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Emulsions ripen with an average droplet size increasing in time. In chemically active emulsions, coarsening can be absent, leading to a non-equilibrium steady state with mono-disperse droplet sizes. By considering a minimal model for phase separation and chemical reactions maintained away from equilibrium, we show that there is a critical transition in the conserved quantity between two classes of chemically active droplets: intensive and extensive ones. Single intensive active droplets reach a stationary size mainly controlled by the reaction-diffusion length scales. Intensive droplets in an emulsion interact only weakly, and the stationary size of a single droplet approximately sets the size of each droplet. On the contrary, the size of a single extensive active droplet scales with the system size, similar to passive phases. In an emulsion of many extensive droplets, their sizes become stationary only due to interactions among them. We discuss how the critical transition between intensive and extensive active droplets affects shape instabilities, including the division of active droplets, paving the way for the observation of successive division events in chemically active emulsions

The spatial organization of DNA involves DNA loop extrusion and the formation of protein-DNA condensates. While the significance of each process is increasingly recognized, their interplay remains unexplored. Using molecular dynamics simulation and theory we investigate this interplay. Our findings reveal that loop extrusion can enhance the dynamics of condensation and promotes coalescence and ripening of condensates. Further, the DNA loop enables condensate formation under DNA tension and position condensates. The concurrent presence of loop extrusion and condensate formation results in the formation of distinct domains similar to TADs, an outcome not achieved by either process alone.

We investigate the formation of condensates in a binary lattice gas in the presence of chiral interactions. These interactions differ between a given microscopic configuration and its mirror image. We consider a two dimensional lattice gas with nearest-neighbour interactions to which we add interactions involving favoured local structures that are chiral. We focus on favoured local structures that have the shape of the letter L and explore condensate formation through simulations and analytical calculations. At low temperature, this model can exhibit four different phases that are characterised by different periodic tiling patterns, depending on the strength of interactions and the chemical potential. When particle numbers are conserved, some of these phases can coexist. We analyse the structure and surface tension of interfaces between coexisting phases and determine the condensate shapes of minimal free energy. We show that these shapes can be quadrilaterals or octagons of different orientation and symmetry., Comment: 12 pages, 7 figures

We construct a hydrodynamic theory of active smectics A in two-dimensional space, including the creation/annihilation and motility of dislocations with Burgers' number $\pm1$. We derive analytical criteria on the set of parameters that lead to flows. We show that the motility of dislocations can lead to flow transitions with distinct features from the previously reported active Helfrich--Hurault shear instability with, notably, a first-order transition in the velocity from quiescence to turbulence., Comment: 5 pages, 5 figures

The fuel-driven process of replication in living systems generates distributions of copied entities with varying degrees of copying accuracy. Here we introduce a thermodynamically consistent ensemble for investigating universal population features of replicating systems. In the context of copolymer copying, coarse-graining over molecular details, we establish a phase diagram of copying accuracy. We discover sharp non-equilibrium transitions between populations of random and accurate copies. Maintaining a population of accurate copies requires a minimum energy expenditure that depends on the configurational entropy of copolymer sequences.

Phase-separated liquid condensates can spatially organize and thereby regulate chemical processes. However, the physicochemical mechanisms underlying such regulation remain elusive as the intramolecular interactions responsible for phase separation give rise to a coupling between diffusion and chemical reactions at non-dilute conditions. Here, we derive a theoretical framework that decouples the phase separation of scaffold molecules from the reaction kinetics of diluted clients. As a result, phase volume and client partitioning coefficients become control parameters, which enables us to dissect the impact of phase-separated condensates on chemical reactions. We apply this framework to two chemical processes and show how condensates affect the yield of reversible chemical reactions and the initial rate of a simple assembly process. In both cases, we find an optimal condensate volume at which the respective chemical reaction property is maximal. Our work can be applied to experimentally quantify how condensed phases alter chemical processes in systems biology and unravel the mechanisms of how biomolecular condensates regulate biochemistry in living cells., Comment: 22 pages, 8 figures, one table

Biomolecules, such as proteins and RNAs, can phase separate in the cytoplasm of cells to form biomolecular condensates. Such condensates are liquid-like droplets that can wet biological surfaces such as membranes. Many molecules that participate in phase separation can also reversibly bind to membrane surfaces. When a droplet wets a surface, molecules can diffuse inside and outside of the droplet or in the bound state on the surface. How the interplay between surface binding, diffusion in surface and bulk affects the wetting kinetics is not well understood. Here, we derive the governing equations using non-equilibrium thermodynamics by relating the thermodynamic fluxes and forces at the surface coupled to the bulk. We study the spreading dynamics in the presence of surface binding and find that binding speeds up wetting by nucleating a droplet inside the surface. Our results suggest that the wetting dynamics of droplets can be regulated by two-dimensional surface droplets in the surface-bound layer through changing the binding affinity to the surfaces. These findings are relevant both to engineering life-like systems with condensates and vesicles, and biomolecular condensates in living cells.

