bims-enlima Biomed News
on Engineered living materials
Issue of 2025–10–05
fifty-nine papers selected by
Rahul Kumar, Tallinna Tehnikaülikool
  1. Synthetic Whole-Cell Bioelectronic Chemical Sensing with In Situ Genetic Computing.
  2. Long-term homeostasis in microbial consortia via auxotrophic cross-feeding.
  3. One-Vat Multimaterial 3D Printing: The Devil is in the Details.
  4. Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms.
  5. Engineering Spatial Control of Bacterial Organelles.
  6. Mechanical insights from functional materials.
  7. Optimization and control of actuator networks in variable geometry truss systems using genetic algorithms.
  8. Laboratory Evolution Reveals Transcriptional Mechanisms Underlying Thermal Adaptation of Escherichia coli.
  9. Self-driving labs for biotechnology.
  10. Ecosystems as adaptive living circuits.
  11. AI is dreaming up millions of new materials. Are they any good?
  12. Synthetic protein degradation circuits using programmable cleavage and ligation by Sortase A.
  13. Entering the age of designer protein materials.
  14. Recombinant Proteins: A Molecular Tool to Understand Marine Adhesion and to Advance Biomaterials.
  15. Jamming with magnetic composites.
  16. Genetic controllers for enhancing the evolutionary longevity of synthetic gene circuits in bacteria.
  17. Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking.
  18. Model-Based Optimization of a qCRISPRi Circuit for Dynamic Control of Metabolic Pathways.
  19. Learning cell-specific networks from dynamics and geometry of single cells.
  20. A blueprint for designing the next-generation of synthetic C1 microbes.
  21. Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo.
  22. Multifunctional Mussel-Inspired Hydrogels and Films Formed via Catechol-VO2 Nanoparticle Coordination.
  23. A robust platform streamlining aromatic noncanonical amino acid biosynthesis and genetic code expansion in Escherichia coli.
  24. Bone-Derived dECM Hydrogels Support Tunable Microenvironments for In Vitro Osteogenic Differentiation.
  25. LassoESM a tailored language model for enhanced lasso peptide property prediction.
  26. Protocol to culture cells on genipin-mixed collagen gels with different stiffnesses.
  27. Spatially resolved in situ profiling of mRNA life cycle at transcriptome scale in intact cells and tissues using STARmap PLUS, RIBOmap and TEMPOmap.
  28. In Vivo DNA Assembly in Yarrowia lipolytica.
  29. Dynamic rigidity changes enable rapid cell migration on soft substrates.
  30. Research progress and potential of organoids based on biomimetic hydrogel materials.
  31. The Hidden Cost of Fusion: Intrinsic Asymmetry in Vesicle Fusion Restricts Synthetic Cell Growth.
  32. Combinatorial protein barcodes enable self-correcting neuron tracing with nanoscale molecular context.
  33. Synthetic Hydrogels Incorporating Hydrolytic/Nonhydrolytic Macromer Ratios Exhibit Improved Tunability of In Vivo Degradation and Immune Responses.
  34. Predicting chromatin conformation contact maps.
  35. Constructing artificial neurons with functional parameters comprehensively matching biological values.
  36. Mesoscale avalanche size underpins the rheology of granular yielding.
  37. Cell-selective multiplexed bioorthogonal noncanonical amino acid tagging for nascent proteomics.
  38. Regiochemical Control of Shape Morphing in Diels-Alder Covalent Adaptable Networks.
  39. Materials Design and Assessment of Redox-Mediated Flow Cell Systems for Enhanced Energy Storage and Conversion.
  40. Optimized user-guided motion control of modular robots.
  41. Thermodynamic dissipation constrains metabolic versatility of unicellular growth.
  42. A network of P-body and Whi3 condensates adjusts cell fate decisions to cellular context.
  43. Single-Cell Nucleus Extraction with Cellular Indexing.
  44. Molecular basis of the biogenesis of a protein organelle for ethanolamine utilization.
  45. Cassini: streamlined and scalable method for in situ profiling of RNA and protein.
  46. Machine learning applied to biocatalysis research.
  47. A tool for modeling gene regulatory networks (GRN_modeler) and its applications to synthetic biology.
  48. Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
  49. COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale.
  50. Programmable 3D Morphing Bionic Gradient Hydrogel Actuators with Fast Response and Large-Amplitude Deformations.
  51. Connecting chemical and protein sequence space to predict biocatalytic reactions.
  52. A self-limiting mechanotransduction feedback loop ensures robust organ formation.
  53. Heat-rechargeable computation in DNA logic circuits and neural networks.
  54. A selection-based knockout approach for a choanoflagellate reveals regulation of multicellular development by Hippo signaling.
  55. Global constraint principle for microbial growth laws.
  56. Machine learning matches enzymes with molecular substrates.
  57. Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution.
  58. Kirigami-inspired parachutes with programmable reconfiguration.
  59. Amorphous phase-change memory alloy with no resistance drift.
  1. Chem Bio Eng. 2025 Sep 25. 2(9): 501-510
    Synthetic Whole-Cell Bioelectronic Chemical Sensing with In Situ Genetic Computing.
    Robert W Bradley, Estefania Nunez-Bajo, Firat Guder, Martin Buck, Baojun Wang.
      Biosensors exploit the capabilities of biological systems to acquire a huge variety of chemical or physical information and convert molecular signals into actionable data. Here we took a bottom-up synthetic biology approach to combine the versatility and programmability of whole-cell bacterial biosensors with the sensitivity of electrochemical sensing devices. We built genetic modules to produce different phenazines and wired these to various sensing and information processing modules. A whole-cell bioelectronic sensor with a T7 RNAP-based signal amplifier was first constructed that detected mercury contaminants below the level of WHO safe limit for drinking water. We demonstrated the modularity and programmability of the sensor design by incorporating Boolean logic computation into a dual-input sensor. We subsequently engineered a sensor strain that can produce two phenazine types, giving a two-channel electrochemical output signal based on the detection of differentiated midpoint potentials. Our modular bioelectronic sensor therefore can be readily adapted for different applications and forms the basis for development of low-cost, field-deployable sensing devices.
    Keywords:  bioelectrochemical; biological signal amplifier; electrogenetic; genetic logic gate; phenazine; whole-cell biosensor
    DOI:  https://doi.org/10.1021/cbe.5c00015
  2. Nat Commun. 2025 Sep 29. 16(1): 8573
    Long-term homeostasis in microbial consortia via auxotrophic cross-feeding.
    Nicolas E Grandel, Amanda M Alexander, Xiao Peng, Caroline Palamountain, Razan N Alnahhas, Andrew J Hirning, Krešimir Josić, Matthew R Bennett.
      Synthetic microbial consortia are collections of multiple strains or species of engineered organisms living in a shared ecosystem. Because they can separate metabolic tasks among different strains, synthetic microbial consortia have applications in developing biomaterials, biomanufacturing, and biotherapeutics. However, synthetic consortia often require burdensome control mechanisms to ensure that consortia members remain at the correct proportions. Here, we present a simple method for controlling consortia proportions using cross-feeding in continuous auxotrophic co-culture. We use mutually auxotrophic E. coli with different essential gene deletions and regulate the growth rates of members of the consortium via cross-feeding of the missing nutrients in each strain. We demonstrate precise regulation of the proportions by exogenous addition of the missing nutrients. We also model the co-culture's behavior using a system of ordinary differential equations that enable us to predict its response to changes in nutrient concentrations. Our work provides a powerful tool for consortia proportion control with minimal metabolic costs to the constituent strains.
    DOI:  https://doi.org/10.1038/s41467-025-63575-z
  3. ACS Cent Sci. 2025 Sep 24. 11(9): 1527-1535
    One-Vat Multimaterial 3D Printing: The Devil is in the Details.
    Elizabeth A Recker, Xiaofeng Chen, Ji-Won Kim, Zachariah A Page.
      Nature combines different materials in a single structure to achieve functions that no single material could accomplish alone, an approach that inspires efforts to build synthetic systems with precisely tailored properties. Vat photopolymerization (VPP) enables fast, high-resolution 3D printing, but most printed parts still use only one material. This Outlook highlights emerging strategies for single-vat multimaterial VPP, where light selectively activates different chemical reactions to build complex structures with multiple materials. Key advances will depend on expanding resin chemistry beyond standard acrylates, improving reaction selectivity, and using grayscale and multiwavelength light control to define where and how materials form. Standardized mechanical, thermal, and interface testing methods are essential for ensuring reliable results. With advances in chemistry, optics, and data-driven design, multimaterial VPP could unlock transformative applications in medicine, manufacturing, and aerospace.
    DOI:  https://doi.org/10.1021/acscentsci.5c00986
  4. Bioact Mater. 2026 Jan;55 144-170
    Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms.
    Chenjia Zhang, Yue Shen, Mingyang Huang, Guoqing Wang, Qichen Miao, Heping Shi, Ruiqi Gao, Kun Wang, Ming Luo.
      The extracellular matrix (ECM) serves as a dynamic biomechanical regulator of cellular behavior, yet conventional 3D culture systems, such as Matrigel, lack the spatiotemporal control required to dissect mechanotransductive mechanisms in organoids. This review systematically explores the synthesis of mechanically tunable hydrogels-spanning stiffness and viscoelasticity-and their transformative applications in organoid research. By integrating natural, synthetic, and hybrid polymers, these hydrogels enable precise recapitulation of tissue-specific ECM mechanics, overcoming limitations of batch variability and static properties. We categorize hydrogel design strategies, emphasizing crosslinking paradigms (physical vs. chemical) and dynamic bond engineering, which permit real-time modulation of mechanical cues. Applications across developmental organoids (intestinal, hepatic, renal, neural) reveal stiffness-dependent morphogenesis, where optimal mechanical niches enhance maturation via YAP/Notch signaling. Tumor organoid models (breast, pancreatic, colorectal) further demonstrate how matrix stiffening drives malignancy through mechanosensitive pathways, such as epithelial-mesenchymal transition and drug resistance. Emerging viscoelastic hydrogels, tailored via alginate molecular weight or decellularized ECM, replicate dynamic tissue mechanics, advancing cartilage and cerebellar organoid models. Critically, this review highlights innovations in programmable hydrogels that bridge 2D reductionist models and in vivo complexity, offering unprecedented insights into ECM-driven organogenesis and disease progression. Future directions include integrating bioprinting and organ-on-a-chip technologies to achieve vascularized, patient-specific organoids. By synthesizing design principles and mechanobiological mechanisms, this work establishes a roadmap for next-generation biomaterials, accelerating translational applications in drug screening, regenerative medicine, and personalized oncology.
