan, Anne Shiu},
title={Absolute concentration robustness: Algebra and geometry.},
journal ={Journal of Symbolic Computation },
volume={128},
pages={1--1},
year=2025
}

Anna Dowbaj*, Aleksandra Sljukic*, Armin Niksic, Cedric Landerer, Julien Delpierre, Haochen Yang, Aparajita Lahree, Ariane C Kühn, David Beers, Helen M Byrne, Sarah Seifert, Heather A Harrington, Marino Zerial, Meritxell Huch
Mouse liver assembloids model periportal architecture and biliary fibrosis.
Nature, Art. No. https://doi.org/10.1038/s41586-025-09183-9 (2025)
PubMed Source Full Text   

Modelling liver disease requires in vitro systems that replicate disease progression1,2. Current tissue-derived organoids fail to reproduce the complex cellular composition and tissue architecture observed in vivo3. Here, we describe a multicellular organoid system composed of adult hepatocytes, cholangiocytes and mesenchymal cells that recapitulates the architecture of the liver periportal region and, when manipulated, models aspects of cholestatic injury and biliary fibrosis. We first generate reproducible hepatocyte organoids with functional bile canaliculi network that retain morphological features of in vivo tissue. By combining these with cholangiocytes and portal fibroblasts, we generate assembloids that mimic the cellular interactions of the periportal region. Assembloids are functional, consistently draining bile from bile canaliculi into the bile duct. Strikingly, manipulating the relative number of portal mesenchymal cells is sufficient to induce a fibrotic-like state, independently of an immune compartment. By generating chimeric assembloids of mutant and wild-type cells, or after gene knockdown, we show proof-of-concept that our system is amenable to investigating gene function and cell-autonomous mechanisms. Taken together, we demonstrate that liver assembloids represent a suitable in vitro system to study bile canaliculi formation, bile drainage, and how different cell types contribute to cholestatic disease and biliary fibrosis, in an all-in-one model.
@article{Dowbaj9003,
author={Anna Dowbaj, Aleksandra Sljukic, Armin Niksic, Cedric Landerer, Julien Delpierre, Haochen Yang, Aparajita Lahree, Ariane C Kühn, David Beers, Helen M Byrne, Sarah Seifert, Heather A Harrington, Marino Zerial, Meritxell Huch},
title={Mouse liver assembloids model periportal architecture and biliary fibrosis.},
journal ={Nature},
volume={},
pages={null--null},
year=2025
}

Chi Fung Willis Chow, Maxim Scheremetjew, HongKee Moon, Soumyadeep Ghosh, Anna Hadarovich, Lena Hersemann, Agnes Toth-Petroczy
SHARK: web server for alignment-free homology assessment for intrinsically disordered and unalignable protein regions.
Nucleic Acids Res, Art. No. doi: 10.1093/nar/gkaf408 (2025)
Open Access PubMed Source   

Whereas alignment has been fundamental to sequence-based assessments of protein homology, it is ineffective for intrinsically disordered regions (IDRs) due to their lowered sequence conservation and unique sequence properties. Here, we present a web server implementation of SHARK (bio-shark.org), an alignment-free algorithm for homology classification that compares the overall amino acid composition and short regions (k-mers) shared between sequences (SHARK-scores). The output of such k-mer-based comparisons is used by SHARK-dive, a machine learning classifier to detect homology between unalignable, disordered sequences. SHARK-web provides sequence-versus-database assessment of protein sequence homology akin to conventional tools such as BLAST and HMMER. Additionally, we provide precomputed sets of IDR sequences from 16 model organism proteomes facilitating searches against species-specific IDR-omes. SHARK-dive offers superior overall homology detection performance to BLAST and HMMER, driven by a large increase in sensitivity to low sequence identity homologs, and can be used to facilitate the study of sequence-function relationships in disordered, difficult-to-align regions.
@article{Chow9006,
author={Chi Fung Willis Chow, Maxim Scheremetjew, HongKee Moon, Soumyadeep Ghosh, Anna Hadarovich, Lena Hersemann, Agnes Toth-Petroczy},
title={SHARK: web server for alignment-free homology assessment for intrinsically disordered and unalignable protein regions.},
journal ={Nucleic acids research},
volume={},
pages={null--null},
year=2025
}

Eugene Christo V R, Esther Charlotte Sophia Kloth, Filippo Nisini, Cordula Reuther, Stefan Diez
Lowering Ionic Strength Improves the Sensitivity of Microtubule Gliding Assay Based Molecular Detection.
Nano Lett, 25(20) 8194-8202 (2025)
Open Access PubMed Source   

Microtubule gliding assays provide a unique mechanism for molecular detection in which binding of analytes to the microtubule lattice reduces the microtubule gliding speed. The reduction in the gliding speed correlates with the density of the bound analytes, enabling its quantification. Although promising, this technique is still in the proof-of-concept stage. Improving the sensitivity and limit of detection of the assay could make the technique comparable to that of advanced molecular detection methods. This study demonstrates that reducing the ionic strength of the buffer increases the sensitivity of the assay by enhancing the interactions between kinesin and microtubules. When using a low ionic strength buffer (BRB10) compared with a standard buffer (BRB80), we observed a more pronounced reduction in microtubule gliding speed in the presence of analytes, improving the detection limit. Therefore, this approach offers a simple and scalable way to improve the sensitivity of motor-based detection assays.
@article{R8998,
author={Eugene Christo V R, Esther Charlotte Sophia Kloth, Filippo Nisini, Cordula Reuther, Stefan Diez},
title={Lowering Ionic Strength Improves the Sensitivity of Microtubule Gliding Assay Based Molecular Detection.},
journal ={Nano letters},
volume={25},
issue ={20},
pages={8194--8202},
year=2025
}