Wetting of liquid droplets on passive surfaces is ubiquitous in our daily lives, and the governing physical laws are well-understood. When surfaces become active, however, the governing laws of wetting remain elusive. Here we propose chemically active wetting as a new class of active systems where the surface is active due to a binding process that is maintained away from equilibrium. We derive the corresponding non-equilibrium thermodynamic theory and show that active binding fundamentally changes the wetting behavior, leading to steady, non-equilibrium states with droplet shapes reminiscent of a pancake or a mushroom. The origin of such anomalous shapes can be explained by mapping to electrostatics, where pairs of binding sinks and sources correspond to electrostatic dipoles along the triple line. This is an example of a more general analogy, where localized chemical activity gives rise to a multipole field of the chemical potential. The underlying physics is relevant for cells, where droplet-forming proteins can bind to membranes accompanied by the turnover of biological fuels.

Odd viscoelastic materials are constrained by fewer symmetries than their even counterparts. The breaking of these symmetries allow these materials to exhibit different features, which have attracted considerable attention in recent years. Immersing a bead in such complex fluids allows for probing their physical properties, highlighting signatures of their oddity and exploring consequences of these broken symmetries. We present the conditions under which the activity of an odd viscoelastic fluid can give rise to linear instabilities in the motion of the probe particle and unveil how the features of the probe particle dynamics depend on the oddity and activity of the viscoelastic medium in which it is immersed.

We present a theory for phase-separated liquid coacervates with salt, taking into account spatial heterogeneities and interfacial profiles. We find that charged layers of alternating sign can form around the interface while the bulk phases remain approximately charge-neutral. We show that the salt concentration regulates the number of layers and the amplitude of the layer's charge density and electrostatic potential. Such charged layers can either repel or attract single-charged molecules diffusing across the interface. Our theory could be relevant for artificial systems and biomolecular condensates in cells. Our work suggests that interfaces of biomolecular condensates could mediate charge-specific transport similar to membrane-bound compartments., Comment: 15 pages, 9 figures

We study a chemically active binary mixture undergoing phase separation and show that under non-equilibrium conditions, stable liquid spherical shells can form via a spinodal instability in the droplet center. A single liquid shell tends to grow until it undergoes a shape instability beyond a critical size. In an active emulsion, many stable and stationary liquid shells can coexist. We discuss conditions under which liquid shells are stable and dominant as compared to regimes where droplets undergo shape instabilities and divide.

Biological condensates are assemblies of proteins and nucleic acids that form membraneless compartments in cells and play essential roles in cellular functions. In many cases they exhibit the physical properties of liquid droplets that coexist in a surrounding fluid. Recently, quantitative studies on the material properties of biological condensates have become available, revealing complex material properties. In vitro experiments have shown that protein condensates exhibit time dependent material properties, similar to aging in glasses. To understand this phenomenon from a theoretical perspective, we develop a rheological model based on the physical picture of protein diffusion and stochastic binding inside condensates. The complex nature of protein interactions is captured by a distribution of binding energies, incorporated in a trap model originally developed to study glass transitions. Our model can describe diffusion of constituent particles, as well as the material response to time-dependent forces, and it recapitulates the age dependent relaxation time of Maxwell glass observed experimentally both in active and passive rheology. We derive a generalized fluctuation-response relations of our model in which the relaxation function does not obey time translation invariance. Our study sheds light on the complex material properties of biological condensates and provides a theoretical framework for understanding their aging behavior.

Active polar fluids exhibit spontaneous flow when sufficient active stress is generated by internal molecular mechanisms. This is also referred to as an active Fr\'{e}edericksz transition. Experiments have revealed the existence of competing in-plane and out-of-plane instabilities in three-dimensional active matter. So far, however, a theoretical model reconciling all observations is missing. In particular, the role of boundary conditions in these instabilities still needs to be explained. Here, we characterize the spontaneous flow transition in a symmetry-preserving three-dimensional active Ericksen-Leslie model, showing that the boundary conditions select the emergent behavior. Using nonlinear numerical solutions and linear perturbation analysis, we explain the mechanism for both in-plane and out-of-plane instabilities under extensile active stress for perpendicular polarity anchoring at the boundary, whereas parallel anchoring only permits in-plane flows under contractile stress or out-of-plane wrinkling under extensile stress.

Fluid pumping and the generation of electric current by living tissues are required during morphogenetic processes and for maintainance of homeostasis. How these flows emerge from active and passive ion transport in cells has been well established. However, the interplay between flow and current generation is not well understood. Here, we study the electro-hydraulic coupling that arises from cell ion pumping. We develop a one-dimensional continuum model of fluid and ion transport across active cell membranes. Solving the Nernst-Planck and Poisson equations in the limit of weak charge imbalance allows us to derive approximate analytical solutions of the model. These approximations, consistent with the numerical results in physiologically relevant regime of parameters, allow us to describe electro-hydraulic activity of cells and tissues in terms of experimentally accessible parameters.