    Keywords:  Extracellular matrix; Mechanically controlled hydrogel; Organoid; Stiffness; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.09.021
  5. bioRxiv. 2025 Sep 22. pii: 2025.09.22.677801. [Epub ahead of print]
    Engineering Spatial Control of Bacterial Organelles.
    Y Hoan, Pankaj V Jadhav, Daniel S Trettel, Rachel E Dow, Seokmu Kwon, Kate Matej, Jordan A Byrne, Christopher A Azaldegui, Tobias W Giessen, Hualiang Pi, Shyamal Mosalaganti, Anthony G Vecchiarelli.
      Bacteria were once thought to lack organelles, but it is now clear they confine cellular reactions using an array of membrane- and protein-based compartments. A central question, however, is how bacterial organelles are organized in the cell, and whether their spatial control can be engineered. Here, we show that a two-protein system (McdAB) that positions carboxysomes-CO 2 -fixing organelles found in autotrophic bacteria-can be repurposed to provide programmable spatial control to diverse organelles in Escherichia coli . McdAB not only restores proper assembly and positioning of heterologously expressed carboxysomes in E. coli , but can also be reprogrammed to spatially organize all other known types of bacterial organelles, including encapsulins, biomolecular condensates, and even membrane-bound organelles. Programmable spatial organization of bacterial organelles establishes a new design principle for synthetic biology, where the location of reactions is as tunable as their content. Our work paves the way for more efficient biocatalysis in engineered microbes.
    DOI:  https://doi.org/10.1101/2025.09.22.677801
  6. Nat Mater. 2025 Oct;24(10): 1503
    Mechanical insights from functional materials.
      
    DOI:  https://doi.org/10.1038/s41563-025-02378-5
  7. Nat Commun. 2025 Sep 30. 16(1): 8432
    Optimization and control of actuator networks in variable geometry truss systems using genetic algorithms.
    Jianzhe Gu, Ziwen Ye, Tucker Rae-Grant, Shuhong Wang, Ding Zhao, Josiah Hester, Victoria A Webster-Wood, Lining Yao.
      A robot's morphology is pivotal to its functionality, as biological organisms demonstrate through shape adjustments - octopi squeeze through small apertures, and caterpillars use peristaltic transformations to navigate complex environments. While existing robotic systems struggle to achieve precise volumetric transformations, Variable Geometry Trusses offer rich morphing capabilities by coordinating hundreds of actuating beams. However, control complexity scales exponentially with beam count, limiting implementations to trusses with only a handful of beams or to designs where only a subset of beams are actuable. Previous work introduced the metatruss, a truss robot that simplifies control by grouping actuators into interconnected pneumatic control networks, but relies on manual network design and control sequences. Here, we introduce a multi-objective optimization framework based on a tailored genetic algorithm to automate actuator grouping, contraction ratios, and actuation timing. We develop a highly damped dynamic simulator that balances computational efficiency with physical accuracy and validate our approach with experimental prototypes. Across multiple tasks, we demonstrate that the metatruss achieves complex shape adaptations with minimal control units. Our results reveal an optimal number of control networks, beyond which additional networks yield diminishing performance gains.
    DOI:  https://doi.org/10.1038/s41467-025-63373-7
  8. Genome Biol Evol. 2025 Sep 30. pii: evaf171. [Epub ahead of print]17(10):
    Laboratory Evolution Reveals Transcriptional Mechanisms Underlying Thermal Adaptation of Escherichia coli.
    Kevin Rychel, Ke Chen, Edward A Catoiu, Elina Olson, Troy E Sandberg, Ye Gao, Sibei Xu, Ying Hefner, Richard Szubin, Arjun Patel, Adam M Feist, Bernhard O Palsson.
      Adaptive laboratory evolution is able to generate microbial strains, which exhibit extreme phenotypes, revealing fundamental biological adaptation mechanisms. Here, we use adaptive laboratory evolution to evolve Escherichia coli strains that grow at temperatures as high as 45.3 °C, a temperature lethal to wild-type cells. The strains adopted a hypermutator phenotype and employed multiple systems-level adaptations that made global analysis of the DNA mutations difficult. Given the challenge at the genomic level, we were motivated to uncover high-temperature tolerance adaptation mechanisms at the transcriptomic level. We employed independently modulated gene set (iModulon) analysis to reveal five transcriptional mechanisms underlying growth at high temperatures. These mechanisms were connected to acquired mutations, changes in transcriptome composition, sensory inputs, phenotypes, and protein structures. They are as follows: (i) downregulation of general stress responses while upregulating the specific heat stress responses, (ii) upregulation of flagellar basal bodies without upregulating motility and upregulation fimbriae, (iii) shift toward anaerobic metabolism, (iv) shift in regulation of iron uptake away from siderophore production, and (v) upregulation of yjfIJKL, a novel heat tolerance operon whose structures we predicted with AlphaFold. iModulons associated with these five mechanisms explain nearly half of all variance in the gene expression in the adapted strains. These thermotolerance strategies reveal that optimal coordination of known stress responses and metabolism can be achieved with a small number of regulatory mutations and may suggest a new role for large protein export systems. Adaptive laboratory evolution with transcriptomic characterization is a productive approach for elucidating and interpreting adaptation to otherwise lethal stresses.
    Keywords:  adaptive laboratory evolution; iModulons; systems biology; temperature stress; transcriptional regulatory networks; transcriptomics
    DOI:  https://doi.org/10.1093/gbe/evaf171
  9. Nat Comput Sci. 2025 Oct 01.
    Self-driving labs for biotechnology.
    Evan Collins, Robert Langer, Daniel G Anderson.
      
    DOI:  https://doi.org/10.1038/s43588-025-00885-8
  10. ArXiv. 2025 Jun 27. pii: arXiv:2506.22017v1. [Epub ahead of print]
    Ecosystems as adaptive living circuits.
    Ankit Dhanuka, Avi I Flamholz, Arvind Murugan, Akshit Goyal.
      Unlike many physical nonequilibrium systems, in biological systems, the coupling to external energy sources is not a fixed parameter but adaptively controlled by the system itself. We do not have theoretical frameworks that allow for such adaptability. As a result, we cannot understand emergent behavior in living systems where structure formation and non-equilibrium drive coevolve. Here, using ecosystems as a model of adaptive systems, we develop a framework of living circuits whose architecture changes adaptively with the energy dissipated in each circuit edge. We find that unlike traditional nonequilibrium systems, living circuits exhibit a phase transition from equilibrium death to a nonequilibrium dissipative state beyond a critical driving potential. This transition emerges through a feedback mechanism that saves the weakest edges by routing dissipation through them, even though the adaptive rule locally rewards the strongest dissipating edges. Despite lacking any global optimization principle, living circuits achieve near-maximal dissipation, with higher drive promoting more complex circuits. Our work establishes ecosystems as paradigmatic examples of living circuits whose structure and dissipation are tuned through local adaptive rules.
  11. Nature. 2025 Oct;646(8083): 22-25
    AI is dreaming up millions of new materials. Are they any good?
    Mark Peplow.
      
    Keywords:  Chemistry; Computer science; Machine learning; Materials science; Technology
    DOI:  https://doi.org/10.1038/d41586-025-03147-9
  12. Nat Commun. 2025 Sep 30. 16(1): 8682
    Synthetic protein degradation circuits using programmable cleavage and ligation by Sortase A.
    Hopen K Yang, Pragati K Muthukumar, Wilfred Chen.
      BioPROTACs are heterobifunctional proteins designed for targeted protein degradation (TPD). They are useful not only for probing protein functions but also offer a therapeutic avenue for modulating disease-related proteins. To extend the use of TPD beyond just protein attenuation, we introduce a synthetic framework for logic-gated, switchable TPD to achieve conditional control of protein content. By exploiting both the cleavage and ligation functionalities of Sortase A (SrtA), we present a new strategy utilizing SrtA as the control input to direct bioPROTAC activity for switchable TPD. Furthermore, by layering the SrtA input with protease gating, conditional degradation phenotypes can be readily adapted with minimal modifications to the design. This Logic-gated AdPROM deploying SrtA-mediated Element Recombination (LASER) platform allows us to expand the possible protein degradation outcomes in mammalian cells using Boolean logic operations depending on the input combinations. The flexibility to modulate the level of multiple native intracellular proteins can potentially lead to applications from therapy to diagnostics and biotechnology.
    DOI:  https://doi.org/10.1038/s41467-025-63819-y
  13. Nat Mater. 2025 Oct;24(10): 1515-1517
    Entering the age of designer protein materials.
    Shuguang Zhang.
      
    DOI:  https://doi.org/10.1038/s41563-025-02372-x
  14. Adv Healthc Mater. 2025 Oct 02. e02340
    Recombinant Proteins: A Molecular Tool to Understand Marine Adhesion and to Advance Biomaterials.
    Alessandra Whaite, Emilie Duthoo, Mathilde Lefevre, Elise Hennebert, Patrick Flammang.
      Inspiration for innovation in healthcare regularly comes from observing the natural environment. Secreted adhesives are important for marine invertebrate attachment to submerged surfaces, and these systems have inspired investigations for better performing surgical adhesives. Natural marine adhesives are fundamentally proteins, therefore, most materials research has focused on the structure and function of proteinaceous components. Omics technologies have been used to identify proteins, but these candidates require further exploration to resolve function. Functional characterization begins by producing one specific protein in larger quantities with recombinant DNA technology. Recombinant proteins (RPs) are generally seen as mimics of individual marine adhesive proteins, representing a fundamental step in the development of bio-inspired glues. The literature details production of RPs from mussels, scallops, barnacles, tubeworms, ascidians, sea anemones, and sea stars, using bacteria, yeast, or insect and mammalian cells. Whole proteins, or components thereof, have been produced comprising the relevant amino acid sequences required for adhesion and have been investigated for use in healthcare via the production of materials that push the current limits of bio-inspired design. This is a thorough review of invertebrate marine adhesives investigated using biomimetic RPs, and a comprehensive overview of the innovative biomaterials designed utilizing knowledge from biological systems.
    Keywords:  biological adhesion; biomimetic adhesives; fusion proteins; marine invertebrates; recombinant biomaterials
    DOI:  https://doi.org/10.1002/adhm.202502340
  15. Nat Commun. 2025 Sep 30. 16(1): 8711
    Jamming with magnetic composites.
    Buse Aktaş, Minsoo Kim, Marc Bäckert, Gianluca Sicilia, Gian-Luca Franchini, Florian Heemeyer, Simone Gervasoni, Xiang-Zhong Chen, Salvador Pané, Bradley J Nelson.
