Nature Physics

Destructive mechanical breakdowns and fractures are ubiquitous events in driven physical matter; living tissues, by contrast, can rupture repeatedly while restoring integrity. Here we study rupture-repair interplay in regenerating Hydra tissues, which cycle through osmotic inflation, pressure release by rupture, and resealing. We utilize bright-field imaging of the tissues projected area as a readout of the rupture magnitude before it is arrested. Analyzing these event statistics, we find that the tail of the area-drop distribution is controlled by Ca2+-dependent repair efficiency. When the Ca2+ response is weakened, either by partially blocking gap-junctions mediating the intercellular communication, or by inhibiting stretch-activated Ca2+ channels, the actomyosin force that arrests the rupture process is delayed or reduced. Under these conditions, rare large pressure releases become more likely, and the tail of the distribution crosses over from an exponential behavior, exhibiting a characteristic scale, to a power-law one consistent with a critical-like regime reflecting intermittent rupture propagation. These results identify mechanically evoked Ca2+ activity as a control axis linking repair to rupture statistics in a living tissue. It supports a picture of rupture front advancing by stick-slip-like dynamics as it encounters a heterogeneous mechanical landscape, akin to failure-front propagation in disordered materials.

In non-equilibrium (active) systems, increased driving is commonly assumed to amplify energy dissipation. This frames the efficiency of protein-based machines as a fixed or monotonically decreasing function with driving. Using picowatt-sensitive calorimetry and advanced entropy production metrics in reconstituted actomyosin networks, we show that energy dissipation depends non-monotonically on myosin-generated stress (driving). At low driving, dissipation increases proportionally with stress, consistent with near-equilibrium linear response. At high driving, however, dissipation decreases, revealing a far-from-equilibrium regime in which excessive load suppresses motor ATPase activity. This non-monotonicity reflects a transition from spatially localized stress at low driving to delocalized stress at high driving, where force per motor, and thus ATPase suppression, is maximized. Crosslinker mechanics tune this transition as fascin (slip bonds) amplifies stress localization and shifts the dissipation peak to higher driving, whereas -actinin (catch bonds) stabilizes under load, delocalizes stress, and shifts the peak to lower driving. Thus, enhanced mechanochemical coupling causes additional driving to restructure rather than amplify dissipation, revealing how material system organization (bonding), and not driving alone, governs energy flow far from equilibrium.

Navigating fluid flow is a fundamental challenge for microbial life across diverse aquatic environments. While rheotaxis in swimming microorganisms has been extensively studied, it remains unresolved whether near-bed shear merely perturbs gliding motility or instead provides directional cues for active navigation on surfaces. Here we show that the benthic diatom Navicula cryptocephala utilises a purely mechanical strategy to achieve downstream rheotaxis and anisotropic spreading on submerged surfaces. Single-cell ellipsoidal tracking reveals a direction-dependent angular response that reorients gliding cells towards the downstream direction. Using interference reflection microscopy, we further reveal that shear induces rolling of obliquely gliding cells, laterally shifting the cell-substrate contact site. This shift renders raphe-based propulsion non-collinear with substrate friction, generating a downstream-restoring yaw torque. Crucially, our results rule out alternative explanations based on longitudinal shifts of the raphe contact site or direct hydrodynamic yaw torque. A minimal stochastic model confirms that this mechanical reorientation alone is sufficient to reproduce the observed drift and diffusion patterns, without invoking either orientation-dependent switching between motility states or orientation-dependent dwell times of those states. Our findings uncover a mechanism by which ambient shear is converted into directional guidance for active surface motility, providing new insights into microbial transport, retention, and resilience on submerged surfaces.

In living systems across developmental and cancer biology, populations of cells on surfaces organize themselves into aggregates that mediate function and disease. Recent experimental studies have identified that such aggregates can have emergent fluid-like properties such as surface tension, yet the physical origin of these properties is not clear. Here, we develop a minimal cell-based model in which cell-cell and cell-substrate interactions are governed by active intermittent attachments. We explain the transition of cells from a dilute population to a dense aggregate, and quantify the emergent material properties underpinning this transition. We use our model to interpret experiments on dewetting of aggregates of MDA-MDB-231 cancer cells and shape fluctuations of surface-associated OVCAR3 cell aggregates. Finally, we show how spatial heterogeneity in attachments governs collective chemotaxis of cell aggregates. Together, these results reveal how active intermittent attachments generate cell aggregates with emergent material properties, with broad implications for development and cancer.

