A shape-driven reentrant jamming transition in confluent monolayers of synthetic cell-mimics.

Many critical biological processes, like wound healing, require densely packed cell monolayers/tissues to transition from a jammed solid-like to a fluid-like state. Although numerical studies anticipate changes in the cell shape alone can lead to unjamming, experimental support for this prediction is not definitive because, in living systems, fluidization due to density changes cannot be ruled out. Additionally, a cell's ability to modulate its motility only compounds difficulties since even in assemblies of rigid active particles, changing the nature of self-propulsion has non-trivial effects on the dynamics. Here, we design and assemble a monolayer of synthetic cell-mimics and examine their collective behaviour. By systematically increasing the persistence time of self-propulsion, we discovered a cell shape-driven, density-independent, re-entrant jamming transition. Notably, we observed cell shape and shape variability were mutually constrained in the confluent limit and followed the same universal scaling as that observed in confluent epithelia. Dynamical heterogeneities, however, did not conform to this scaling, with the fast cells showing suppressed shape variability, which our simulations revealed is due to a transient confinement effect of these cells by their slower neighbors. Our experiments unequivocally establish a morphodynamic link, demonstrating that geometric constraints alone can dictate epithelial jamming/unjamming.

Different glassy characteristics are related to either caging or dynamical heterogeneity.

Despite the enormous theoretical and application interests, a fundamental understanding of the glassy dynamics remains elusive. The static properties of glassy and ordinary liquids are similar, but their dynamics are dramatically different. What leads to this difference is the central puzzle of the field. Even the primary defining glassy characteristics, their implications, and if they are related to a single mechanism remain unclear. This lack of clarity is a severe hindrance to theoretical progress. Here, we combine analytical arguments and simulations of various systems in different dimensions and address these questions. Our results suggest that the myriad of glassy features are manifestations of two distinct mechanisms. Particle caging controls the mean, and coexisting slow- and fast-moving regions govern the distribution of particle displacements. All the other glassy characteristics are manifestations of these two mechanisms; thus, the Fickian yet non-Gaussian nature of glassy liquids is not surprising. We discover a crossover, from stretched exponential to a power law, in the behavior of the overlap function. This crossover is prominent in simulation data and forms the basis of our analyses. Our results have crucial implications on how the glassy dynamics data are analyzed, challenge some recent suggestions on the mechanisms governing glassy dynamics, and impose strict constraints that a correct theory of glasses must have.

Dynamical heterogeneity in active glasses is inherently different from its equilibrium behavior.

Activity-driven glassy dynamics, while ubiquitous in collective cell migration, intracellular transport, dynamics in bacterial and ant colonies, etc., also extends the scope and extent of the as-yet mysterious physics of glass transition. Active glasses are hitherto assumed to be qualitatively similar to their equilibrium counterparts at an effective temperature, [Formula: see text]. Here, we combine large-scale simulations and an analytical mode-coupling theory (MCT) for such systems and show that, in fact, an active glass is inherently different from an equilibrium glass. Although the relaxation dynamics can be equilibrium-like at a [Formula: see text], effects of activity on the dynamic heterogeneity (DH), which is a hallmark of glassy dynamics, are quite nontrivial and complex. With no preexisting data, we employ four distinct methods for reliable estimates of the DH length scales. Our work shows that active glasses exhibit dramatic growth of DH and systems with similar relaxation times, and thus, [Formula: see text] can have widely varying DH. To theoretically study DH, we extend active MCT and find good qualitative agreement between the theory and simulation results. Our results pave avenues for understanding the role of DH in glassy dynamics and can have fundamental significance even in equilibrium.

On the origin of universal cell shape variability in confluent epithelial monolayers.