We investigate how randomly oriented cell traction forces lead to fluidisation in a vertex model of epithelial tissues. We find that the fluidisation occurs at a critical value of the traction force magnitude $F_c$. We show that this transition exhibits critical behaviour, similar to the yielding transition of sheared amorphous solids. However, we find that it belongs to a different universality class, even though it satisfies the same scaling relations between critical exponents established in the yielding transition of sheared amorphous solids. Our work provides a fluidisation mechanism through active force generation that could be relevant in biological tissues.

Stress-strain constitutive relations in solids with an internal angular degree of freedom can be modelled using Cosserat (also called micropolar) elasticity. In this paper, we explore the phenomenology for a natural extension of Cosserat materials that includes chiral active components and odd elasticity. We calculate static elastic properties of such a solid, where we show that static response to rotational stresses leads to strains that depend on both Cosserat and odd elasticity. We then compute the dispersion of linear solutions in these odd Cosserat materials in the overdamped regime and find the presence of \emph{exceptional points} in the dispersion relation. We discover that these exceptional points create a sharp boundary between a Cosserat-dominated regime of complete wave attenuation and an odd-elasticity-dominated regime of propagating waves. We conclude by showing the effect of Cosserat and odd elastic terms on the polarization of Rayleigh surface waves.

We review the theory of martingales as applied to stochastic thermodynamics and stochastic processes in physics more generally., Comment: 324 pages, 68 figures, submitted to Advances in Physics

We compute the response matrix for a tracer particle in a compressible fluid with odd viscosity living on a two-dimensional surface. Unlike the incompressible case, we find that an odd compressible fluid can produce an odd lift force on a tracer particle. Using a "shell localization" formalism, we provide analytic expressions for the drag and odd lift forces acting on the tracer particle in a steady state and also at finite frequency. Importantly, we find that the existence of an odd lift force in a steady state requires taking into account the non-conservation of the fluid mass density due to the coupling between the two-dimensional surface and the three-dimensional bulk fluid., Comment: The first two authors contributed equally ; accepted manuscript version

A living cell uses long tubular appendages for locomotion and sensory purposes. Hence, assembling and maintaining a protrusion of correct length is crucial for its survival and overall performance. Usually the protrusions lack the machinery for the synthesis of building blocks and imports them from the cell body. What are the unique features of the transport logistics which facilitate the exchange of these building blocks between the cell and the protrusion? What kind of `rulers' and `timers' does the cell use for constructing its appendages of correct length on time? How do the multiple appendages coordinate and communicate among themselves during different stages of their existence? How frequently do the fluctuations drive the length of these dynamic protrusions out of the acceptable bounds? These questions are addressed from a broad perspective in this review which is organized in three parts. In part-I the list of all known cell protrusions is followed by a comprehensive list of the mechanisms of length control of cell protrusions reported in the literature. We review not only the dynamics of the genesis of the protrusions, but also their resorption and regrowth as well as regeneration after amputation. As a case study in part-II, the specific cell protrusion that has been discussed in detail is eukaryotic flagellum (also known as cilium); this choice was dictated by the fact that flagellar length control mechanisms have been studied most extensively over more than half a century in cells with two or more flagella. Although limited in scope, brief discussions on a few non-flagellar cell protrusions in part-III of this review is intended to provide a glimpse of the uncharted territories and challenging frontiers of research on subcellular length control phenomena that awaits vigorous investigations., Comment: Preprint of a Review Article; comments are welcome

Chemically active droplets provide simple models for cell-like systems that can grow and divide. Such active droplet systems are driven away from thermodynamic equilibrium and turn over chemically, which corresponds to a simple metabolism. We consider two scenarios of non-equilibrium driving. First, droplets are driven via the system boundaries by external reservoirs that supply nutrient and remove waste (boundary-driven). Second, droplets are driven by a chemical energy provided by a fuel in the bulk (bulk-driven). For both scenarios, we discuss the conservation of energy and matter as well as the balance of entropy. We use conserved and non-conserved fields to analyze the non-equilibrium steady states of active droplets. Using an effective droplet model, we explore droplet stability and instabilities leading to droplet division. Our work reveals that droplet division occurs quite generally in active droplet systems. Our results suggest that life-like processes such as metabolism and division can emerge in simple non-equilibrium systems that combine the physics of phase separation and chemical reactions.

Chemically active systems such as living cells are maintained out of thermal equilibrium due to chemical events which generate heat and lead to active fluctuations. A key question is to understand on which time and length scales active fluctuations dominate thermal fluctuations. Here, we formulate a stochastic field theory with Poisson white noise to describe the heat fluctuations which are generated by stochastic chemical events and lead to active temperature fluctuations. We find that on large length and time scales, active fluctuations always dominate thermal fluctuations. However, at intermediate length and time scales, multiple crossovers exist which highlight the different characteristics of active and thermal fluctuations. Our work provides a framework to characterize fluctuations in active systems and reveals that local equilibrium holds at certain length and time scales., Comment: 11 pages, 3 figures

We derive a fully covariant theory of the hydrodynamics of nematic and polar active surfaces, subjected to internal and external forces and torques. We study the symmetries of polar and nematic surfaces and find that in addition to 5 different types of in-plane isotropic surfaces, polar and nematic surfaces can be classified into 5 polar, 2 pseudopolar, 5 nematic and 2 pseudonematic types of surfaces. We give examples of physical realisations of the different types of surfaces we have identified. We obtain expressions for the equilibrium tensions, moments, and external forces and torques acting on a passive polar or nematic surface. We calculate the entropy production rate using the framework of thermodynamics close to equilibrium and find constitutive equations for polar and nematic active surfaces with different symmetries. We study the instabilities of a confined flat planar-chiral polar active layer and of a confined deformable polar active surface with broken up-down symmetry.