Cells can experience time-varying mechanical cues, particularly when navigating through changing and complex microenvironments. Yet whether and how cells retain and use a short-term mechanical memory of recent deformations remains unclear. Here we show that, in glioblastoma cells, this memory is encoded by transient cytoskeletal anisotropy. Using uniaxial magneto-mechanical actuation aligned or perpendicular to the cell long axis, nanoindentation, and selective cytoskeletal perturbations, we find that distinct architectures of the actin cytoskeleton drive opposite mechanical responses: actin stress fibers mediate stiffening under stretch, whereas the actin cortex underlies softening under perpendicular loading. Vimentin intermediate filaments are essential to stabilize actin organization under load, preserving deformation-specific mechanics. Quantitative imaging reveals that mechanical actuation induces network-specific alignment and anisotropy, stronger for actin than vimentin, that persists transiently after unloading and bias subsequent responses, revealing a short-lived, deformation-dependent mechanical memory. To integrate these observations, we develop a multi-network constitutive model that links cytoskeletal architecture and loading history to cell-scale mechanics, reproducing both the asymmetric mechanical responses and the measured reorganization dynamics. These findings provide a structural basis for short-term mechanical memory and suggest how cancer cells could exploit residual anisotropy to adapt to fluctuating solid stresses and confinement, transiently biasing polarization, force transmission, and directional persistence during invasion. They also identify vimentin-actin coupling and the kinetics of cytoskeletal remodeling as potential levers to limit the mechanical adaptability of invasive cancer cells.

Transcription factors organize into liquid-like condensates to facilitate gene expression, yet the physical mechanisms governing their formation and properties remain poorly understood. We study the size statistics of transcriptional condensates in human HAP1 cells using widefield and super-resolution microscopy tagging the epigenetic reader BRD4. We find that hubs that appear monolithic in widefield resolve into clusters of smaller droplets that resist coarsening. We link this size control to Active Model B+, a non-equilibrium field theory that captures a regime of reverse Ostwald ripening out of thermal equilibrium. In this regime, chemically driven currents cause larger droplets to transfer mass back to smaller ones, stabilizing a state of microphase segregation. The observed exponential size distribution of BRD4 foci quantitatively matches our numerical simulations, suggesting a universal physical picture for the non-equilibrium self-limitation of cellular condensates.

Collective migration and pulsatile flows in epithelial monolayers are commonly quantified using projected area, implicitly assuming constant cell volume and prism-like cell geometry. These "21/2D" assumptions neglect the intrinsic three-dimensional height and volume dynamics that accompany density fluctuations in confluent, space-filling tissues. Here, we combine 2D quantitative phase imaging (QPI) and 3D refractive index tomography to obtain time-lapse maps of height, volume, and dry mass in Madin-Darby canine kidney (MDCK) epithelial monolayers undergoing collective motion. This is, to our knowledge, the first systematic use of QPI to quantify epithelial monolayer height, volume, and mass dynamics in situ. From independent measurements of refractive index and height, we determine an average dry mass concentration cd = 0.287 g/ml with 2% variability between cells and over time, demonstrating tight regulation of dry-mass density even during large-amplitude pulsations and density changes. The mean height of the monolayer increases with cell density, while the mean cell volume decreases, revealing contact inhibition of cell size. Pixel- and disc-wise statistics show broad, gamma-like height distributions and strong spatio-temporal height fluctuations that remain substantial at high cell density. Cell-resolved tracking demonstrates that height, area, and volume fluctuate synchronously, with volume changes dominated by area rather than height variations, while dry-mass density remains nearly constant. Dynamic structure-factor analysis reveals subdiffusive dynamics and propagating compression-decompression waves, and a continuum mass-flux analysis shows that the depth-averaged continuity equation fails on cellular scales and is restored only after spatial and temporal coarse-graining. Using simple geometrical models, we show that prismatoid cell shapes with constant true volume can reproduce the observed correlations between height, apical area, and "projected" volume, implying that non-prismatic cell geometry biases 21/2D estimates. Together, these results overturn the assumptions of mass/volume conservation and plug-flow-like monolayer kinematics at cellular scales, and highlight the need to incorporate dry-mass regulation and 3D cell shape into models of epithelial dynamics. SIGNIFICANCE STATEMENTUsing QPI, we provide the first comprehensive and time-resolved characterisation of epithelial monolayer height, volume, and dry mass in situ, yielding quantitative measures that both extend and revise earlier work based on 2D imaging alone. Our measurements challenge two long-standing assumptions in epithelial physics: that cell mass or volume is conserved on the timescales of collective motion, and that monolayers behave as "21/2D" plug-flow sheets with vertical, prism-like cells of equal apical and basal area. These findings necessitate a re-examination of prior experimental interpretations and a reassessment of when existing continuum and cell-based models faithfully describe epithelial monolayer dynamics. They also provide benchmarks for future 3D theories and experiments.