Cell shape is fundamental in biology. The average cell shape can influence crucial biological functions, such as cell fate and division orientation. But cell-to-cell shape variability is often regarded as noise. In contrast, recent works reveal that shape variability in diverse epithelial monolayers follows a nearly universal distribution. However, the origin and implications of this universality remain unclear. Here, assuming contractility and adhesion are crucial for cell shape, characterized via aspect ratio (r), we develop a mean-field analytical theory for shape variability. We find that all the system-specific details combine into a single parameter α that governs the probability distribution function (PDF) of r; this leads to a universal relation between the standard deviation and the average of r. The PDF for the scaled r is not strictly but nearly universal. In addition, we obtain the scaled area distribution, described by the parameter µ. Information of α and µ together can distinguish the effects of changing physical conditions, such as maturation, on different system properties. We have verified the theory via simulations of two distinct models of epithelial monolayers and with existing experiments on diverse systems. We demonstrate that in a confluent monolayer, average shape determines both the shape variability and dynamics. Our results imply that cell shape distribution is inevitable, where a single parameter describes both statics and dynamics and provides a framework to analyze and compare diverse epithelial systems. In contrast to existing theories, our work shows that the universal properties are consequences of a mathematical property and should be valid in general, even in the fluid regime.

Affinity and Valence Impact the Extent and Symmetry of Phase Separation of Multivalent Proteins.

Biomolecular self-assembly spatially segregates proteins with a limited number of binding sites (valence) into condensates that coexist with a dilute phase. We develop a many-body lattice model for a three-component system of proteins with fixed valence in a solvent. We compare the predictions of the model to experimental phase diagrams that we measure in vivo, which allows us to vary specifically a binding site's affinity and valency. We find that the extent of phase separation varies exponentially with affinity and increases with valency. Valency alone determines the symmetry of the phase diagram.

Theory and simulation for equilibrium glassy dynamics in cellular Potts model of confluent biological tissue.

Glassy dynamics in a confluent monolayer is indispensable in morphogenesis, wound healing, bronchial asthma, and many others; a detailed theoretical framework for such a system is, therefore, important. Vertex-model (VM) simulations have provided crucial insights into the dynamics of such systems, but their nonequilibrium nature makes theoretical development difficult. The cellular Potts model (CPM) of confluent monolayers provides an alternative model for such systems with a well-defined equilibrium limit. We combine numerical simulations of the CPM and an analytical study based on one of the most successful theories of equilibrium glass, the random first-order transition theory, and develop a comprehensive theoretical framework for a confluent glassy system. We find that the glassy dynamics within the CPM is qualitatively similar to that in the VM. Our study elucidates the crucial role of geometric constraints in bringing about two distinct regimes in the dynamics, as the target perimeter P_{0} is varied. The unusual sub-Arrhenius relaxation results from the distinctive interaction potential arising from the perimeter constraint in such systems. The fragility of the system decreases with increasing P_{0} in the low-P_{0} regime, whereas the dynamics is independent of P_{0} in the other regime. The rigidity transition, found in the VM, is absent within the CPM; this difference seems to come from the nonequilibrium nature of the former. We show that the CPM captures the basic phenomenology of glassy dynamics in a confluent biological system via comparison of our numerical results with existing experiments on different systems.

Size-stretched exponential relaxation in a model with arrested states.

We study the effect of a rapid quench to zero temperature in a model with competing interactions, evolving through conserved spin dynamics. In a certain regime of model parameters, we find that the model belongs to the broader class of kinetically constrained models, however, the dynamics is different from that of a glass. The system shows stretched exponential relaxation with the unusual feature that the relaxation time diverges as a power of the system size. Explicitly, we find that the spatial correlation function decays as exp(-2r/sqrt[L]) as a function of spatial separation r in a system with L sites in the steady state, while the temporal autocorrelation function follows exp[-(t/τ_{L})^{1/2}], where t is the time and τ_{L} proportional to L. In the coarsening regime, after time t_{w}, there are two growing length scales, namely L(t_{w})∼t_{w}^{1/2} and R(t_{w})∼t_{w}^{1/4}; the spatial correlation function decays as exp[-r/R(t_{w})]. Interestingly, the stretched exponential form of the autocorrelation function of a single typical sample in the steady state differs markedly from that averaged over an ensemble of initial conditions resulting from different quenches; the latter shows a slow power-law decay at large times.