The kinetics of chemical reactions are determined by the law of mass action, which has been successfully applied to homogeneous, dilute mixtures. At non-dilute conditions, interactions among the components can give rise to coexisting phases, which can significantly alter the kinetics of chemical reactions. Here, we derive a theory for chemical reactions in coexisting phases at phase equilibrium. We show that phase equilibrium couples the rates of chemical reactions of components with their diffusive exchanges between the phases. Strikingly, the chemical relaxation kinetics can be represented as a flow along the phase equilibrium line in the phase diagram. A key finding of our theory is that differences in reaction rates between coexisting phases stem solely from phase-dependent reaction rate coefficients. Our theory is key to interpret how concentration levels of reactive components in condensed phases control chemical reaction rates in synthetic and biological systems.

In amorphous solids as in tissues, neighbor exchanges can relax local stresses and allow the material to flow. In this paper, we use an anisotropic vertex model to study T1 rearrangements in polygonal cellular networks. We consider two different physical realizations of the active anisotropic stresses: (i) anisotropic bond tension and (ii) anisotropic cell stress. Interestingly, the two types of active stress lead to patterns of relative orientation of T1 transitions and cell elongation that are different. Our work suggests that these two realizations of anisotropic active stresses can be observed \textit{in vivo}. We describe and explain these results through the lens of a continuum description of the tissue as an anisotropic active material. We furthermore discuss the energetics of the dynamic tissue and express the energy balance in terms of internal elastic energy, mechanical work, chemical work and heat. This allows us to define active T1 transitions that can perform mechanical work while consuming chemical energy., Comment: Accepted for publication in EPJE. Appendix A with details of the simulations is identical to that in arXiv:2103.16462

Active chiral viscoelastic materials exhibit elastic responses perpendicular to the applied stresses, referred to as odd elasticity. We use a covariant formulation of viscoelasticity combined with an entropy production analysis to show that odd elasticity is not only present in active systems but also in broad classes of passive chiral viscoelastic fluids. In addition, we demonstrate that linear viscoelastic chiral solids do require activity in order to manifest odd elastic responses. In order to model the phenomenon of passive odd viscoelasticity we propose a chiral extension of Jeffreys model. We apply our covariant formalism in order to derive the dispersion relations of hydrodynamic modes and obtain clear imprints of odd viscoelastic behavior., Comment: 13 pages, 6 figures, corrected implementation of the time-reversal symmetry

In living cells, protein-rich condensates can wet the cell membrane and surfaces of membrane-bound organelles. Interestingly, many phase-separating proteins also bind to membranes leading to a molecular layer of bound molecules. Here we investigate how binding to membranes affects wetting, prewetting and surface phase transitions. We derive a thermodynamic theory for a three-dimensional bulk in the presence of a two-dimensional, flat membrane. At phase coexistence, we find that membrane binding facilitates complete wetting and thus lowers the wetting angle. Moreover, below the saturation concentration, binding facilitates the formation of a thick layer at the membrane and thereby shifts the prewetting phase transition far below the saturation concentration. The distinction between bound and unbound molecules near the surface leads to a large variety of surface states {and complex surface phase diagrams with a rich topology of phase transitions. Our work suggests that surface phase transitions combined with molecular binding represent a versatile mechanism to control the formation of protein-rich domains at intra-cellular surfaces.

Using concepts from integral geometry, we propose a definition for a local coarse-grained curvature tensor that is well-defined on polygonal surfaces. This coarse-grained curvature tensor shows fast convergence to the curvature tensor of smooth surfaces, capturing with accuracy not only the principal curvatures but also the principal directions of curvature. Thanks to the additivity of the integrated curvature tensor, coarse-graining procedures can be implemented to compute it over arbitrary patches of polygons. When computed for a closed surface, the integrated curvature tensor is identical to a rank-2 Minkowski tensor. We also provide an algorithm to extend an existing C++ package, that can be used to compute efficiently local curvature tensors on triangulated surfaces., Comment: 20 pages, 9 figures