A central problem in soft and biological physics is how molecular-scale activity and remodelling coarse-grain into emergent mechanical laws at larger scales. In growing cell walls (polymeric composite materials that surround 90% of living organisms cells) irreversible deformation is not controlled by elastic stress alone. Instead, growth depends on the interplay between energy storage, dissipation, and the local timing of viscoelastic relaxation. Although dynamic atomic force microscopy (AFM) resolves storage and loss moduli (E', E'') of living walls at nanometre resolution, these observables have remained phenomenological and disconnected from constitutive field variables. Here we introduce a physics-based inversion framework that converts AFM measurements of epidermal cells of living Arabidopsis plants into spatially resolved fields of stiffness k, viscosity , and relaxation time{tau} . By analysing the spatial gradients of E' and E'', we uncover organized mechanical heterogeneities governed by cellular confinement and stress focusing. We demonstrate that the local relaxation time is encoded directly in the coupling between storage and dissipation, yielding the pointwise relation{tau} = (1/{omega}) {partial}E/{partial}E, where{omega} is the indentation frequency. This relation enables model-independent extraction of mechanical timescales and establishes a general route from nanoscale non-equilibrium rheology to continuum descriptions of growth in living and active soft materials. SignificanceHow molecular-scale activity gives rise to tissue-scale form is a central challenge in biological physics. Although growth is fundamentally a non-equilibrium mechanical process, experimental measurements at the nanoscale have not been directly connected to the constitutive parameters that govern morphogenesis. We introduce a framework that converts dynamic atomic force microscopy maps of storage and loss moduli into spatially resolved fields of stiffness, viscosity, and relaxation time in living cell walls. By revealing that mechanical relaxation is encoded in the local coupling between elastic storage and viscous dissipation, our work provides a route from nanoscale rheology to growth-relevant mechanical timing. This establishes a quantitative bridge between molecular remodeling and continuum mechanics, enabling direct experimental constraints on multiscale theories of morphogenesis.

The temporal precision of biochemical oscillators is fundamentally constrained by the energy dissipated to suppress molecular fluctuations, a widely predicted trade-off governing information processing across biology and physics, from molecular motors to kinetic proofreading to computing. Yet, experimental validation in complex biological oscillators remains elusive due to challenges of systematically modulating energy while quantifying stochastic dynamics across large ensembles. Here, we establish a high-throughput droplet-microfluidics platform to reconstitute mitotic oscillations from Xenopus laevis egg extracts within thousands of sub-nanoliter compartments. By precisely tuning ATP across a broad free-energy landscape and developing an analytical framework that decouples intrinsic phase diffusion from quenched period heterogeneity, we uncover a hidden trade-off linking metabolic budget, oscillation speed, and precision. While speed peaks non-monotonically near physiological ATP levels and declines toward both high and low bifurcation limits, precision increases monotonically with energy. These findings provide direct experimental evidence that mitotic timing is actively shaped by energy budgets. Intriguingly, embryonic cell cycles are not optimized for maximum fidelity, but for a metabolic compromise maintaining just enough coherence for synchronous yet rapid divisions, placing the endogenous ATP budget near an energetic optimum balancing speed and accuracy. Our integrated artificial-cell and analytical strategy provides a generalizable framework for mapping thermodynamic limits in non-equilibrium biological dynamics.