      The jamming transition-marked by dramatic changes in mechanical properties, such as stiffness and damping-enables programmable and adaptive structures for robotic applications. This phenomenon, driven by changes in the coupling between individual subunits of an aggregate, can be controlled through external actuation sources. Existing jamming actuation methods, such as applying a vacuum with an airtight envelope, pose significant limitations, as they require the structures to be tethered, limiting reconfigurability and scalability. Here, we introduce an untethered jamming mechanism based on magnetic interactions between soft-ferromagnetic composites. We establish composite design principles to program the magnetization of the subunits, demonstrate linear, planar, and volumetric jamming and shape-locking, and model the magneto-mechanical behavior. This approach contributes to the development of jamming-based materials in which the jamming directions and transition points can be tuned on-the-fly by adjusting the external magnetic field orientation and strength, respectively.
    DOI:  https://doi.org/10.1038/s41467-025-63729-z
  16. Nat Commun. 2025 Sep 29. 16(1): 8590
    Genetic controllers for enhancing the evolutionary longevity of synthetic gene circuits in bacteria.
    Daniel P Byrom, Alexander P S Darlington.
      Engineered gene circuits often degrade due to mutation and selection, limiting their long-term utility. Here we present designs for genetic controllers which maintain synthetic gene expression over time. Using a multi-scale "host-aware" computational framework, which captures interactions between host and circuit expression, mutation, and mutant competition, we evaluate several controller architectures based on three metrics for evolutionary stability: total protein output, duration of stable output, and half-life of production. We propose a number of designs with varying inputs (e.g., output per cell, growth rate) and actuation methods (transcriptional vs. post-transcriptional regulation). We find post-transcriptional controllers generally outperform transcriptional ones, but no single design optimizes all goals. Negative autoregulation prolongs short term performance, while growth-based feedback extends functional half-life. We propose three biologically feasible, multi-input controllers that improve circuit half-life over threefold without requiring coupling the process to an essential gene or a genetic kill switch.
    DOI:  https://doi.org/10.1038/s41467-025-63627-4
  17. ACS Cent Sci. 2025 Sep 24. 11(9): 1736-1752
    Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking.
    Noemi Jiménez-Rojo, Suihan Feng, Johannes Morstein, Stefanie D Pritzl, Antonino Asaro, Sergio López, Yun Xu, Takeshi Harayama, Nynke A Vepřek, Christopher J Arp, Martin Reynders, Alexander J E Novak, Evgeny Kanshin, Jan Lipfert, Beatrix Ueberheide, Manuel Muñiz, Theobald Lohmüller, Howard Riezman, Dirk Trauner.
      The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical approach to manipulate membrane viscosity based on an exogenous synthetic fatty acid with an azobenzene photoswitch, termed FAAzo4. Cells rapidly incorporate FAAzo4 into phosphatidylcholine and phosphatidylethanolamine in a concentration- and cell type-dependent manner. This generates photoswitchable PC and PE analogs, which are predominantly located in the endoplasmic reticulum. Irradiation causes a rapid photoisomerization that decreases membrane viscosity with high spatiotemporal precision. We use the resulting "PhotoCells" to study the impact of membrane viscosity on ER-to-Golgi transport and demonstrate that this two-step process has distinct membrane viscosity requirements. Our approach provides an unprecedented way of manipulating membrane biophysical properties directly in living cells and opens novel avenues to probe the effects of viscosity in a wide variety of biological processes.
    DOI:  https://doi.org/10.1021/acscentsci.5c00606
  18. ACS Synth Biol. 2025 Sep 29.
    Model-Based Optimization of a qCRISPRi Circuit for Dynamic Control of Metabolic Pathways.
    Sai Akhil Golla, Mona Abo-Hashesh, Dev Gupta, Yilan Liu, Radhakrishnan Mahadevan.
      Metabolic engineering enables sustainable chemical production but often imposes metabolic burdens that reduce cellular viability and productivity. Dynamic control strategies, such as quorum sensing (QS)-based circuits, can mitigate these effects by autonomously regulating gene expression in response to cell density. In this study, we investigated a QS-regulated CRISPR interference (qCRISPRi) circuit for the dynamic control of metabolic pathways, focusing on the role of leaky expression and regulator stringency. Using a combination of mathematical modeling and experiments, we evaluated how promoter leakiness and LuxR stringency influence key switching characteristics including maximum gene expression, switching density, fold repression, and transition time. Our results show that high leaky expression of dCas9 reduces switching density and represses GFP prematurely, whereas a high-stringency LuxR variant enhances switching precision by reducing leakiness and enabling sharper transitions. These model predictions were validated experimentally in E. coli, confirming that LuxR stringency improves dynamic circuit performance. Together, this work provides a quantitative framework for optimizing QS-based regulatory systems and offers generalizable design insights for implementing dynamic control in metabolic engineering.
    Keywords:  LuxR stringency; dynamic gene regulation; mathematical modeling; qCRISPRi; quorum sensing
    DOI:  https://doi.org/10.1021/acssynbio.5c00095
  19. Cell Syst. 2025 Oct 01. pii: S2405-4712(25)00232-7. [Epub ahead of print] 101399
    Learning cell-specific networks from dynamics and geometry of single cells.
    Stephen Y Zhang, Michael P H Stumpf.
      Cell dynamics and biological function are governed by intricate networks of molecular interactions. Inferring these interactions from data is a notoriously difficult inverse problem. Most existing network inference methods construct population-averaged representations of gene interaction networks, and they do not naturally allow us to infer differences in interaction activity across heterogeneous cell populations. We introduce locaTE, an information theoretic approach that leverages single-cell, dynamical information, together with geometry of the cell-state manifold, to infer cell-specific, causal gene interaction networks in a manner that is agnostic to the topology of the underlying biological trajectory. Through extensive simulation studies and applications to experimental datasets spanning mouse primitive endoderm formation, pancreatic development, and hematopoiesis, we demonstrate superior performance and the generation of additional insights, compared with standard population-averaged inference methods. We find that locaTE provides a powerful network inference method that allows us to distil cell-specific networks from single-cell data. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  gene regulation networks; network inference; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101399
  20. Nat Commun. 2025 Oct 03. 16(1): 8843
    A blueprint for designing the next-generation of synthetic C1 microbes.
    Giusi Favoino, Òscar Puiggené, Pablo I Nikel.
      Engineering microbes for synthetic one-carbon (C1) assimilation continues to gain momentum with the expanding demand for sustainable bioprocesses. While most efforts focused on model microbes, non-canonical hosts offer untapped potential due to native metabolic properties, enzyme activities, and substrate tolerance. This perspective outlines key considerations for selecting and engineering such strains, including metabolic modeling, use of native C1-inducible promoters, and adaptation to anaerobic conditions. Environmental impacts are evaluated through life cycle assessment, identifying substrates with low carbon footprints. Integrating techno-economic and sustainability insights at early stages is essential to guide the development of efficient, scalable C1-based biomanufacturing systems.
    DOI:  https://doi.org/10.1038/s41467-025-64483-y
  21. Nat Commun. 2025 Sep 30. 16(1): 8699
    Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo.
    Elizabeth Voke, Mariah L Arral, Henry J Squire, Teng-Jui Lin, Lining Zheng, Roxana Coreas, Alison Lui, Anthony T Iavarone, Rebecca L Pinals, Kathryn A Whitehead, Markita P Landry.
      Lipid nanoparticles (LNPs) are the most clinically advanced nonviral RNA-delivery vehicles, though challenges remain in fully understanding how LNPs interact with biological systems. In vivo, proteins form an associated corona on LNPs that redefines their physicochemical properties and influences delivery outcomes. Despite its importance, the LNP protein corona is challenging to study owing to the technical difficulty of selectively recovering soft nanoparticles from biological samples. Herein, we develop a quantitative, label-free mass spectrometry-based proteomics approach to characterize the protein corona on LNPs. Critically, this protein corona isolation workflow avoids artifacts introduced by the presence of endogenous nanoparticles in human biofluids. We apply continuous density gradient ultracentrifugation for protein-LNP complex isolation, with mass spectrometry for protein identification normalized to protein composition in the biofluid alone. With this approach, we quantify proteins consistently enriched in the LNP corona including vitronectin, C-reactive protein, and alpha-2-macroglobulin. We explore the impact of these corona proteins on cell uptake and mRNA expression in HepG2 human liver cells, and find that, surprisingly, increased levels of cell uptake do not correlate with increased mRNA expression in part due to protein corona-induced lysosomal trafficking of LNPs. Our results underscore the need to consider the protein corona in the design of LNP-based therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-63726-2
  22. Macromol Rapid Commun. 2025 Sep 27. e00587
    Multifunctional Mussel-Inspired Hydrogels and Films Formed via Catechol-VO2 Nanoparticle Coordination.
    Mostafa Rammal, Matthew J Harrington.
      Marine mussels utilize DOPA-V metal coordination bonds as dynamic cross-links to fabricate tough and self-healing coatings and glues. Inspired by mussels, researchers have harnessed DOPA-metal coordination to create dynamic and mechanically responsive polymeric materials. Here, we harness the robust DOPA-V interactions observed in mussels combined with the temperature-responsive properties of vanadium dioxide (VO2) to develop a room-temperature process to produce thermochromic VO2 hydrogels and films. 4-arm polyethylene glycol (PEG) polymers functionalized with DOPA-catechol moieties were mixed with VO2 nanoparticles in solution. Raising pH led to formation of hydrogels, while spin coating enabled processing into thin films. Hydrogels possessed mechanically tunable viscoelasticity and self-healing response. Furthermore, dried free-standing films were highly flexible and exhibited plastic deformation with extensibilities of 200% and beyond, while still retaining the thermochromic properties of the nanoparticles. The facile fabrication method and the resulting versatile mechanical response combined with thermochromic properties are promising for future development VO2-polymer composite materials.
    Keywords:  DOPA; mussel‐inspired; nanocomposite hydrogel; self‐healing; thermochromism; vanadium dioxide
    DOI:  https://doi.org/10.1002/marc.202500587
  23. Nat Commun. 2025 Sep 29. 16(1): 8605
    A robust platform streamlining aromatic noncanonical amino acid biosynthesis and genetic code expansion in Escherichia coli.
    Jingxuan Zhang, Keying Yu, Yali Xu, Wushuang Zhao, Yulian Li, Ying Wang, Florian P Seebeck, Xiao-Hua Chen, Cangsong Liao.