Morphogenesis depends crucially on the complex rheological properties of cell tissues and on their ability to maintain mechanical integrity while rearranging at long times. In this paper, we study the rheology of polygonal cellular networks described by a vertex model in the presence of fluctuations. We use a triangulation method to decompose shear into cell shape changes and cell rearrangements. Considering the steady-state stress under constant shear, we observe nonlinear shear-thinning behavior at all magnitudes of the fluctuations, and an even stronger nonlinear regime at lower values of the fluctuations. We successfully capture this nonlinear rheology by a mean-field model that describes the tissue in terms of cell elongation and cell rearrangements. We furthermore introduce anisotropic active stresses in the vertex model and analyze their effect on rheology. We include this anisotropy in the mean-field model and show that it recapitulates the behavior observed in the simulations. Our work clarifies how tissue rheology is related to stochastic cell rearrangements and provides a simple biophysical model to describe biological tissues. Further, it highlights the importance of nonlinearities when discussing tissue mechanics., Comment: 39 pages, 9 figures

Large protein complexes are assembled from protein subunits to form a specific structure. In our theoretic work, we propose that assembly into the correct structure could be reliably achieved through an assembly line with a specific sequence of assembly steps. Using droplet interfaces to position compartment boundaries, we show that an assembly line can be self organized by active droplets. As a consequence, assembly steps can be arranged spatially so that a specific order of assembly is achieved and incorrect assembly is strongly suppressed.

We use a theoretical approach to examine the effect of a radial fluid flow or electric current on the growth and homeostasis of a cell spheroid. Such conditions may be generated by a drain of micrometric diameter. To perform this analysis, we describe the tissue as a continuum. We include active mechanical, electric, and hydraulic components in the tissue material properties. We consider a spherical geometry and study the effect of the drain on the dynamics of the cell aggregate. We show that a steady fluid flow or electric current imposed by the drain could be able to significantly change the spheroid long-time state. In particular, our work suggests that a growing spheroid can systematically be driven to a shrinking state if an appropriate external field is applied. Order-of-magnitude estimates suggest that such fields are of the order of the indigenous ones. Similarities and differences with the case of tumors and embryo development are briefly discussed., Comment: 28 pages, 6 figures

We generalize the Susceptible-Infected-Removed model for epidemics to take into account generic effects of heterogeneity in the degree of susceptibility to infection in the population. We introduce a single new parameter corresponding to a power-law exponent of the susceptibility distribution that characterizes the population heterogeneity. We show that our generalized model is as simple as the original model which is contained as a limiting case. Because of this simplicity, numerical solutions can be generated easily and key properties of the epidemic wave can still be obtained exactly. In particular, we present exact expressions for the herd immunity level, the final size of the epidemic, as well as for the shape of the wave and for observables that can be quantified during an epidemic. We find that in strongly heterogeneous populations the epidemic reaches only a small fraction of the population. This implies that the herd immunity level can be much lower than in commonly used models with homogeneous populations. Using our model to analyze data for the SARS-CoV-2 epidemic in Germany shows that the reported time course is consistent with several scenarios characterized by different levels of immunity. These scenarios differ in population heterogeneity and in the time course of the infection rate, for example due to mitigation efforts or seasonality. Our analysis reveals that quantifying the effects of mitigation requires knowledge on the degree of heterogeneity in the population. Our work shows that key effects of population heterogeneity can be captured without increasing the complexity of the model. We show that information about population heterogeneity will be key to understand how far an epidemic has progressed and what can be expected for its future course., Comment: 34 pages, 8 figures

The mechanical response of active media ranging from biological gels to living tissues is governed by a subtle interplay between viscosity and elasticity. In this Letter, we generalize the canonical Kelvin-Voigt and Maxwell models to active viscoelastic media that break both parity and time-reversal symmetries. The resulting continuum theories exhibit viscous and elastic tensors that are both antisymmetric, or odd, under exchange of pairs of indices. We analyze how these parity violating viscoelastic coefficients determine the relaxation mechanisms and wave-propagation properties of odd materials., Comment: 6 pages, 3 figures

Amorphous materials exhibit complex material proprteties with strongly nonlinear behaviors. Below a yield stress they behave as plastic solids, while they start to yield above a critical stress $\Sigma_c$. A key quantity controlling plasticity which is, however, hard to measure is the density $P(x)$ of weak spots, where $x$ is the additional stress required for local plastic failure. In the thermodynamic limit $P(x)\sim x^\theta$ is singular at $x= 0$ in the solid phase below the yield stress $\Sigma_c$. This singularity is related to the presence of system spannig avalanches of plastic events. Here we address the question if the density of weak spots and the flow properties of a material can be determined from the geometry of an amporphous structure alone. We show that a vertex model for cell packings in tissues exhibits the phenomenology of plastic amorphous systems. As the yield stress is approached from above, the strain rate vanishes and the avalanches size $S$ and their duration $\tau$ diverge. We then show that in general, in materials where the energy functional depend on topology, the value $x$ is proportional to the length $L$ of a bond that vanishes in a plastic event. For this class of models $P(x)$ is therefore readily measurable from geometry alone. Applying this approach to a quantification of the cell packing geometry in the developing wing epithelium of the fruit fly, we find that in this tissue $P(L)$ exhibits a power law with exponents similar to those found numerically for a vertex model in its solid phase. This suggests that this tissue exhibits plasticity and non-linear material properties that emerge from collective cell behaviors and that these material properties govern developmental processes. Our approach based on the relation between topology and energetics suggests a new route to outstanding questions associated with the yielding transition.