Designer protein assemblies with tunable phase diagrams in living cells.

Protein self-organization is a hallmark of biological systems. Although the physicochemical principles governing protein-protein interactions have long been known, the principles by which such nanoscale interactions generate diverse phenotypes of mesoscale assemblies, including phase-separated compartments, remain challenging to characterize. To illuminate such principles, we create a system of two proteins designed to interact and form mesh-like assemblies. We devise a new strategy to map high-resolution phase diagrams in living cells, which provide self-assembly signatures of this system. The structural modularity of the two protein components allows straightforward modification of their molecular properties, enabling us to characterize how interaction affinity impacts the phase diagram and material state of the assemblies in vivo. The phase diagrams and their dependence on interaction affinity were captured by theory and simulations, including out-of-equilibrium effects seen in growing cells. Finally, we find that cotranslational protein binding suffices to recruit a messenger RNA to the designed micron-scale structures.

Erratum to: Effective temperature of active fluids and sheared soft glassy materials.

The authors were notified by their collaborators Golan Bel and Dan Wexler that the expression for the over-damped limit of the kinetic energy of the trapped particle, that they have used in the orignal paper, was in error. They provide the correct expressions in this erratum.

Effective temperature of active fluids and sheared soft glassy materials.

The dynamics within active fluids, driven by internal activity of the self-propelled particles, is a subject of intense study in non-equilibrium physics. These systems have been explored using simulations, where the motion of a passive tracer particle is followed. Similar studies have been carried out for a soft glassy material that is driven by shearing its boundaries. In both types of systems the non-equilibrium motion have been quantified by defining a set of "effective temperatures", using both the tracer particle kinetic energy and the fluctuation-dissipation relation. We demonstrate that these effective temperatures extracted from the many-body simulations fit analytical expressions that are obtained for a single active particle inside a visco-elastic fluid. This result provides testable predictions and suggests a unified description for the dynamics inside active systems.

A random first-order transition theory for an active glass.

How does nonequilibrium activity modify the approach to a glass? This is an important question, since many experiments reveal the near-glassy nature of the cell interior, remodeled by activity. However, different simulations of dense assemblies of active particles, parametrized by a self-propulsion force, [Formula: see text], and persistence time, [Formula: see text], appear to make contradictory predictions about the influence of activity on characteristic features of glass, such as fragility. This calls for a broad conceptual framework to understand active glasses; here, we extend the random first-order transition (RFOT) theory to a dense assembly of self-propelled particles. We compute the active contribution to the configurational entropy through an effective model of a single particle in a caging potential. This simple active extension of RFOT provides excellent quantitative fits to existing simulation results. We find that whereas [Formula: see text] always inhibits glassiness, the effect of [Formula: see text] is more subtle and depends on the microscopic details of activity. In doing so, the theory automatically resolves the apparent contradiction between the simulation models. The theory also makes several testable predictions, which we verify by both existing and new simulation data, and should be viewed as a step toward a more rigorous analytical treatment of active glass.

Activity-dependent self-regulation of viscous length scales in biological systems.

The cellular cortex, which is a highly viscous thin cytoplasmic layer just below the cell membrane, controls the cell's mechanical properties, which can be characterized by a hydrodynamic length scale ℓ. Cells actively regulate ℓ via the activity of force-generating molecules, such as myosin II. Here we develop a general theory for such systems through a coarse-grained hydrodynamic approach including activity in the static description of the system providing an experimentally accessible parameter and elucidate the detailed mechanism of how a living system can actively self-regulate its hydrodynamic length scale, controlling the rigidity of the system. Remarkably, we find that ℓ, as a function of activity, behaves universally and roughly inversely proportional to the activity of the system. Our theory rationalizes a number of experimental findings on diverse systems, and comparison of our theory with existing experimental data shows good agreement.

Protein gradients in single cells induced by their coupling to "morphogen"-like diffusion.