Directed cell migration underlies many biological phenomena, from embryonic development to tumor metastasis and organ fibrosis. Most cells typically migrate toward stiffer regions of their extracellular matrix -a behavior known as positive durotaxis. Here we show that culture on rigid plastic reinforces this response, whereas preconditioning in soft 3D physiomimetic environments reprograms migration towards softer environments, a phenomenon known as negative durotaxis. Fetal rat lung fibroblasts preconditioned in 3D physiomimetic hydrogels exhibited negative durotaxis and accumulated near [~]5 kPa, corresponding to the physiological stiffness of the lung. In contrast, genetically identical cells maintained on conventional 2D plastic substrates migrated up stiffness gradients, toward stiffer regions. Although both populations displayed a biphasic force-stiffness relationship, they differed in force magnitude and cytoskeletal organization. Molecular-clutch modeling revealed that durotaxis reversal emerges from two distinct mechanical regimes: a mechanosensitive, high-motor-clutch state that stabilizes adhesions on stiff substrates and drives positive durotaxis, and a low-motor, weak-adhesion state in which clutch slippage on the stiff side causes negative durotaxis. Our results show that durotaxis direction is not an intrinsic cellular property. Rather, it emerges from the interplay between motor activity and adhesion dynamics and can be tuned by culture conditions.

The efficient pumping of the mammalian heart relies on torsional contractile motion generated by its highly ordered three-dimensional (3D) architecture of myocardial fibres. However, the topological principles governing how its complex geometry translates into contractile mechanics remain elusive. Here, we show that the mammalian heart forms a chiral nematic field, a biological analogue to 3D liquid crystals, whose topological organisation underlies its function. Analysis of 3D imaging data revealed disclination lines, continuous assemblies of topological defects characteristic of nematic systems, within the compact myocardium. Finite-element simulations reveal that these defects are not mere structural irregularities but can locally modulate contractile behaviour and reduce mechanical work. In heterotaxy hearts with reversed global anatomy (situs inversus), myocardial fibres retain a predominantly counter-clockwise twist, similar to that of the normal heart, but with a small clockwise component near the base. This decoupling of tissue-level chirality from systemic left-right patterning suggests that cardiac twist is an intrinsic property of the myocardial fibre. Mechanical simulations of situs inversus heart demonstrate that the coherence of transmural chirality, rather than its specific orientation, is critical for contractile efficiency. Together, these findings establish the heart as a topological material and reveal how organised chiral fields generate robust organ-level mechanical function.

Cyanobacterial macrostructures are ubiquitous in nature. They harbour spatially organised metabolic processes that impact biogeochemistry and enable biotechnologies. How macrostructures form remains unknown due to a lack of tractable model systems. We overcome this limitation using a motile filamentous cyanobacterium that reproducibly forms macrostructures in laboratory conditions. We discover an emergent microparticle collection behaviour, mediated by gliding motility and leading to granular macrostructures. We link collection to filament buckling and entangling, and predict a dependence on filament length and stiffness, using a novel physical model. Shortened filaments and a naturally short Pseudanabaenales filament do not collect particles or form granular macrostructures. These findings link macrostructures to gliding motility and filament physics, giving insight into their formation in nature and design for biotechnologies.

