A view from the President of the Indian Biophysical Society.

This Commentary introduces the readers of Biophysical Reviews to the current president of the Indian Biophysical Society and details a few recent activities of the society in its domestic and international promotion of the biophysics as a scientific discipline.

Reliable and robust control of nucleus centering is contingent on nonequilibrium force patterns.

Cell centers their division apparatus to ensure symmetric cell division, a challenging task when the governing dynamics is stochastic. Using fission yeast, we show that the patterning of nonequilibrium polymerization forces of microtubule (MT) bundles controls the precise localization of spindle pole body (SPB), and hence the division septum, at the onset of mitosis. We define two cellular objectives, reliability, the mean SPB position relative to the geometric center, and robustness, the variance of the SPB position, which are sensitive to genetic perturbations that change cell length, MT bundle number/orientation, and MT dynamics. We show that simultaneous control of reliability and robustness is required to minimize septum positioning error achieved by the wild type (WT). A stochastic model for the MT-based nucleus centering, with parameters measured directly or estimated using Bayesian inference, recapitulates the maximum fidelity of WT. Using this, we perform a sensitivity analysis of the parameters that control nuclear centering.

A census of actin-associated proteins in humans.

Actin filaments help in maintaining the cell structure and coordinating cellular movements and cargo transport within the cell. Actin participates in the interaction with several proteins and also with itself to form the helical filamentous actin (F-actin). Actin-binding proteins (ABPs) and actin-associated proteins (AAPs) coordinate the actin filament assembly and processing, regulate the flux between globular G-actin and F-actin in the cell, and help maintain the cellular structure and integrity. We have used protein-protein interaction data available through multiple sources (STRING, BioGRID, mentha, and a few others), functional annotation, and classical actin-binding domains to identify actin-binding and actin-associated proteins in the human proteome. Here, we report 2482 AAPs and present an analysis of their structural and sequential domains, functions, evolutionary conservation, cellular localization, abundance, and tissue-specific expression patterns. This analysis provides a base for the characterization of proteins involved in actin dynamics and turnover in the cell.

Cellular compartmentalisation and receptor promiscuity as a strategy for accurate and robust inference of position during morphogenesis.

Precise spatial patterning of cell fate during morphogenesis requires accurate inference of cellular position. In making such inferences from morphogen profiles, cells must contend with inherent stochasticity in morphogen production, transport, sensing and signalling. Motivated by the multitude of signalling mechanisms in various developmental contexts, we show how cells may utilise multiple tiers of processing (compartmentalisation) and parallel branches (multiple receptor types), together with feedback control, to bring about fidelity in morphogenetic decoding of their positions within a developing tissue. By simultaneously deploying specific and nonspecific receptors, cells achieve a more accurate and robust inference. We explore these ideas in the patterning of Drosophila melanogaster wing imaginal disc by Wingless morphogen signalling, where multiple endocytic pathways participate in decoding the morphogen gradient. The geometry of the inference landscape in the high dimensional space of parameters provides a measure for robustness and delineates stiff and sloppy directions. This distributed information processing at the scale of the cell highlights how local cell autonomous control facilitates global tissue scale design.

SMC protein RecN drives RecA filament translocation for in vivo homology search.

While the molecular repertoire of the homologous recombination pathways is well studied, the search mechanism that enables recombination between distant homologous regions is poorly understood. Earlier work suggests that the recombinase RecA, an essential component for homology search, forms an elongated filament, nucleating at the break site. How this RecA structure carries out long-distance search remains unclear. Here, we follow the dynamics of RecA after induction of a single double-strand break on the Caulobacter chromosome. We find that the RecA-nucleoprotein filament, once formed, rapidly translocates in a directional manner in the cell, undergoing several pole-to-pole traversals, until homology search is complete. Concomitant with translocation, we observe dynamic variation in the length of the filament. Importantly in vivo, the RecA filament alone is incapable of such long-distance movement; both translocation and associated length variations are contingent on action of structural maintenance of chromosome (SMC)-like protein RecN, via its ATPase cycle. In summary, we have uncovered the three key elements of homology search driven by RecN: mobility of a finite segment of RecA, changes in filament length, and ability to conduct multiple pole-to-pole traversals, which together point to an optimal search strategy.

Unjamming and emergent nonreciprocity in active ploughing through a compressible viscoelastic fluid.

A dilute suspension of active Brownian particles in a dense compressible viscoelastic fluid, forms a natural setting to study the emergence of nonreciprocity during a dynamical phase transition. At these densities, the transport of active particles is strongly influenced by the passive medium and shows a dynamical jamming transition as a function of activity and medium density. In the process, the compressible medium is actively churned up - for low activity, the active particle gets self-trapped in a cavity of its own making, while for large activity, the active particle ploughs through the medium, either accompanied by a moving anisotropic wake, or leaving a porous trail. A hydrodynamic approach makes it evident that the active particle generates a long-range density wake which breaks fore-aft symmetry, consistent with the simulations. Accounting for the back-reaction of the compressible medium leads to (i) dynamical jamming of the active particle, and (ii) a dynamical non-reciprocal attraction between two active particles moving along the same direction, with the trailing particle catching up with the leading one in finite time. We emphasize that these nonreciprocal effects appear only when the active particles are moving and so manifest in the vicinity of the jamming-unjamming transition.

Active emulsions in living cell membranes driven by contractile stresses and transbilayer coupling.