      Genetic code expansion (GCE) has significantly enhanced the diversity of proteins in the biological world, leading to a wide range of applications. Despite the advances in GCE, the cost of noncanonical amino acids (ncAAs) remains one of the major obstacles for large-scale production. In situ biosynthesis of ncAAs from commercial precursors offers a promising solution to this challenge, yet only a few biosynthetic pathways have been reported. Here, we present a platform that couples the biosynthesis of aromatic ncAAs with genetic code expansion in E. coli, enabling the production of proteins and peptides containing ncAAs. Forty ncAAs are synthesized from aryl aldehydes by the biosynthetic pathway, while nineteen ncAAs are incorporated into superfolder GFP using three orthogonal translation systems. The platform's versatility is demonstrated by the production of macrocyclic peptides and antibody fragments. We envision that the platform will facilitate the production of peptides, enzymes, and antibody fragments containing ncAAs.
    DOI:  https://doi.org/10.1038/s41467-025-63679-6
  24. Adv Healthc Mater. 2025 Oct 02. e2501350
    Bone-Derived dECM Hydrogels Support Tunable Microenvironments for In Vitro Osteogenic Differentiation.
    Minne Dekker, Luke Hipwood, Akhilandeshwari Ravichandran, Dietmar W Hutmacher, Christoph Meinert, Jacqui McGovern.
      Decellularized extracellular matrix (dECM)-based biomaterials mimic native ECM and support 3D cell culture. A photocrosslinkable porcine bone-derived dECM hydrogel (dECM-MA) is developed with tunable mechanical properties for tissue-specific in vitro models. Trabecular bone is demineralized with 10% EDTA and decellularized via osmotic shock using 3.4 m NaCl, reducing DNA content by 94% while preserving key ECM proteins. Proteomic analysis identifies 81 matrisome proteins, with 76 shared between native and decellularized tissue. The dECM is solubilized by pepsin digestion and functionalized with methacryloyl groups, achieving 87-98% functionalization. Photocrosslinked dECM-MA hydrogels shows tunable Young's moduli (0.5-120 kPa) depending on polymer concentration (0.25-2% w/v) and crosslinking duration (8-120 s). Primary human osteoblasts (hOBs) encapsulated in dECM-MA (5, 10, and 20 kPa) remains viable and exhibits osteogenic morphology. In 10 kPa hydrogels, hOBs shows increased metabolic activity, elevated alkaline phosphatase, and mineral deposition (µCT, Alizarin Red). Expression of DMP-1 and osteocalcin indicates cell maturation and ECM remodeling. This study demonstrates the feasibility of creating tunable, bone-specific dECM hydrogels for 3D culture. dECM-MA provides a controllable matrix environment and represents a versatile platform for disease modeling and drug screening in tissue-specific microenvironments.
    Keywords:  biomimetic hydrogels; bone‐derived extracellular matrices (dECM); osteogenic differentiation; photocrosslinkable hydrogels; tunable mechanical properties
    DOI:  https://doi.org/10.1002/adhm.202501350
  25. Nat Commun. 2025 Sep 29. 16(1): 8545
    LassoESM a tailored language model for enhanced lasso peptide property prediction.
    Xuenan Mi, Susanna E Barrett, Douglas A Mitchell, Diwakar Shukla.
      Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a diverse group of natural products. The lasso peptide class of RiPPs adopt a unique [1]rotaxane conformation formed by a lasso cyclase, conferring diverse bioactivities and remarkable stability. The prediction of lasso peptide properties, such as substrate compatibility with a particular lasso cyclase or desired biological activity, remains challenging due to limited experimental data and the complexity of substrate fitness landscapes. Here, we develop LassoESM, a tailored language model that improves lasso peptide property prediction. LassoESM embeddings enable accurate prediction of substrate compatibility, facilitate identification of novel non-cognate cyclase-substrate pairs, and enhance prediction of RNA polymerase inhibitory activity, a biological activity of several known lasso peptides. We anticipate that LassoESM and future iterations will be instrumental in the rational design and discovery of lasso peptides with tailored functions.
    DOI:  https://doi.org/10.1038/s41467-025-63412-3
  26. STAR Protoc. 2025 Oct 01. pii: S2666-1667(25)00531-3. [Epub ahead of print]6(4): 104125
    Protocol to culture cells on genipin-mixed collagen gels with different stiffnesses.
    Seiichiro Ishihara, Hisashi Haga.
      The stiffness of extracellular matrices is critical for cellular functions such as growth and differentiation. Here, we present a protocol for culturing cells on stiffness-modulated collagen gels by adding genipin, an amine crosslinker with low cytotoxicity. We describe the steps for preparing collagen gels with genipin, culturing the cells, and immunofluorescent staining of the cells on the gels. This protocol has potential applications in the analysis of function or protein/gene expression in cultured cells on extracellular matrices of different stiffnesses. For complete details on the use and execution of this protocol, please refer to Ishihara et al.1.
    Keywords:  Biotechnology and bioengineering; cell Biology; cell culture
    DOI:  https://doi.org/10.1016/j.xpro.2025.104125
  27. Nat Protoc. 2025 Sep 30.
    Spatially resolved in situ profiling of mRNA life cycle at transcriptome scale in intact cells and tissues using STARmap PLUS, RIBOmap and TEMPOmap.
    Jingyi Ren, Hu Zeng, Jiahao Huang, Jiakun Tian, Morgan Wu, Hailing Shi, Xin Sui, Connie Kangni Wang, Haowen Zhou, Zefang Tang, Shuchen Luo, Xiao Wang.
      Controlled gene expression programs have a crucial role in shaping cellular functions and activities. At the core of this process lies the RNA life cycle, ensuring protein products are synthesized in the right place at the right time. Here we detail an integrated protocol for imaging-based highly multiplexed in situ profiling of spatial transcriptome using antibody-based protein comapping (STARmap PLUS), spatial translatome mapping (RIBOmap) and spatiotemporal transcriptome mapping (TEMPOmap). These methods selectively convert targeted RNAs, ribosome-bound mRNAs or metabolically labeled RNAs to DNA amplicons with gene-unique barcodes, which are read out through in situ sequencing under a confocal microscope. Compared with other methods, they provide the analytical capacity to track the spatial and temporal dynamics of thousands of RNA species in intact cells and tissues. Our protocol can be readily performed in laboratories experienced in working with RNA and equipped with confocal microscopy instruments. The wet lab experiments in preparing the amplicon library take 2-3 d, followed by variable sequencing times depending on the sample size and target gene number. The spatially resolved single-cell profiles enable downstream analysis, including cell type classification, cell cycle identification and determination of RNA life cycle kinetic parameters through computational analysis guided by the established tutorials. This spatial omics toolkit will help users to better understand spatial and temporal RNA dynamics in heterogeneous cells and tissues.
    DOI:  https://doi.org/10.1038/s41596-025-01248-3
  28. ACS Synth Biol. 2025 Sep 30.
    In Vivo DNA Assembly in Yarrowia lipolytica.
    Wei Jiang, Ioannis Georgiadis, Tommaso Fumagalli, Shengbao Wang, Christina Vasileiou, Jonathan Dahlin, Irina Borodina.
      The oleaginous yeast Yarrowia lipolytica is an important platform organism for biotechnology applications. In this study, we established an in vivo DNA assembly system leveraging CRISPR-Cas9 for efficient genomic integration of multiple DNA fragments into the genome of Y. lipolytica. Using the green fluorescent protein mNeonGreen as a model, we demonstrated 53% correct assembly of three DNA fragments with homology arms as short as 50 bp. The system was further validated by constructing 2-3 step biosynthetic pathways for pigments betaxanthin and betanin. To improve the homologous recombination efficiency of Y. lipolytica, we expressed S. cerevisiae RAD52 (ScRAD52) or a Cas9-hBrex27 fusion protein. While ScRAD52 expression impaired growth, the cas9-hBrex27 fusion enhanced integration efficiency, particularly for multifragment pathway assemblies. The in vivo assembly method simplifies pathway construction and gene overexpression in Y. lipolytica.
    Keywords:  Yarrowia lipolytica; homologous recombination; in vivo DNA assembly; pathway construction
    DOI:  https://doi.org/10.1021/acssynbio.5c00296
  29. Nat Commun. 2025 Oct 02. 16(1): 8793
    Dynamic rigidity changes enable rapid cell migration on soft substrates.
    Jiapeng Yang, Yu Zhang, Shuo Wang, Peng Wang, Liang Dong, Luofei Li, Yuanqi Cheng, Xiaoyu Huang, Bin Xue, Wei Wang, Chunping Jiang, Xiaosong Gu, Yi Cao, Qiang Wei.
      Cell migration is crucial in various biological processes, regulated by surrounding rigidity. Studies under static conditions suggest migration favors rigid substrates, as softer substrates (<4 kPa) do not provide sufficient traction forces. Here we show that mesenchymal stem cells (MSCs) can overcome this limitation when exposed to rapid cyclic changes in substrate rigidity. Under dynamic conditions, cell traction forces progressively rise, promoting a swift mechanical turnover of focal adhesions. This adaptation obviates the need for cell polarity and the mechanochemical turnover of focal adhesions typically required for traditional mesenchymal-type migration. The rapid migration speed together with the shape evolution during migration can be adequately predicted by our theoretical model that considers the force balance under dynamic conditions. Our findings underscore the innate capacity of cells to navigate through fluctuating mechanical cues, highlighting a versatile cellular response mechanism for understanding cell behaviors under dynamic physiological or pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-025-63854-9
  30. Colloids Surf B Biointerfaces. 2025 Sep 27. pii: S0927-7765(25)00675-7. [Epub ahead of print]257 115168
    Research progress and potential of organoids based on biomimetic hydrogel materials.
    Guojie Zhao, Yanlei Ge, Ye Jin, Junqing Gan, Weinan Yao, Yanna Bi, Guogui Sun.
      Organoids are three-dimensional (3D) micro-biological structures constructed by self-renewing and self-organizing cell populations in vitro, which can reappear some key structural and functional characteristics of actual human tissues and organs. However, conventional organoid cultures rely heavily on the use of complex animal-derived extracellular matrix (ECM), limiting biomedical researches and clinical applications due to its complex composition, batch-to-batch variability, and potential immunogenicity. In contrast, the advent of natural and synthetic hydrogels has propelled the further advancement of organoid research, owing to the advantages of well-defined chemical compositions, stable mechanical properties and tunable microscopic morphology. In this review, we briefly introduce the current construction strategies and culture systems of organoids, as well as the classification and characteristics of hydrogel materials. Then, the key mechanism of action of biomimetic hydrogels are summarize in organoid research. Notably, two well-defined hydrogels utilized in organoid culture and their applications in drug research, disease modeling, precision medicine, and regenerative medicine are highlighted. Finally, certain challenges and future prospects of hydrogel materials in organoid research are also discussed. Therefore, it is anticipated that this review will enhance the academic exchanges within the field of organoid research and provide some impetus for the progression of organoid culture techniques.