Climbing plants use self-generated oscillatory movements called circumnutations to search their environment for supports to attach to. Yet little is known about what information these movements provide. Here we show that circumnutations enable climbing plants to actively assess the mechanical stability of a newly encountered support and determine whether to initiate twining. Analogous to whisking in mammals, circumnutating shoots generate predictable mechanical loading that probes support resistance. Force measurements of freely circumnutating bean shoots reveal that contact forces follow a characteristic sinusoidal pattern. We develop a minimal physical model of this system, and experimentally informed simulations recover the measured force trajectories. We find that the stem-support interaction is captured by a simple torque balance between external loading and the intrinsic bending moment of the stem, equivalent to a cantilever beam with a rotating load. Analysis of force trajectories, supported by experimentally informed simulations, shows that force amplitude is set by stem stiffness and geometry, whereas the characteristic timescale is governed by the circumnutation rate. Twining occurs only after the stem reaches a critical torque threshold, corresponding to a threshold deformation of the stem that likely serves as the mechanical trigger for twining initiation, reflecting both sufficient support stability and a minimal geometric overshoot required for grasp. Motorized-stage experiments further demonstrate that increasing the effective circumnutation rate accelerates twining initiation to minutes, whereas reducing it can suppress twining despite prolonged contact. Together, these results establish embodied mechanical sensing in plants and show how morphology and self-generated motion enable support selection without centralized control.

Glassy dynamics in active biological cells remain a subject of debate, as cellular activity rarely slows enough for true glassy features to emerge. In this study, we address this paradox of glassy dynamics in epithelial cells by integrating experimental observations with an active vertex model. We demonstrate that while crowding is essential, it is not sufficient for glassy dynamics to emerge. A mechanochemical feedback loop (MCFL), mediated by cell shape changes through the contractile actomyosin network, is required to drive glass transition in dense epithelial tissues, as revealed via a crosstalk between actin-based cell clustering and dynamic heterogeneity in experiments. Incorporating MCFL into the vertex model reveals contrasting results from those previously predicted by theories- we show that the MCFL can counteract cell division-induced fluidisation and enable glassy dynamics to emerge through active cell-to-cell communication. Furthermore, our analysis reveals, for the first time, the existence of novel collective mechanochemical oscillations that arise from the crosstalk of two MCFLs. Together, we demonstrate that an interplay between crowding and active mechanochemical feedback enables the emergence of glass-like traits and collective biochemical oscillations in epithelial tissues with active cell-cell contacts.

Cells sense and respond to the mechanical properties of their environment, yet the minimal physical principles sufficient to reproduce mechanotransduction and durotaxis remain debated. This work introduces FraCeMM, a physics-first mechanochemical simulation framework coupling stochastic ligand-integrin-talin binding to a deformable soft-body cell model on an elastic substrate. Without imposed polarity, directional cues, or migration rules, the model reproduces hallmark mechanobiological behaviors including stiffness-dependent spreading, traction reinforcement, focal adhesion asymmetry, and directed durotaxis. A finite pool of adhesion molecules, mechanically coupled through elastic linkages, drives emergent force asymmetry and polarization via self-consistent feedback between stochastic binding, molecular availability, and substrate stiffness. Despite minimal assumptions and a coarse-grained molecular representation, resulting traction forces, adhesion loads, and migration speeds fall within experimentally reported ranges. These results support the view that local force balance, limited adhesion resources, and mechanically binding are sufficient to generate adaptive mechanosensing and directed migration, establishing a transparent and extensible foundation for computational mechanobiology.

Biological tissues require branched cellular architectures to maximize spatial coverage while minimizing redundancy. Yet, how cells decode local spatial information to collectively tile territories without a global blueprint remains a key open question. Here, we develop a biophysical theory of interacting branched cells, and show that coupling their growth to short-range repulsion drives efficient tiling with minimal territorial overlap. Our model predicts that the same local mechanism simultaneously suppresses long-range density fluctuations, driving the cellular collective toward hyperuniformity. We confirm these theoretical predictions with experiments on microglial patterning in the developing retina, and show that perturbations resulting in limited cell growth disrupt both tiling and fluctuation suppression. Our results reveal that two seemingly distinct optimization principles of biological patterning, large-scale regularity and efficient tiling, are intimately linked and can arise from a single growth-repulsion feedback, suggesting a general principle for self-organized tissue coverage.