Flagella of eukaryotic cells are transient long cylindrical protrusions. The proteins needed to form and maintain flagella are synthesized in the cell body and transported to the distal tips. What `rulers' or `timers' a specific type of cells use to strike a balance between the outward and inward transport of materials so as to maintain a particular length of its flagella in the steady state is one of the open questions in cellular self-organization. Even more curious is how the two flagella of biflagellates, like Chlamydomonas Reinhardtii, communicate through their base to coordinate their lengths. In this paper we develop a stochastic model for flagellar length control based on a time-of-flight (ToF) mechanism. This ToF mechanism decides whether or not structural proteins are to be loaded onto an intraflagellar transport (IFT) train just before it begins its motorized journey from the base to the tip of the flagellum. Because of the ongoing turnover, the structural proteins released from the flagellar tip are transported back to the cell body also by IFT trains. We represent the traffic of IFT trains as a totally asymmetric simple exclusion process (TASEP). The ToF mechanism for each flagellum, together with the TASEP-based description of the IFT trains, combined with a scenario of sharing of a common pool of flagellar structural proteins in biflagellates, can account for all key features of experimentally known phenomena. These include ciliogenesis, resorption, deflagellation as well as regeneration after selective amputation of one of the two flagella. We also show that the experimental observations of Ishikawa and Marshall are consistent with the ToF mechanism of length control if the effects of the mutual exclusion of the IFT trains captured by the TASEP are taken into account. Moreover, we make new predictions on the flagellar length fluctuations and the role of the common pool., Comment: Revised presentation, 36 pages, including 17 figures

We present a minimal model to study liquid phase separation in a fixed pH ensemble. The model describes a mixture composed of macromolecules that exist in three different charge states and have a tendency to phase separate. We introduce the pH dependence of phase separation by means of a set of reactions describing the protonation and deprotonation of macromolecules, as well as the self-ionisation of water. We use conservation laws to identify the conjugate thermodynamic variables at chemical equilibrium. Using this thermodynamic conjugate variables we perform a Legendre transform which defines the corresponding free energy at fixed pH. We first study the possible phase diagram topologies at the isoelectric point of the macromolecules. We then show how the phase behavior depends on pH by moving away from the isoelectric point. We find that phase diagrams as a function of pH strongly depend on whether oppositely charged macromolecules or neutral macromolecules have a stronger tendency to phase separate. We predict the existence of reentrant behavior as a function of pH. In addition, our model also predicts that the region of phase separation is typically broader at the isoelectric point. This model could account for both, the protein separation observed in yeast cells for pH values close to the isoelectric point of many cytosolic proteins and also for the in vitro experiments of single proteins exhibiting phase separation as a function of pH.

Morphogens are secreted signaling molecules that mediate tissue patterning and growth of embryonic tissues. They are secreted in a localized region and spread through the tissue to form a graded concentration profile. We present a cell-based model of morphogen spreading that combines secretion in a local source, extracellular diffusion and cellular trafficking. We introduce hydrodynamic modes of morphogen transport and characterize the dynamics of transport by dispersion relations of these dynamic eigenmodes. These dispersion relations specify the characteristic relaxation time of a mode as a function of its wavelength. In a simple model we distinguish two distinct dynamic modes characterized by different timescales. We find that the slower mode defines the effective diffusion and degradation as well as the shape of the concentration profile in steady state. Using our approach we discuss mechanisms of morphogen transport in the developing wing imaginal disc of the fruit fly \textit{Drosophila}, distinguishing three transport regimes: transport by extracellular diffusion, transport by transcytosis and a regime where both transport mechanisms are combined.

The cell cortex, a thin film of active material assembled below the cell membrane, plays a key role in cellular symmetry breaking processes such as cell polarity establishment and cell division. Here, we present a minimal model of the self-organization of the cell cortex that is based on a hydrodynamic theory of curved active surfaces. Active stresses on this surface are regulated by a diffusing molecular species. We show that coupling of the active surface to a passive bulk fluid enables spontaneous polarization and the formation of a contractile ring on the surface via mechano-chemical instabilities. We discuss the role of external fields in guiding such pattern formation. Our work reveals that key features of cellular symmetry breaking and cell division can emerge in a minimal model via general dynamic instabilities., Comment: Accepted for publication in Physical Review Letters (Sept 2019)

We derive exact expressions for the finite-time statistics of extrema (maximum and minimum) of the spatial displacement and the fluctuating entropy flow of biased random walks. Our approach captures key features of extreme events in molecular motor motion along linear filaments. Our results generalize the infimum law for entropy production and reveal a symmetry of the distribution of its maxima and minima. We also show that the relaxation spectrum of the full generating function, and hence of any moment, of the finite-time extrema distributions can be written in terms of the Mar{\v{c}}enko-Pastur distribution of random-matrix theory. Using this result, we obtain estimates for the extreme-value statistics of stochastic transport from the eigenvalue distributions of suitable Wishart and Laguerre random matrices. We confirm our results by numerical simulations of stochastic models of molecular motors and discuss as illustrative example our theory in the context of sports., Comment: 19 pages, 8 figures