    Keywords:  Biological materials; Extracellular matrix; Hydrogels; Organoids; Regenerative medicine
    DOI:  https://doi.org/10.1016/j.colsurfb.2025.115168
  31. bioRxiv. 2025 Sep 23. pii: 2025.09.22.677743. [Epub ahead of print]
    The Hidden Cost of Fusion: Intrinsic Asymmetry in Vesicle Fusion Restricts Synthetic Cell Growth.
    Rafael B Lira, Rafaela M Cavalcanti, Karin A Riske, Rumiana Dimova.
      Membrane fusion is essential for signaling, cargo delivery, and synthetic cell growth, yet its mechanical consequences remain poorly defined. How fusion-driven membrane growth can be sustained without compromising compartment stability remains an unresolved challenge. Here, we established a minimal reconstituted system where content-loaded small liposomes fuse with single cell-sized giant unilamellar vesicles (GUVs), combining micropipette delivery, electrodeformation, and live imaging. Fusion outcomes were quantified through lipid and content mixing assays, GUV electrodeformation to track area and tension, and phase contrast imaging to monitor leakage. GUVs incorporated lipids and cargo from hundreds of thousands of vesicles at unprecedented efficiency rates, enabling substantial growth. However, accumulation of leaflet asymmetries induced curvature and tension, driving budding, rupture and leakage. Hemifusion amplified these destabilizing effects. Lipid number asymmetries emerge as a dominant mechanical cost of fusion, highlighting how cells may regulate these processes and guiding the design of therapeutic delivery systems and synthetic cells capable of robust and stable growth.
    Significance Statement: Membrane fusion enables essential biological processes from secretion to cell growth. Using a synthetic system, we show that rapid fusion of small vesicles with model cell-like compartments drives dramatic growth but also introduces leaflet asymmetries that build curvature and tension, limit expansion and compromise membrane stability. By uncovering lipid number asymmetry as a key mechanical cost of fusion, our study explains why cells tightly regulate fusion events and provides principles for designing delivery vehicles and synthetic cells capable of robust, sustainable growth.
    DOI:  https://doi.org/10.1101/2025.09.22.677743
  32. bioRxiv. 2025 Sep 28. pii: 2025.09.26.678648. [Epub ahead of print]
    Combinatorial protein barcodes enable self-correcting neuron tracing with nanoscale molecular context.
    Sung Yun Park, Arlo Sheridan, Bobae An, Erin Jarvis, Julia Lyudchik, William Patton, Jun Y Axup, Stephanie W Chan, Hugo G J Damstra, Daniel Leible, Kylie S Leung, Clarence A Magno, Aashir Meeran, Julia M Michalska, Franz Rieger, Claire Wang, Michelle Wu, George M Church, Jan Funke, Todd Huffman, Kathleen G C Leeper, Sven Truckenbrodt, Johan Winnubst, Joergen M R Kornfeld, Edward S Boyden, Samuel G Rodriques, Andrew C Payne.
      Mapping nanoscale neuronal morphology with molecular annotations is critical for understanding healthy and dysfunctional brain circuits. Current methods are constrained by image segmentation errors and by sample defects (e.g., signal gaps, section loss). Genetic strategies promise to overcome these challenges by using easily distinguishable cell identity labels. However, multicolor approaches are spectrally limited in diversity, whereas nucleic acid barcoding lacks a cell-filling morphology signal for segmentation. Here, we introduce PRISM (Protein-barcode Reconstruction via Iterative Staining with Molecular annotations), a platform that integrates combinatorial delivery of antigenically distinct, cell-filling proteins with tissue expansion, multi-cycle imaging, barcode-augmented reconstruction, and molecular annotation. Protein barcodes increase label diversity by >750-fold over multicolor labeling and enable morphology reconstruction with intrinsic error correction. We acquired a ∼10 million μm 3 volume of mouse hippocampal area CA2/3, multiplexed across 23 barcode antigen and synaptic marker channels. By combining barcodes with shape information we achieve an 8x increase in automatic tracing accuracy of genetically labelled neurons. We demonstrate PRISM supports automatic proofreading across micron-scale spatial gaps and reconnects neurites across discontinuities spanning hundreds of microns. Using PRISM's molecular annotation capability, we map the distribution of synapses onto traced neural morphology, characterizing challenging synaptic structures such as thorny excrescences (TEs), and discovering a size correlation among spatially proximal TEs on the same dendrite. PRISM thus supports self-correcting neuron reconstruction with molecular context.
    DOI:  https://doi.org/10.1101/2025.09.26.678648
  33. Adv Healthc Mater. 2025 Oct 01. e02475
    Synthetic Hydrogels Incorporating Hydrolytic/Nonhydrolytic Macromer Ratios Exhibit Improved Tunability of In Vivo Degradation and Immune Responses.
    Michael D Hunckler, Sophia Kioulaphides, Karen E Martin, Angelica L Torres, Graham F Barber, Stephen W Linderman, Rebecca S Schneider, Andrés J García.
      Proteolytically degradable hydrogels are widely used as delivery carriers in regenerative medicine. However, the in vivo degradation rate of these materials is difficult to control because of site-specific enzymatic activity, implant design, and disease state, impairing tissue regeneration. Hydrogels with crosslinks that degrade hydrolytically offer an alternate route to tune in vivo degradation profile. In this study, a synthetic 4-arm maleimide-terminated poly(ethylene glycol) (PEG-4MAL) hydrogel system that combines hydrolytic ester-linked PEG-4MAL (PEG-4eMAL) macromer with nondegradable amide-linked PEG-4MAL (PEG-4aMAL) macromer in various stoichiometric ratios to tune the degradability rate is engineered. The macromers are crosslinked with dithiothreitol (DTT) via thiol-maleimide click reaction. Rheological analysis shows that a family of PEG-4eMAL/PEG-4aMAL hydrogels has equivalent mechanical properties, but increasing the PEG-4eMAL content increases the rate of degradation in vitro and in vivo. PEG-4eMAL/PEG-4aMAL hydrogels support high viability of encapsulated human cells. Notably, the ratio of PEG-4eMAL/PEG-4aMAL modulates local immune cell recruitment when implanted in the subcutaneous space. These results establish the use of PEG-4eMAL/PEG-4aMAL hydrogels as a hydrolytically degradable platform to tune in vivo degradation and immune responses.
    Keywords:  hydrogels; hydrolytic degradability; poly(ethylene glycol); tunability
    DOI:  https://doi.org/10.1002/adhm.202502475
  34. PLoS One. 2025 ;20(9): e0331124
    Predicting chromatin conformation contact maps.
    Alan Min, Jacob Schreiber, Anshul Kundaje, William S Noble.
      Over the past 15 years, a variety of next-generation sequencing assays have been developed for measuring the 3D conformation of DNA in the nucleus. Each of these assays gives, for a particular cell or tissue type, a distinct picture of 3D chromatin architecture. Accordingly, making sense of the relationship between genome structure and function requires teasing apart two closely related questions: how does chromatin 3D structure change from one cell type to the next, and how do different measurements of that structure differ from one another, even when the two assays are carried out in the same cell type? In this work, we assemble a collection of chromatin 3D datasets-each represented as a 2D contact map-spanning multiple assay types and cell types. We then build a machine learning model that predicts missing contact maps in this collection. We use the model to systematically explore how genome 3D architecture changes, at the level of compartments, domains, and loops, between cell type and between assay types.
    DOI:  https://doi.org/10.1371/journal.pone.0331124
  35. Nat Commun. 2025 Sep 29. 16(1): 8599
    Constructing artificial neurons with functional parameters comprehensively matching biological values.
    Shuai Fu, Hongyan Gao, Siqi Wang, Xiaoyu Wang, Trevor Woodard, Zhien Wang, Jing Kong, Derek R Lovley, Jun Yao.
      The efficient signal processing in biosystems is largely attributed to the powerful constituent unit of a neuron, which encodes and decodes spatiotemporal information using spiking action potentials of ultralow amplitude and energy. Constructing devices that can emulate neuronal functions is thus considered a promising step toward advancing neuromorphic electronics and enhancing signal flow in bioelectronic interfaces. However, existent artificial neurons often have functional parameters that are distinctly mismatched with their biological counterparts, including signal amplitude and energy levels that are typically an order of magnitude larger. Here, we demonstrate artificial neurons that not only closely emulate biological neurons in functions but also match their parameters in key aspects such as signal amplitude, spiking energy, temporal features, and frequency response. Moreover, these artificial neurons can be modulated by extracellular chemical species in a manner consistent with neuromodulation in biological neurons. We further show that an artificial neuron can connect to a biological cell to process cellular signals in real-time and interpret cell states. These results advance the potential for constructing bio-emulated electronics to improve bioelectronic interface and neuromorphic integration.
    DOI:  https://doi.org/10.1038/s41467-025-63640-7
  36. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2516426122
    Mesoscale avalanche size underpins the rheology of granular yielding.
    Keng-Lin Lee, Ting-Yin Yeh.
      Granular materials under loading exhibit intermittent avalanches of varying sizes prior to full yielding, a hallmark of natural failure phenomena such as landslides and earthquakes. While continuum models for postyield plastic flow are well established, a unified framework connecting preyield avalanche dynamics to bulk rheology remains lacking. Here, we introduce a birefringent double-shear experiment that enables sustained probing of avalanche statistics and quasistatic flow behavior near the yielding transition. We find that the avalanche regime exhibits rate-weakening behavior, while the plastic regime is rate-independent, resulting in dual rheology under identical local shear rates and indicating hysteresis and mechanical instability. Within a stress-activated framework, we identify the mean normalized stress drop, a measure for mesoscale avalanche size, as a key field variable that bridges the two regimes. Incorporating this variable, we formulate a unified constitutive model that captures the entire yielding transition. These findings establish mesoscale avalanche evolution as a central mechanism underlying granular yielding rheology.
    Keywords:  granular materials; photoelastic method; yielding rheology
    DOI:  https://doi.org/10.1073/pnas.2516426122
  37. Nat Chem Biol. 2025 Oct 02.
    Cell-selective multiplexed bioorthogonal noncanonical amino acid tagging for nascent proteomics.
    Conor Loynd, Soumya Jyoti Singha Roy, Sarah E Canarelli, Daniel W Bak, Bharathi Sundaresh, Zachary Babbitz, Tim van Opijnen, Eranthie Weerapana, Abhishek Chatterjee.