One of the many ways cells transmit information within their volume is through steady spatial gradients of different proteins. However, the mechanism through which proteins without any sources or sinks form such single-cell gradients is not yet fully understood. One of the models for such gradient formation, based on differential diffusion, is limited to proteins with large ratios of their diffusion constants or to specific protein-large molecule interactions. We introduce a novel mechanism for gradient formation via the coupling of the proteins within a single cell with a molecule, that we call a "pronogen," whose action is similar to that of morphogens in multi-cell assemblies; the pronogen is produced with a fixed flux at one side of the cell. This coupling results in an effectively non-linear diffusion degradation model for the pronogen dynamics within the cell, which leads to a steady-state gradient of the protein concentration. We use stability analysis to show that these gradients are linearly stable with respect to perturbations.

Nonequilibrium mode-coupling theory for dense active systems of self-propelled particles.

The physics of active systems of self-propelled particles, in the regime of a dense liquid state, is an open puzzle of great current interest, both for statistical physics and because such systems appear in many biological contexts. We develop a nonequilibrium mode-coupling theory (MCT) for such systems, where activity is included as a colored noise with the particles having a self-propulsion force f0 and a persistence time τp. Using the extended MCT and a generalized fluctuation-dissipation theorem, we calculate the effective temperature Teff of the active fluid. The nonequilibrium nature of the systems is manifested through a time-dependent Teff that approaches a constant in the long-time limit, which depends on the activity parameters f0 and τp. We find, phenomenologically, that this long-time limit is captured by the potential energy of a single, trapped active particle (STAP). Through a scaling analysis close to the MCT glass transition point, we show that τα, the α-relaxation time, behaves as τα ∼ f0-2γ, where γ = 1.74 is the MCT exponent for the passive system. τα may increase or decrease as a function of τp depending on the type of active force correlations, but the behavior is always governed by the same value of the exponent γ. Comparison with the numerical solution of the nonequilibrium MCT and simulation results give excellent agreement with scaling analysis.

Glass susceptibility: Growth kinetics and saturation under shear.

We study the growth kinetics of glassy correlations in a structural glass by monitoring the evolution, within mode-coupling theory, of a suitably defined three-point function χ_{C}(t,t_{w}) with time t and waiting time t_{w}. From the complete wave-vector-dependent equations of motion for domain growth, we pass to a schematic limit to obtain a numerically tractable form. We find that the peak value χ_{C}^{P} of χ_{C}(t,t_{w}), which can be viewed as a correlation volume, grows as t_{w}^{0.5}, and the relaxation time as t_{w}^{0.8}, following a quench to a point deep in the glassy state. These results constitute a theoretical explanation of the simulation findings of Parisi [J. Phys. Chem. B 103, 4128 (1999)JPCBFK1520-610610.1021/jp983967m] and Kob and Barrat [Phys. Rev. Lett. 78, 4581 (1997)PRLTAO0031-900710.1103/PhysRevLett.78.4581], and they are also in qualitative agreement with Parsaeian and Castillo [Phys. Rev. E 78, 060105(R) (2008)PLEEE81539-375510.1103/PhysRevE.78.060105]. On the other hand, if the quench is to a point on the liquid side, the correlation volume grows to saturation. We present a similar calculation for the growth kinetics in a p-spin spin glass mean-field model where we find a slower growth, χ_{C}^{P}∼t_{w}^{0.13}. Further, we show that a shear rate γ[over ̇] cuts off the growth of glassy correlations when t_{w}∼1/γ[over ̇] for quench in the glassy regime and t_{w}=min(t_{r},1/γ[over ̇]) in the liquid, where t_{r} is the relaxation time of the unsheared liquid. The relaxation time of the steady-state fluid in this case is ∝γ[over ̇]^{-0.8}.

Spinodals with Disorder: From Avalanches in Random Magnets to Glassy Dynamics.