We discuss the physical mechanisms that promote or suppress the nucleation of a fluid-filled lumen inside a cell assembly or a tissue. We discuss lumen formation in a continuum theory of tissue material properties in which the tissue is described as a two-fluid system to account for its permeation by the interstitial fluid, and we include fluid pumping as well as active electric effects. Considering a spherical geometry and a polarized tissue, our work shows that fluid pumping and tissue flexoelectricity play a crucial role in lumen formation. We furthermore explore the large variety of long-time states that are accessible for the cell aggregate and its lumen. Our work reveals a role of the coupling of mechanical, electrical and hydraulic phenomena in tissue lumen formation., Comment: Published version

We calculate the Casimir stresses in a thin layer of active fluid with nematic order. By using a stochastic hydrodynamic approach for an active fluid layer of finite thickness $L$, we generalize the Casimir stress for nematic liquid crystals in thermal equilibrium to active systems. We show that the active Casimir stress differs significantly from its equilibrium counterpart. For contractile activity, the active Casimir stress, although attractive like its equilibrium counterpart, diverges logarithmically as $L$ approaches a threshold of the spontaneous flow instability from below. In contrast, for small extensile activity, it is repulsive, has no divergence at any $L$ and has a scaling with $L$ different from its equilibrium counterpart.

How epithelial cells coordinate their polarity to form functional tissues is an open question in cell biology. Here, we characterize a unique type of polarity found in liver tissue, nematic cell polarity, which is different from vectorial cell polarity in simple, sheet-like epithelia. We propose a conceptual and algorithmic framework to characterize complex patterns of polarity proteins on the surface of a cell in terms of a multipole expansion. To rigorously quantify previously observed tissue-level patterns of nematic cell polarity (Morales-Navarette et al., eLife 8:e44860, 2019), we introduce the concept of co-orientational order parameters, which generalize the known biaxial order parameters of the theory of liquid crystals. Applying these concepts to three-dimensional reconstructions of single cells from high-resolution imaging data of mouse liver tissue, we show that the axes of nematic cell polarity of hepatocytes exhibit local coordination and are aligned with the biaxially anisotropic sinusoidal network for blood transport. Our study characterizes liver tissue as a biological example of a biaxial liquid crystal. The general methodology developed here could be applied to other tissues or in-vitro organoids., Comment: 27 pages, 9 color figures

A stopping time $T$ is the first time when a trajectory of a stochastic process satisfies a specific criterion. In this paper, we use martingale theory to derive the integral fluctuation relation $\langle e^{-S_{\rm tot}(T)}\rangle=1$ for the stochastic entropy production $S_{\rm tot}$ in a stationary physical system at stochastic stopping times $T$. This fluctuation relation implies the law $\langle S_{\rm tot}(T)\rangle\geq 0$, which states that it is not possible to reduce entropy on average, even by stopping a stochastic process at a stopping time, and which we call the second law of thermodynamics at stopping times. This law implies bounds on the average amount of heat and work a system can extract from its environment when stopped at a random time. Furthermore, the integral fluctuation relation implies that certain fluctuations of entropy production are universal or are bounded by universal functions. These universal properties descend from the integral fluctuation relation by selecting appropriate stopping times: for example, when $T$ is a first-passage time for entropy production, then we obtain a bound on the statistics of negative records of entropy production. We illustrate these results on simple models of nonequilibrium systems described by Langevin equations and reveal two interesting phenomena. First, we demonstrate that isothermal mesoscopic systems can extract on average heat from their environment when stopped at a cleverly chosen moment and the second law at stopping times provides a bound on the average extracted heat. Second, we demonstrate that the average efficiency at stopping times of an autonomous stochastic heat engines, such as Feymann's ratchet, can be larger than the Carnot efficiency and the second law of thermodynamics at stopping times provides a bound on the average efficiency at stopping times., Comment: 37 pages, 6 figures

We study the dynamics of a thick polar epithelium subjected to the action of both an electric and a flow field in a planar geometry. We develop a generalized continuum hydrodynamic description and describe the tissue as a two component fluid system. The cells and the interstitial fluid are the two components and we keep all terms allowed by symmetry. In particular we keep track of the cell pumping activity for both solvent flow and electric current and discuss the corresponding orders of magnitude. We study the growth dynamics of tissue slabs, their steady states and obtain the dependence of the cell velocity, net cell division rate, and cell stress on the flow strength and the applied electric field. We find that finite thickness tissue slabs exist only in a restricted region of phase space and that relatively modest electric fields or imposed external flows can induce either proliferation or death., Comment: 18 pages, 12 figures