      Cell-selective bioorthogonal noncanonical amino acid tagging (BONCAT) enables time-resolved characterization of newly synthesized proteins using engineered aminoacyl-tRNA synthetases. In bacteria, this is typically accomplished using an engineered methionyl-tRNA synthetase (MetRS-NLL). Here we substantially expand the scope of this technology by introducing an engineered tyrosyl-tRNA synthetase (EcTyrRS) and a tryptophanyl-tRNA synthetase (EcTrpRS). These enzymes enable the ultrafast proteome tagging at much lower expression levels than MetRS-NLL, thereby improving both time resolution and robustness in nonmodel bacteria. Additionally, both enzymes can incorporate multiple different noncanonical amino acids with distinct click handles. This enabled new multiplexing capabilities such as distinct tagging of the nascent proteome generated in a cell in response to different cues, and tighter temporal control through pulse-chase BONCAT. EcTyrRS and EcTrpRS are also mutually orthogonal, enabling distinct proteome tagging of different cell types in mixed populations. We therefore demonstrate the utility of this technology in Escherichia coli and nonmodel ESKAPE pathogens.
    DOI:  https://doi.org/10.1038/s41589-025-02039-3
  38. ACS Macro Lett. 2025 Oct 01. 1497-1503
    Regiochemical Control of Shape Morphing in Diels-Alder Covalent Adaptable Networks.
    Yilei Zhao, Junho Moon, Svetlana A Sukhishvili.
      We demonstrate that regioisomerism in Diels-Alder (DA) reactions offers a subtle yet powerful way to tune the thermomechanical and shape morphing behavior of dynamic polymer networks. Here, we directly compare DA polymer (DAP) networks built from linear polymers with identical backbones but containing either 2- or 3-substituted furan pendant groups. For a wide range of cross-linking degrees, the 3-substituted DAP (3-DAP) networks exhibited higher thermal stability, with retro-DA dissociation temperatures (TrDA) of ∼150 °C versus 120 °C for the 2-substituted counterparts, higher elastic moduli and significantly slower temperature-dependent stress relaxation rates. The difference in the stress relaxation rates of 2- and 3-DAP elastomers was leveraged to demonstrate controlled bending in a bilayer structure via selective network plasticization. Moreover, due to the higher TrDA values, the use of 3-DAP elastomers in the single-material constructs opened a wider and a higher-temperature window (i.e., between 80 and 140 °C) for shape morphing, which is more practical compared to the traditionally employed DA-based networks such as 2-DAP elastomers which could be morphed only between 60 and 90 °C. These findings establish regioisomerism in the furan ring as a powerful parameter for designing DA-based shape morphing materials.
    DOI:  https://doi.org/10.1021/acsmacrolett.5c00465
  39. Adv Mater. 2025 Oct 04. e09991
    Materials Design and Assessment of Redox-Mediated Flow Cell Systems for Enhanced Energy Storage and Conversion.
    Zhiyu Wang, Yan Jing, Qing Wang.
      The transition toward sustainable energy systems necessitates innovations that overcome the limitations of conventional electrochemical systems. Redox-mediated flow cell systems emerge as a transformative paradigm by decoupling energy storage, conversion, and chemical processes from traditional electrode-bound reactions. These systems employ soluble redox mediators to shuttle electrons between electrodes and spatially separated reactive phases (solid, liquid, or gas), thereby enabling unprecedented operational flexibility and scalability. This standpoint underscores the adaptability of redox-mediated electrified systems across a range of applications, encompassing high-energy-density redox targeting-based flow batteries, fuel cells, electrified CO2 capture, sustainable chemical synthesis, waste recycling, etc. The rational design of redox-active materials is central to their success, with precise alignment of redox potentials, enhanced electron-transfer kinetics, and robust stability underpinning performance. The challenges of new materials development, system durability, and cost-effectiveness can be addressed through advances in experimental measurement, computational modeling, operando characterization, and interdisciplinary collaboration. Moving forward, the integration of redox-mediated technologies with renewable energy systems and industrial processes is predicted to transform energy and chemical landscapes. The integration of laboratory innovations with real-world deployment facilitates a pathway to decarbonization, resource efficiency, and the circular economy. This perspective emphasizes the pivotal functions of redox-mediated architectures in fostering a robust, electrified future, where the convergence of energy storage, environmental stewardship, and sustainable chemical production is pivotal in addressing global challenges.
    Keywords:  energy storage and conversion; flow cell systems; materials design and assessment; redox‐mediated; redox‐targeting
    DOI:  https://doi.org/10.1002/adma.202509991
  40. Nat Commun. 2025 Sep 30. 16(1): 8675
    Optimized user-guided motion control of modular robots.
    Anastasia Bolotnikova, Kevin Holdcroft, Henry Cerbone, Christoph Belke, Auke Ijspeert, Jamie Paik.
      Transferring motion instructions from a user enables robots to perform new and unforeseen operations. Robot collectives, in particular, offer greater adaptability to changing tasks and environments. However, effectively transferring motion instructions becomes challenging as the collective's shape and size evolve. These changes often require additional system constraints to maintain robust motion control, which typically depends on pre-programmed knowledge of new tasks, ultimately limiting the collective's adaptability. To overcome the above challenges, we propose a physical and computational platform for user-guided control of self-reconfigurable modular robots. This platform consists of an optimization scheme for online processing of user commands, which prevents any modular robot actions that would violate system or environment constraints. The second component consists of Joint-space Joysticks, which match the robot's morphology, enabling the user to control diverse and dynamically changing modular robot structures through direct physical interaction. We present a platform that enables users to safely control modular, shape-changing robots through a physical interface. We demonstrate the platform's efficacy and generalizability across a diverse set of modular robot morphologies using two independent robotic systems - Mori3 and Roombots - performing a range of tasks including pick-and-place, human assistance, legged locomotion, and workspace expansion.
    DOI:  https://doi.org/10.1038/s41467-025-63706-6
  41. Nat Commun. 2025 Sep 29. 16(1): 8543
    Thermodynamic dissipation constrains metabolic versatility of unicellular growth.
    Tommaso Cossetto, Jonathan Rodenfels, Pablo Sartori.
      Metabolic versatility enables unicellular organisms to grow in vastly different environments. Since growth occurs far from thermodynamic equilibrium, the second law of thermodynamics has long been believed to pose key constraints to life. Yet, such constraints remain largely unknown. Here, we integrate published data spanning decades of experiments on unicellular chemotrophic growth and compute the corresponding thermodynamic dissipation. Due to its span in chemical substrates and microbial species, this dataset samples the versatility of metabolism. We find two empirical thermodynamic rules: first, the amount of energy dissipation per unit of biomass grown is largely conserved across metabolic types and domains of life; second, aerobic respiration exhibits a trade-off between dissipation and growth, reflecting in its high thermodynamic efficiency. By relating these rules to the fundamental thermodynamic forces that drive and oppose growth, our results show that dissipation imposes tight constraints on metabolic versatility.
    DOI:  https://doi.org/10.1038/s41467-025-62975-5
  42. Mol Cell. 2025 Oct 02. pii: S1097-2765(25)00742-7. [Epub ahead of print]85(19): 3661-3676.e8
    A network of P-body and Whi3 condensates adjusts cell fate decisions to cellular context.
    Thomas R Peskett, Ana-Maria Farcas, Sung Sik Lee, Yves Barral.
      Cells use information about their environments and internal states to decide whether to proliferate, differentiate, or enter non-proliferative states such as quiescence and senescence. But how do they integrate this information to make unambiguous decisions? Here, we describe how the interaction between two independent condensates, P-bodies and Whi3-dependent condensates, enables individual yeast cells to integrate information about their biological age and the presence of potential mates during fate decisions. Both formation and interaction of these condensates were necessary and sufficient to drive old cells into senescence and store age information in the yeast mother cell at mitosis. This same network also primed old cells to choose proliferation over mating when exposed to mating pheromone, demonstrating that it injects contextual information into multiple decisions. Thus, biomolecular condensates and their interactions can collect and integrate contextual information to adjust cellular decisions to overlapping life events.
    Keywords:  P-body; Whi3; aging; cell fate decision; condensate; information; network; senescence; yeast
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.001
  43. Adv Sci (Weinh). 2025 Sep 29. e14883
    Single-Cell Nucleus Extraction with Cellular Indexing.
    Trinh Lam, Ana Esmeralda Gomez Martinez, Alison Su, Anna Fomitcheva-Khartchenko, Xin Wang, Md Nazibul Islam, Paul Lum, Amy Elizabeth Herr.
      Bulk organelle‑fractionation masks cell‑to‑cell heterogeneity, and existing microfluidic methods cannot reliably reconnect each isolated organelle to its parent cell, an essential capability for multiomics readouts. VacTrap, a high-throughput microfluidic device that isolates and spatially indexes single nuclei from mammalian cells is developed. The VacTrap device consisted of three aligned layers: 1) a Bis-gel microwells layer with a "trapdoor" (BAC-gel) base, fabricated atop a through-hole glass slide; 2) a polydimethylsiloxane (PDMS) microwell layer to receive transferred nuclei; and 3) a vacuum manifold. VacTrap operation begins with cell cytoplasmic lysis using differential detergent fractionation (DDF) to release intact nuclei into the Bis-gel microwells, while cytoplasmic proteins are electrophoresed into the Bis-gel layer. Subsequent addition of dithiothreitol (DTT) and vacuum dissolves the trapdoors within 3-5 min, synchronously transferring nuclei into the PDMS microwells, achieving 98% efficiency across 80% of trapdoors. To verify fractionation of the cytoplasmic proteins from each cell nucleus, select protein targets are successfully detected by in situ immunoprobing in the archival Bis-gel layer. To verify the fractionation and collection of individual intact nuclei, the morphology analysis confirms preservation of the nuclear features. By introducing spatial indexing of nuclei back to the originating cell, VacTrap provides a robust, automated cell-preparation platform for single-cell multiomics applications.
    Keywords:  hydrogels; microfluidics; multiomics; organelles; proteomics; single‐cell
    DOI:  https://doi.org/10.1002/advs.202514883
  44. Sci Adv. 2025 Oct 03. 11(40): eadx9774
    Molecular basis of the biogenesis of a protein organelle for ethanolamine utilization.
    Mengru Yang, Oluwatobi Adegbite, Ping Chang, Jin Cheng, Yue Wang, Marie Held, Xiaojun Zhu, Yan Li, Gregory F Dykes, Yu Chen, Natasha Savage, Yu-Zhong Zhang, Jun Gao, Jay C D Hinton, Lu-Yun Lian, Lu-Ning Liu.