The hierarchical organization of multiphase biomolecular condensates into core-shell architectures is a fundamental problem in soft matter and biophysics. While classical explanations rely on hierarchies of interfacial tension ({gamma}) between coexisting liquids, the ultralow tensions of condensates (0.1-1 {micro}N/m) render such hierarchies potentially fragile. We introduce a robust assembly principle based on Polymer-Assisted Condensation (PAC), in which a single polymer species dictates the entire structure. The polymer nucleates a dense core by recruiting a condensation-incompetent protein (P1). A second incompetent protein (P2), which is repelled or otherwise thermodynamically disfavored from entering the polymer-rich core, is nonetheless recruited to the interface by weak attraction to P1, forming a stable shell. This effective repulsion-driven layering operates across a wide parameter space without requiring{gamma} asymmetries and yields a robust structure that is impervious to concentration fluctuations and environmental perturbations. Phase-field modeling and molecular simulations establish this mechanism and capture key features of nucleolar organization. Our work reveals a general physical pathway for encoding spatial order in soft, multicomponent fluids.

Robust development depends on maintaining correct proportions as overall size varies. What controls and limits this ability to scale remains poorly understood in part due to the complex interplay between mechanical and biochemical factors within developing embryos. Using confinement of dissociated embryonic presomitic mesoderm cells, combined with imaging and chemical perturbations, we identified aggregation as the initial event in de novo anterior-posterior axis patterning. Using a continuum model solely based on cell-cell attraction, we quantitatively map out how the time available for aggregation-driven patterning limits the system size over which scaling can be maintained: Small systems allow for rapid and robust pattern scaling whereas coarsening dynamics substantially de-lay the appearance of a scaled pattern in large systems. Our experiments quantitatively confirm these predicted scaling regimes. Together, our results suggest a developmental time-size tradeoff on the scaling of aggregation-driven patterns.

Receptor-mediated ligand endocytosis is traditionally viewed as a negative feedback mechanism for signal attenuation. Here we show that ligand removal can paradoxically enhance directional information in autonomous cell-cell attraction. Many cell systems migrate toward one another in the absence of externally imposed gradients, implying that secretion, diffusion, and uptake must themselves generate usable directional cues. We develop a surface-resolved theory of a finite-sized detector exposed to a nearby source and derive analytical expressions for the steady-state ligand field. The resulting concentration profiles are governed by a single dimensionless Damkohler number that compares receptor-mediated endocytosis to diffusive ligand transport. Increasing ligand removal lowers extracellular ligand concentrations and reduces absolute concentration differences across the detector surface, but preferentially enhances relative surface anisotropy. Thus, destroying the signal can increase the usable information encoded in relative gradients. Incorporating nonlinear downstream processing reveals a tradeoff between contrast enhancement and signal depletion that yields a well-defined optimal endocytosis rate, in a regime consistent with experimentally measured receptor internalization kinetics. These results recast receptor-mediated endocytosis as an extracellular information-processing mechanism that reshapes self-generated gradients to enhance directional information.

How can simple organisms lacking nervous systems encode and transmit environmental signals to generate complex, adaptive behaviours? Using the unicellular organism Physarum polycephalum as a model, we identify a unifying mechanochemical mechanism that links intracellular calcium oscillations to large-scale behavioural coordination. We first demonstrate experimentally that local perturbation of the actomyosin cortex is sufficient to induce symmetry breaking and directed migration, even in the absence of nutrient cues. Building on evidence linking calcium concentration to actin depolymerization and contractile relaxation, we develop a mechanochemical tubule model in which self-sustained calcium oscillations are coupled to pressure-driven mechanics. We show that environmental cues, encoded through the local modulation of these oscillations, give rise to directed transport and the redistribution of biomass. By extending this framework to a two-dimensional phase-field model, we demonstrate that this mechanism is sufficient to generate a diverse set of slime mould behaviours, including chemotaxis, network formation, and balancing exploration-exploitation trade-offs. In doing so, we provide a single mechanistic framework linking intracellular dynamics to organism-scale behaviour across spatial and temporal scales. Our work shows that these sophisticated behaviours can emerge from the modulation of self-sustained oscillations coupled by diffusion, providing a physically grounded mechanism for information processing in non-neural organisms and offering insight into the evolutionary origins of coordinated behaviour.