We revisit the phenomenon of spinodals in the presence of quenched disorder and develop a complete theory for it. We focus on the spinodal of an Ising model in a quenched random field (RFIM), which has applications in many areas from materials to social science. By working at zero temperature in the quasistatically driven RFIM, thermal fluctuations are eliminated and one can give a rigorous content to the notion of spinodal. We show that the latter is due to the depinning and the subsequent expansion of rare droplets. We work out the associated critical behavior, which, in any finite dimension, is very different from the mean-field one: the characteristic length diverges exponentially and the thermodynamic quantities display very mild nonanalyticities much like in a Griffith phenomenon. From the recently established connection between the spinodal of the RFIM and glassy dynamics, our results also allow us to conclusively assess the physical content and the status of the dynamical transition predicted by the mean-field theory of glass-forming liquids.

Understanding the approximations of mode-coupling theory for sheared steady states of colloids.

The lack of clarity of various mode-coupling theory (MCT) approximations, even in equilibrium, makes it hard to understand the relation between various MCT approaches for sheared steady states as well as their regime of validity. Here we try to understand these approximations indirectly by deriving the MCT equations through two different approaches for a colloidal system under shear, first through a microscopic approach, as suggested by Zaccarelli et al., and second through fluctuating hydrodynamics, where the approximations used in the derivation are quite clear. The qualitative similarity of our theory with a number of existing theories show that linear response theory might play a role in various approximations employed in deriving those theories and one needs to be careful while applying them for systems arbitrarily far away from equilibrium, such as a granular system or when shear is very strong. As a by-product of our calculation, we obtain the extension of the Yvon-Born-Green (YBG) equation for a sheared system and under the assumption of random-phase approximation, the YBG equation yields the distorted structure factor that was earlier obtained through different approaches.

Critical dynamical heterogeneities close to continuous second-order glass transitions.

We analyze, using inhomogeneous mode-coupling theory, the critical scaling behavior of the dynamical susceptibility at a distance ε from continuous second-order glass transitions. We find that the dynamical correlation length ξ behaves generically as ε(-1/3) and that the upper critical dimension is equal to six. More surprisingly, we find that ξ grows with time as ln²t exactly at criticality. All of these results suggest a deep analogy between the glassy behavior of attractive colloids or randomly pinned supercooled liquids and that of the random field Ising model.

How do glassy domains grow?

We construct equations for the growth kinetics of structural glass within mode-coupling theory, through a nonstationary variant of the three-density correlator defined by G. Biroli et al. [Phys. Rev. Lett. 97, 195701 (2006)]. We solve a schematic form of the resulting equations to obtain the coarsening of the three-point correlator χ(3)(t,t(w)) as a function of waiting time t(w). For a quench into the glass, we find that χ(3) attains a peak value ∼t(w)(0.5) at t-t(w)∼t(w)(0.8), providing a theoretical basis for the numerical observations of Parisi [J. Phys. Chem. B 103, 4128 (1999)] and Kob and Barrat [Phys. Rev. Lett. 78, 4581 (1997)]. The aging is not "simple": the t(w) dependence cannot be attributed to an evolving effective temperature.

Mode-coupling glass transition in a fluid confined by a periodic potential.

We show that a fluid under strong spatially periodic confinement displays a glass transition within mode-coupling theory at a much lower density than the corresponding bulk system. We use fluctuating hydrodynamics, with confinement imposed through a periodic potential whose wavelength plays an important role in our treatment. To make the calculation tractable we implement a detailed calculation in one dimension. Although we do not expect simple 1d fluids to show a glass transition, our results are indicative of the behavior expected in higher dimensions. In a certain region of parameter space we observe a three-step relaxation reported recently in computer simulations [S. H. Krishnan, Ph.D. thesis, Indian Institute of Science (2005); Kim et al., Eur. Phys. J. Special Topics 189, 135 (2010)] and a glass-glass transition. We compare our results to those of Krakoviack [Phys. Rev. E 75, 031503 (2007)] and Lang et al. [Phys. Rev. Lett. 105, 125701 (2010)].