      Many pathogenic bacteria use proteinaceous ethanolamine utilization microcompartments (Eut BMCs) to catabolize ethanolamine. This ability gives pathogens a competitive edge over commensal microbiota, which can drive virulence in the inflamed gut. Despite such a critical function, the molecular mechanisms underlying the synthesis of Eut BMCs remain elusive. We report a systematic study for dissecting the molecular basis underlying Eut BMC assembly in Salmonella. We determined the functions of individual constituent proteins in the structure and function of Eut BMCs and demonstrated that EutQ is essential for cargo encapsulation and Eut BMC formation through specific association with the shell and cargo enzymes. We found that Eut proteins can self-assemble to form cargo and shell aggregates independently in vivo and that the biogenesis of Eut BMCs follows a "shell-initiated" pathway. Cargo enzymes exhibit dynamic liquid-like organization within the Eut BMC. Our findings provide mechanistic insights into the structure and assembly of the Eut BMC that serves as a paradigm for membraneless organelles.
    DOI:  https://doi.org/10.1126/sciadv.adx9774
  45. Nat Commun. 2025 Oct 01. 16(1): 8747
    Cassini: streamlined and scalable method for in situ profiling of RNA and protein.
    Nicolas Lapique, Michael Taewoo Kim, Nicholas Thom, Naeem M Nadaf, Juan Pineda, Evan Z Macosko.
      In the expanding field of spatial genomics, numerous methods have emerged to decode biomolecules in intact tissue sections. Advanced techniques based on combinatorial decoding can resolve thousands of features in a reasonable time but are often constrained by either the prohibitive costs associated with commercial platforms or the complexity of developing custom instruments. Alternatively, sequential detection methods, like single-molecule FISH, are easier to implement but offer limited multiplexing capability or signal amplification. Here, we introduce Cassini, an innovative approach for straightforward, cost-effective multiplexed measurements of mRNA and protein features simultaneously. Cassini leverages rolling circle amplification, known for its robust amplification and remarkable stability even after intense stripping, to serially detect each feature in under 20 minutes. The method also enables simultaneous immunostaining with either fluorophore-conjugated or DNA-barcoded antibodies, through an optimized immunostaining buffer. In a single overnight run, we show that Cassini can quantify 32 features (comprising both RNA and proteins) with sensitivity similar to state-of-the-art FISH techniques. We provide a comprehensive protocol alongside an online probe-design platform (cassini.me), aiming to enhance accessibility and user-friendliness. With our open-source solution, we aspire to empower researchers to uncover the nuances of spatial gene expression dynamics across diverse biological landscapes.
    DOI:  https://doi.org/10.1038/s41467-025-63798-0
  46. Nat Commun. 2025 Oct 02. 16(1): 8771
    Machine learning applied to biocatalysis research.
      
    DOI:  https://doi.org/10.1038/s41467-025-64510-y
  47. Mol Syst Biol. 2025 Sep 29.
    A tool for modeling gene regulatory networks (GRN_modeler) and its applications to synthetic biology.
    Gábor Holló, Jung Hun Park, Emanuele Boni, Yolanda Schaerli.
      Modeling and simulating gene regulatory networks (GRNs) is crucial for understanding biological processes, predicting system behavior, interpreting experimental data and guiding the design of synthetic systems. In synthetic biology, GRNs are fundamental to enable the design and control of complex functions. However, GRN simulations can be time-consuming and often require specialized expertise. To address this challenge, we developed GRN_modeler - a user-friendly tool with a graphical user interface that enables users without programming experience to create phenomenological models, while also offering command-line support for advanced users. GRN_modeler supports the analysis of both dynamical behaviors and spatial pattern formation. We demonstrate its versatility through several examples in synthetic biology, including the design of novel oscillator families capable of robust oscillation with an even number of nodes, complementing the classical repressilator family, which requires odd-numbered nodes. Furthermore, we showcase how GRN_modeler allowed us to develop a light-detecting biosensor in Escherichia coli that tracks light intensity over several days and leaves a record in the form of ring patterns in bacterial colonies.
    Keywords:  Gene Regulatory Networks; Light Biosensor; Optogenetics; Simulation Tool; Synthetic Biology
    DOI:  https://doi.org/10.1038/s44320-025-00148-8
  48. Nat Genet. 2025 Oct 03.
    Dissecting the impact of transcription factor dose on cell reprogramming heterogeneity using scTF-seq.
    Wangjie Liu, Wouter Saelens, Pernille Rainer, Marjan Biočanin, Vincent Gardeux, Antoni Jakub Gralak, Guido van Mierlo, Angelika Gebhart, Julie Russeil, Tingdang Liu, Wanze Chen, Bart Deplancke.
      Reprogramming often yields heterogeneous cell fates, yet the underlying mechanisms remain poorly understood. To address this, we developed single-cell transcription factor sequencing (scTF-seq), a single-cell technique that induces barcoded, doxycycline-inducible TF overexpression and quantifies TF dose-dependent transcriptomic changes. Applied to mouse embryonic multipotent stromal cells, scTF-seq generated a gain-of-function atlas for 384 mouse TFs, identifying key regulators of lineage specification, cell cycle control and their interplay. Leveraging single-cell resolution, we uncovered how TF dose shapes reprogramming heterogeneity, revealing both dose-dependent and stochastic cell state transitions. We classified TFs into low-capacity and high-capacity groups, with the latter further subdivided by dose sensitivity. Combinatorial scTF-seq demonstrated that TF interactions can shift from synergistic to antagonistic depending on the relative dose. Altogether, scTF-seq enables the dissection of TF function, dose and cell fate control, providing a high-resolution framework to understand and predict reprogramming outcomes, advancing gene regulation research and the design of cell engineering strategies.
    DOI:  https://doi.org/10.1038/s41588-025-02343-7
  49. Nat Commun. 2025 Sep 30. 16(1): 8373
    COOKIE-Pro: covalent inhibitor binding kinetics profiling on the proteome scale.
    Hanfeng Lin, Bin Yang, Lang Ding, Yen-Yu Yang, Matthew V Holt, Sung Yun Jung, Bing Zhang, Meng C Wang, Jin Wang.
      Covalent inhibitors are an emerging class of therapeutics, but methods to comprehensively profile their binding kinetics and selectivity across the proteome have been limited. Here we introduce COOKIE-Pro (COvalent Occupancy KInetic Enrichment via Proteomics), an unbiased method for quantifying irreversible covalent inhibitor binding kinetics on a proteome-wide scale. COOKIE-Pro uses a two-step incubation process with mass spectrometry-based proteomics to determine kinact and KI values for covalent inhibitors against both on-target and off-target proteins. We validated COOKIE-Pro using BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and unreported off-targets. The method revealed that spebrutinib has over 10-fold higher potency for TEC kinase compared to its intended target BTK. To demonstrate the method's utility for high-throughput screening, we applied a streamlined two-point strategy to a library of 16 covalent fragments. This approach successfully generated thousands of kinetic profiles, enabling the quantitative decoupling of intrinsic chemical reactivity from binding affinity at scale and validating the method's broad applicability. By providing a comprehensive view of covalent inhibitor binding across the proteome, COOKIE-Pro represents a powerful tool for optimizing the potency and selectivity of covalent drugs during preclinical development.
    DOI:  https://doi.org/10.1038/s41467-025-63491-2
  50. Small. 2025 Sep 27. e07976
    Programmable 3D Morphing Bionic Gradient Hydrogel Actuators with Fast Response and Large-Amplitude Deformations.
    Jiaxin Zeng, Zhiyu Zheng, Sicheng Wu, Ruxin Xiao, Liqiong Liao.
      Hydrogel actuators have shown promising applications in biomedical devices, wearable electronics, and soft robotics. To fulfill practical applications, hydrogel actuators must achieve high-speed adaptive motion, programmable large-strain actuation and 3D morphing ability, however, the fabrication of such actuators remains a challenge. In this work, temperature responsive gradient hydrogel is prepared through the UV-absorbing effects of the precursors at specific wavelength of UV light during photopolymerization. Moreover, chito-oligosaccharides (COS) are introduced to enhance the hydrogel's gradient structure by migrating to the low-density side during photopolymerization and acting as porogen, resulting in a hydrogel with an ultrafast bending rate (190°/s) and large amplitude (760°). Furthermore, a light-responsive gradient hydrogel can be easily fabricated using the "naturally derived" genipin-crosslinked gelatin network as the photothermal transducer. By employing the photomask techniques to customize the local gradient structures, hydrogels with programmable 3D1-to-3D2 deformation behavior are realized. Inspired by inchworms and springtails, the hydrogels are pre-programmed to harness its fast-response and large-amplitude deformation, enabling light-driven soft robots to achieve biomimetic actuation, including tumbling, jumping, and crawling. This programmable, fast-response, 3D shape-morphing gradient hydrogel actuator expands the possibilities for applications in complex dynamic systems, including soft robotics and bionic devices.
    Keywords:  biomimetic actuation; fast response; gradient hydrogel; large‐amplitude deformation
    DOI:  https://doi.org/10.1002/smll.202507976
  51. Nature. 2025 Oct;646(8083): 108-116
    Connecting chemical and protein sequence space to predict biocatalytic reactions.
    Alexandra E Paton, Daniil A Boiko, Jonathan C Perkins, Nicholas I Cemalovic, Thiago Reschützegger, Gabe Gomes, Alison R H Narayan.
      The application of biocatalysis in synthesis has the potential to offer streamlined routes towards target molecules1, tunable catalyst-controlled selectivity2, as well as processes with improved sustainability3. Despite these advantages, biocatalysis is often a high-risk strategy to implement, as identifying an enzyme capable of performing chemistry on a specific intermediate required for a synthesis can be a roadblock that requires extensive screening of enzymes and protein engineering to overcome4. Strategies for predicting which enzyme and small molecule are compatible have been hindered by the lack of well-studied biocatalytic reaction datasets5. The underexploration of connections between chemical and protein sequence space constrains navigation between these two landscapes. Here we report a two-phase effort relying on high-throughput experimentation to populate connections between productive substrate and enzyme pairs and the subsequent development of a tool, CATNIP, for predicting compatible α-ketoglutarate (α-KG)/Fe(II)-dependent enzymes for a given substrate or, conversely, for ranking potential substrates for a given α-KG/Fe(II)-dependent enzyme sequence. We anticipate that our approach can be readily expanded to further enzyme and transformation classes and will derisk the investigation and application of biocatalytic methods.
    DOI:  https://doi.org/10.1038/s41586-025-09519-5
  52. bioRxiv. 2025 Sep 25. pii: 2025.09.25.678607. [Epub ahead of print]
    A self-limiting mechanotransduction feedback loop ensures robust organ formation.
    Yusuke Mori, Paul Robin, Anne Belle Briggs, Daniel S Levic, Jiacheng Wang, Kira L Heikes, Michel Bagnat, Edouard Hannezo, Akankshi Munjal.