An increasing number of proteins with intrinsically disordered domains have been shown to phase separate in buffer to form liquid-like phases. These protein condensates serve as simple models for the investigation of the more complex membrane-less organelles in cells. To understand the function of such proteins in cells, the material properties of the condensates they form are important. However, these material properties are not well understood. Here, we develop a novel method based on optical traps to study the frequency-dependent rheology and the surface tension of PGL-3 condensates as a function of salt concentration. We find that PGL-3 droplets are predominantly viscous but also exhibit elastic properties. As the salt concentration is reduced, their elastic modulus, viscosity and surface tension increase. Our findings show that salt concentration has a strong influence on the rheology and dynamics of protein condensates suggesting an important role of electrostatic interactions for their material properties., Comment: 5 pages, 3 figures, 1 supplement

Phase separating systems that are maintained away from thermodynamic equilibrium via molecular processes represent a class of active systems, which we call active emulsions. These systems are driven by external energy input for example provided by an external fuel reservoir. The external energy input gives rise to novel phenomena that are not present in passive systems. For instance, concentration gradients can spatially organise emulsions and cause novel droplet size distributions. Another example are active droplets that are subject to chemical reactions such that their nucleation and size can be controlled and they can spontaneously divide. In this review we discuss the physics of phase separation and emulsions and show how the concepts that governs such phenomena can be extended to capture the physics of active emulsions. This physics is relevant to the spatial organisation of the biochemistry in living cells, for the development novel applications in chemical engineering and models for the origin of life., Comment: Review article about passive and active emulsions

In systems of coupled oscillators, the effects of complex signaling can be captured by time delays and phase shifts. Here, we show how time delays and phase shifts lead to different oscillator dynamics and how synchronization rates can be regulated by substituting time delays by phase shifts at constant collective frequency. For spatially extended systems with time delays, we show that fastest synchronization can occur for intermediate wavelengths, giving rise to novel synchronization scenarios., Comment: 5 pages, 3 figures

We introduce a stochastic model of coupled genetic oscillators in which chains of chemical events involved in gene regulation and expression are represented as sequences of Poisson processes. We characterize steady states by their frequency, their quality factor and their synchrony by the oscillator cross correlation. The steady state is determined by coupling and exhibits stochastic transitions between different modes. The interplay of stochasticity and nonlinearity leads to isolated regions in parameter space in which the coupled system works best as a biological pacemaker. Key features of the stochastic oscillations can be captured by an effective model for phase oscillators that are coupled by signals with distributed delays., Comment: 12 pages, 8 figures

We introduce lower bounds for the rate of entropy production of an active stochastic process by quantifying the irreversibility of stochastic traces obtained from mesoscopic degrees of freedom. Our measures of irreversibility reveal signatures of time's arrow and provide bounds for entropy production even in the case of active fluctuations that have no drift. We apply these irreversibility measures to experimental recordings of spontaneous hair-bundle oscillations in mechanosensory hair cells from the ear of the bullfrog. By analysing the fluctuations of only the tip position of hair bundles, we reveal irreversibility in active oscillations and estimate an associated rate of entropy production of at least $\sim 3 k_{\rm B}$/s, on average. Applying thermodynamic uncertainty relations, we predict that measuring both the tip position of the hair bundle and the mechano-electrical transduction current that enters the hair cell leads to tighter lower bounds for the rate of entropy production, up to $\sim 10^3 k_{\rm B}$/s in the oscillatory regime., Comment: 15 pages (including Appendix), 10 figures

We study the hydrodynamics and shape changes of chemically active droplets. In non-spherical droplets, surface tension generates hydrodynamic flows that drive liquid droplets into a spherical shape. Here we show that spherical droplets that are maintained away from thermodynamic equilibrium by chemical reactions may not remain spherical but can undergo a shape instability which can lead to spontaneous droplet division. In this case chemical activity acts against surface tension and tension-induced hydrodynamic flows. By combining low Reynolds-number hydrodynamics with phase separation dynamics and chemical reaction kinetics we determine stability diagrams of spherical droplets as a function of dimensionless viscosity and reaction parameters. We determine concentration and flow fields inside and outside the droplets during shape changes and division. Our work shows that hydrodynamic flows tends to stabilize spherical shapes but that droplet division occurs for sufficiently strong chemical driving, sufficiently large droplet viscosity or sufficiently small surface tension. Active droplets could provide simple models for prebiotic protocells that are able to proliferate. Our work captures the key hydrodynamics of droplet division that could be observable in chemically active colloidal droplets.

This paper provides a statistical method to test whether a system that performs a binary sequential hypothesis test is optimal in the sense of minimizing the average decision times while taking decisions with given reliabilities. The proposed method requires samples of the decision times, the decision outcomes, and the true hypotheses, but does not require knowledge on the statistics of the observations or the properties of the decision-making system. The method is based on fluctuation relations for decision time distributions which are proved for sequential probability ratio tests. These relations follow from the martingale property of probability ratios and hold under fairly general conditions. We illustrate these tests with numerical experiments and discuss potential applications., Comment: 42 pages, 7 figures