Natasha Steffi Lewis, Silja Zedlitz, Hannes Ausserwöger, Patrick M McCall, Lars Hubatsch, Marco Nousch, Martine Ruer-Gruß, Carsten Hoege, Frank Jülicher, Christian R. Eckmann, Tuomas P J Knowles, Anthony Hyman
A mechanism for MEX-5-driven disassembly of PGL-3/RNA condensates in vitro.
Proc Natl Acad Sci U.S.A., 122(20) Art. No. e2412218122 (2025)
Open Access PubMed Source   

MEX-5 regulates the formation and dissolution of P granules in Caenorhabditis elegans embryos, yet the thermodynamic basis of its activity remains unclear. Here, using a time-resolved in vitro reconstitution system, we show that MEX-5 dissolves preassembled liquid-like PGL-3/RNA condensates by altering RNA availability and shifting the phase boundary. We develop a microfluidic assay to systematically analyze how MEX-5 influences phase separation. By measuring the contribution of PGL-3 to phase separation, we show that MEX-5 reduces the free energy of PGL-3, shifting the equilibrium toward dissolution. Our findings provide a quantitative framework for understanding how RNA-binding proteins modulate condensate stability and demonstrate the power of microfluidics in precisely mapping phase transitions.
@article{Lewis9002,
author={Natasha Steffi Lewis, Silja Zedlitz, Hannes Ausserwöger, Patrick M McCall, Lars Hubatsch, Marco Nousch, Martine Ruer-Gruß, Carsten Hoege, Frank Jülicher, Christian R. Eckmann, Tuomas P J Knowles, Anthony Hyman},
title={A mechanism for MEX-5-driven disassembly of PGL-3/RNA condensates in vitro.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={122},
issue ={20},
pages={null--null},
year=2025
}

Yonit Maroudas-Sacks*, Marc Trani Bustos*, Jesse V Veenvliet
In preprints: exploring developmental robustness and timing with gastruloids.
Development, 152(10) Art. No. dev204870 (2025)
PubMed Source  

@article{Maroudas-Sacks8999,
author={Yonit Maroudas-Sacks, Marc Trani Bustos, Jesse V Veenvliet},
title={In preprints: exploring developmental robustness and timing with gastruloids.},
journal ={Development (Cambridge, England)},
volume={152},
issue ={10},
pages={null--null},
year=2025
}

Xiao Yan, David Kuster, Priyesh Mohanty, Jik Nijssen, Karina Pombo-García, Jorge Garcia Morato, Azamat Rizuan, Titus Franzmann, Aleksandra Sergeeva, Anh M Ly, Feilin Liu, Patricia M Passos, Leah George, Szu-Huan Wang, Jayakrishna Shenoy, Helen L Danielson, Busra Ozguney, Alf Honigmann, Yuna M Ayala, Nicolas L Fawzi, Dennis W Dickson, Wilfried Rossoll, Jeetain Mittal#, Simon Alberti#, Anthony Hyman#
Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.
Cell, Art. No. doi: 10.1016/j.cell.2025.04.039 (2025)
Open Access PubMed Source   

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.
@article{Yan9005,
author={Xiao Yan, David Kuster, Priyesh Mohanty, Jik Nijssen, Karina Pombo-García, Jorge Garcia Morato, Azamat Rizuan, Titus Franzmann, Aleksandra Sergeeva, Anh M Ly, Feilin Liu, Patricia M Passos, Leah George, Szu-Huan Wang, Jayakrishna Shenoy, Helen L Danielson, Busra Ozguney, Alf Honigmann, Yuna M Ayala, Nicolas L Fawzi, Dennis W Dickson, Wilfried Rossoll, Jeetain Mittal, Simon Alberti, Anthony Hyman},
title={Intra-condensate demixing of TDP-43 inside stress granules generates pathological aggregates.},
journal ={Cell},
volume={},
pages={1--1},
year=2025
}

Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, Antonio Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric D Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C Murthy, Simon Alberti, Marc Bickle, Nicolas L Fawzi, André Nadler, Della C David, Udai Pandey, Andreas Hermann, Florian Stengel, Benjamin G Davis, Andrew J Baldwin, Mikhail M Savitski, Anthony Hyman#, Richard Wheeler#
Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
Nat Chem Biol, Art. No. doi: 10.1038/s41589-025-01893-5 (2025)
Open Access PubMed Source   

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.
@article{Uechi9000,
author={Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, Antonio Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric D Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C Murthy, Simon Alberti, Marc Bickle, Nicolas L Fawzi, André Nadler, Della C David, Udai Pandey, Andreas Hermann, Florian Stengel, Benjamin G Davis, Andrew J Baldwin, Mikhail M Savitski, Anthony Hyman, Richard Wheeler},
title={Small-molecule dissolution of stress granules by redox modulation benefits ALS models.},
journal ={Nature chemical biology},
volume={},
pages={1--1},
year=2025
}
* joint first authors, # joint corresponding authors