      Organ development requires integration of mechanical forces, biochemical signals, and transcriptional programs to achieve proper size and architecture. Mechanotransduction feedback loops convert mechanical forces into gene-expression changes that, in turn, regulate cell behaviors such as growth and extracellular matrix (ECM) production. How these loops are coupled to developmental programs to ensure robust morphogenetic outcomes remains poorly understood. Here, we show that Yap-dependent mechanotransduction establishes a self-limiting positive feedback loop that drives the successful formation of semicircular canals in zebrafish. These canals form through reproducible steps of bud initiation, extension, and fusion within the otic epithelium. Local swelling of a hyaluronan-rich ECM initiates bud formation. We demonstrate that this ECM expansion activates Yap in a spatially patterned manner within the bud. Activated Yap induces its target, ccn1l1, which drives further ECM production, establishing a positive feedback loop. The ensuing rapid ECM expansion sustains bud extension. Graded perturbations to the mechanotransduction loop reduced extension, with bud fusion remaining robust at lower levels of disruption but blocked at the highest dose. Critically, the loop contains its own termination mechanism: when buds fuse, the PKA-CREB signaling is activated by the adhesion GPCR Gpr126 to suppress ccn1l1 , preventing overgrowth. These findings reveal how mechanotransduction-driven positive feedback loops can be coupled to their own termination, providing developmental control through the integration of mechanical forces with transcriptional responses and morphogenetic outcomes.
    DOI:  https://doi.org/10.1101/2025.09.25.678607
  53. Nature. 2025 Oct 01.
    Heat-rechargeable computation in DNA logic circuits and neural networks.
    Tianqi Song, Lulu Qian.
      Metabolism enables life to sustain dynamics and to repeatedly interact with the environment by storing and consuming chemical energy. A major challenge for artificial molecular machines is to find a universal energy source akin to ATP for biological organisms and electricity for electromechanical machines. More than 20 years ago, DNA was first used as fuel to drive nanomechanical devices1,2 and catalytic reactions3. However, each system requires distinct fuel sequences, preventing DNA alone from becoming a universal energy source. Despite extensive efforts4, we still lack an ATP-like or electricity-like power supply to sustain diverse molecular machines. Here we show that heat can restore enzyme-free DNA circuits from equilibrium to out-of-equilibrium states. During heating and cooling, nucleic acids with strong secondary structures reach kinetically trapped states5,6, providing energy for subsequent computation. We demonstrate that complex logic circuits and neural networks, involving more than 200 distinct molecular species, can respond to a temperature ramp and recharge within minutes, allowing at least 16 rounds of computation with varying sequential inputs. Our strategy enables diverse systems to be powered by the same energy source without problematic waste build-up, thereby ensuring consistent performance over time. This scalable approach supports the sustained operation of enzyme-free molecular circuits and opens opportunities for advanced autonomous behaviours, such as iterative computation and unsupervised learning in artificial chemical systems.
    DOI:  https://doi.org/10.1038/s41586-025-09570-2
  54. Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01116-7. [Epub ahead of print]44(10): 116345
    A selection-based knockout approach for a choanoflagellate reveals regulation of multicellular development by Hippo signaling.
    Chantal Combredet, Mylan Ansel, Thibaut Brunet.
      Choanoflagellates, the closest living relatives of animals, provide crucial insights into animal origins. The multicellular choanoflagellate Salpingoeca rosetta can be genetically modified, but existing knockout (KO) pipelines are time consuming and have variable efficiency. Here, we present a fast and robust KO method for S. rosetta. We use CRISPR-Cas9 to inactivate target genes by interrupting, or fully replacing, their coding sequence with a selectable antibiotic resistance cassette. We inactivated three known S. rosetta multicellular developmental regulators (rosetteless, couscous, and jumble) and two homologs of Hippo pathway genes that control multicellular size in animals (warts and yorkie). Interestingly, warts-KO rosettes were consistently larger than their wild-type counterparts. RNA sequencing revealed that Warts and Yorkie regulated several extracellular matrix genes involved in multicellularity (including couscous), suggesting that Hippo signaling regulates multicellular size in choanoflagellates by modulating matrix secretion. We discuss the potential of our method to accelerate choanoflagellate functional genetics.
    Keywords:  CP: Developmental biology; CRISPR-Cas9; Hippo signaling; animal origins; choanoflagellates; evo-devo; evolutionary cell biology; evolutionary developmental biology; extracellular matrix; genetic engineering; multicellularity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116345
  55. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2515031122
    Global constraint principle for microbial growth laws.
    Jumpei F Yamagishi, Tetsuhiro S Hatakeyama.
      Understanding complex living systems requires identifying universal phenomenological laws that are independent of species and molecular-biological details. The Monod equation is a cornerstone of phenomenological microbial growth laws, depicting the growth rate as a saturating function of a single substrate. Because of its similarity in functional form to the Michaelis-Menten equation, cellular growth is often thought to be limited by a single reaction. However, cellular growth generically results from the coordination of thousands of metabolic reactions and diverse intracellular limited resources. Consequently, the mechanistic origins of the Monod equation remain controversial, and its extension has encountered limitations. Here, we propose the global constraint principle for cellular growth: As one nutrient becomes more available, other intracellular resources become limiting, driving transitions to distinct modes of resource allocation. Based on a general framework of constraint-based modeling and its dual formulations, we mathematically prove that, in general, microbial growth kinetics curves are monotonically increasing and concave with respect to nutrient availability. Numerical simulations using genome-scale Escherichia coli models with proteome allocation, molecular crowding, and membrane capacity constraints reproduce these features in a multiphasic manner. In contrast to the original Monod's growth law, the global constraint principle also captures the dependence of microbial growth on the availability of multiple nutrients, by generalizing the Liebig's law of the minimum, another phenomenological growth law for higher organisms, into a terraced landscape of diminishing returns. It thus integrates the classical phenomenological laws proposed by Monod and Liebig into a comprehensive theory of cellular growth.
    Keywords:  cellular growth; convex optimization; dual problem; metabolism; resource allocation
    DOI:  https://doi.org/10.1073/pnas.2515031122
  56. Nature. 2025 Oct 01.
    Machine learning matches enzymes with molecular substrates.
      
    Keywords:  Biochemistry; Catalysis
    DOI:  https://doi.org/10.1038/d41586-025-03161-x
  57. Cell. 2025 Oct 01. pii: S0092-8674(25)01037-2. [Epub ahead of print]
    Sequencing-free whole-genome spatial transcriptomics at single-molecule resolution.
    Yubao Cheng, Shengyuan Dang, Yuan Zhang, Yanbo Chen, Ruihuan Yu, Miao Liu, Shengyan Jin, Ailin Han, Samuel Katz, Siyuan Wang.
      Recent breakthroughs in spatial transcriptomics technologies have enhanced our understanding of diverse cellular identities, spatial organizations, and functions. Yet existing spatial transcriptomics tools are still limited in either transcriptomic coverage or spatial resolution, hindering unbiased, hypothesis-free transcriptomic analyses at high spatial resolution. Here, we develop reverse-padlock amplicon-encoding fluorescence in situ hybridization (RAEFISH), an image-based spatial transcriptomics method with whole-genome coverage and single-molecule resolution in intact tissues. We demonstrate the spatial profiling of transcripts from 23,000 human or 22,000 mouse genes in single cells and tissue sections. Our analyses reveal transcript-specific subcellular localization, cell-type-specific and cell-type-invariant zonation-dependent transcriptomes, and gene programs underlying preferential cell-cell interactions. Finally, we further develop our technology for the direct spatial readout of guide RNAs (gRNAs) in an image-based, high-content CRISPR screen. Overall, these developments offer a broadly applicable technology that enables high-coverage, high-resolution spatial profiling of both long and short, native and engineered RNAs in many biomedical contexts.
    Keywords:  high content CRISPR screen; highly multiplexed RNA imaging; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.cell.2025.09.006
  58. Nature. 2025 Oct;646(8083): 88-94
    Kirigami-inspired parachutes with programmable reconfiguration.
    Danick Lamoureux, Jérémi Fillion, Sophie Ramananarivo, Frédérick P Gosselin, David Melancon.
      The art of kirigami allows programming a sheet to deform into a particular manner with a pattern of cuts, endowing it with exotic mechanical properties and behaviours1-17. Here we program discs to deform into stably falling parachutes as they deploy under fluid-structure interaction. Parachutes are expensive and delicate to manufacture, which limits their use for humanitarian airdrops or drone delivery. Laser cutting a closed-loop kirigami pattern18 in a disc induces porosity and flexibility into an easily fabricated parachute. By performing wind tunnel testing and numerical simulations using a custom flow-induced reconfiguration model19, we develop a design tool to realize kirigami-inspired parachutes. Guided by these results, we fabricate parachutes from the centimetre to the metre scale and test them in realistic conditions. We show that at low load-to-area ratios, kirigami-inspired parachutes exhibit a comparable terminal velocity to conventional ones. However, unlike conventional parachutes that require a gliding angle for vertical stability20 and fall at random far from a target, our kirigami-inspired parachutes always fall near the target, regardless of their initial release angle. These kinds of parachutes could limit material losses during airdropping as well as decrease manufacturing costs and complexity.
    DOI:  https://doi.org/10.1038/s41586-025-09515-9
  59. Nat Mater. 2025 Oct 01.
    Amorphous phase-change memory alloy with no resistance drift.
    Xiaozhe Wang, Ruobing Wang, Suyang Sun, Ding Xu, Chao Nie, Zhou Zhou, Chenyu Wen, Junying Zhang, Ruixuan Chu, Xueyang Shen, Wen Zhou, Zhitang Song, Jiang-Jing Wang, En Ma, Wei Zhang.
      Spontaneous structural relaxation is intrinsic to glassy materials due to their metastable nature. For phase-change materials, the resultant temporal change in electrical resistance seriously hampers neuromorphic computing applications. Here we report an ab-initio-calculation-informed design of amorphous phase-change materials composed of robust 'molecule-like' motifs, depriving the amorphous alloy of critical structural ingredients responsible for relaxation and, hence, resistance drift. We demonstrate amorphous CrTe3 thin films that display practically no resistance drift at any working temperature from -200 °C to 165 °C, and highlight the multilevel encoding ability via a hybrid opto-electronic approach. We further reveal that the same no-drift behaviour holds for melt-quenched amorphous CrTe3 in electronic devices. Moreover, the application potential of CrTe3 is testified by its incorporation in a vehicle with an automatic path-tracking function. Our work provides an alternative route to achieve requisite properties for potential phase-change neuromorphic computing via the judicious design of disordered phase-change materials.
    DOI:  https://doi.org/10.1038/s41563-025-02361-0
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