The spatiotemporal organization of proteins and lipids on the cell surface has direct functional consequences for signaling, sorting, and endocytosis. Earlier studies have shown that multiple types of membrane proteins, including transmembrane proteins that have cytoplasmic actin binding capacity and lipid-tethered glycosylphosphatidylinositol-anchored proteins (GPI-APs), form nanoscale clusters driven by active contractile flows generated by the actin cortex. To gain insight into the role of lipids in organizing membrane domains in living cells, we study the molecular interactions that promote the actively generated nanoclusters of GPI-APs and transmembrane proteins. This motivates a theoretical description, wherein a combination of active contractile stresses and transbilayer coupling drives the creation of active emulsions, mesoscale liquid order (lo) domains of the GPI-APs and lipids, at temperatures greater than equilibrium lipid phase segregation. To test these ideas, we use spatial imaging of molecular clustering combined with local membrane order, and we demonstrate that mesoscopic domains enriched in nanoclusters of GPI-APs are maintained by cortical actin activity and transbilayer interactions and exhibit significant lipid order, consistent with predictions of the active composite model.

Glycan processing in the Golgi as optimal information coding that constrains cisternal number and enzyme specificity.

Many proteins that undergo sequential enzymatic modification in the Golgi cisternae are displayed at the plasma membrane as cell identity markers. The modified proteins, called glycans, represent a molecular code. The fidelity of this glycan code is measured by how accurately the glycan synthesis machinery realizes the desired target glycan distribution for a particular cell type and niche. In this article, we construct a simplified chemical synthesis model to quantitatively analyse the trade-offs between the number of cisternae, and the number and specificity of enzymes, required to synthesize a prescribed target glycan distribution of a certain complexity to within a given fidelity. We find that to synthesize complex distributions, such as those observed in real cells, one needs to have multiple cisternae and precise enzyme partitioning in the Golgi. Additionally, for a fixed number of enzymes and cisternae, there is an optimal level of specificity (promiscuity) of enzymes that achieves the target distribution with high fidelity. The geometry of the fidelity landscape in the multidimensional space of the number and specificity of enzymes, inter-cisternal transfer rates, and number of cisternae provides a measure for robustness and identifies stiff and sloppy directions. Our results show how the complexity of the target glycan distribution and number of glycosylation enzymes places functional constraints on the Golgi cisternal number and enzyme specificity.

Active Remodeling of Chromatin and Implications for In Vivo Folding.

Building on the observation that chromatin compaction can be locally modulated by activity, we propose a model of in vivo chromatin as an active polymer and study its large scale conformations. In particular, we study an active mechanochemical model of chromosomal folding based on the interplay among polymer elasticity, confinement, topological constraints, and fluctuating active stresses arising from the ATP-dependent action of a variety of chromatin-associated protein machines and chromatin-remodeling proteins and their stochastic turnover. We find that activity drives the chromatin to a nonequilibrium steady state; the statistics of conformations in this nonequilibrium steady state are consistent with recent measurements on intrachromosomal contact probabilities and chromosomal compaction. The contact exponents at steady state show a systematic variation with changes in the nature of activity and the rates of turnover. The steady state configuration of the active chromatin in two dimensions resembles a space-filling Peano curve, which might have implications for the optimization of genome information storage.

Extreme active matter at high densities.

We study the remarkable behaviour of dense active matter comprising self-propelled particles at large Péclet numbers, over a range of persistence times, from τp â†’ 0, when the active fluid undergoes a slowing down of density relaxations leading to a glass transition as the active propulsion force f reduces, to τp â†’ ∞, when as f reduces, the fluid jams at a critical point, with stresses along force-chains. For intermediate τp, a decrease in f drives the fluid through an intermittent phase before dynamical arrest at low f. This intermittency is a consequence of periods of jamming followed by bursts of plastic yielding associated with Eshelby deformations. On the other hand, an increase in f leads to an increase in the burst frequency; the correlated plastic events result in large scale vorticity and turbulence. Dense extreme active matter brings together the physics of glass, jamming, plasticity and turbulence, in a new state of driven classical matter.

Stratification relieves constraints from steric hindrance in the generation of compact actomyosin asters at the membrane cortex.

Recent in vivo studies reveal that several membrane proteins are driven to form nanoclusters by active contractile flows arising from localized dynamic patterning of F-actin and myosin at the cortex. Since myosin-II assemble as minifilaments with tens of myosin heads, one might worry that steric considerations would obstruct the emergence of nanoclustering. Using coarse-grained, agent-based simulations that account for steric constraints, we find that the patterns exhibited by actomyosin in two dimensions, do not resemble the steady-state patterns in our in vitro reconstitution of actomyosin on a supported bilayer. We perform simulations in a thin rectangular slab, separating the layer of actin filaments from myosin-II minifilaments. This recapitulates the observed features of in vitro patterning. Using super resolution microscopy, we find evidence for such stratification in our in vitro system. Our study suggests that molecular stratification may be an important organizing feature of the cortical cytoskeleton in vivo.

Active morphogenesis of epithelial monolayers.

During typical early-stage embryo development, single-cell-thick tissues of tightly bound epithelial cells autonomously generate profound changes in their shape, forming the basis of organism anatomy. We report on a (covariant) active-hydrodynamic theory of such monolayer morphogenesis that is closed under its shape-changing dynamics-i.e., the degrees of freedom that encode monolayer geometry appear properly as broken-symmetry variables. In our theory, the salient physics of tissue-scale deformations emerges from a balance between the displacement and/or shear of a low-Reynolds-number embedding fluid (the "yolk") and cell-autonomous stresses, themselves a result of combining apical contractile stresses with an elastic-like mechanical response under the constraint of constant cell volume. The leading-order hydrodynamic instabilities include both passive constrained-buckling and active deformation, which can be further categorized by cell shape changes that are either "squamous to columnar" or "regular-prism to truncated-pyramid." The deformations resulting from the latter qualitatively reproduce in vivo observations of the onset of both mesoderm and posterior midgut invaginations, which take place during gastrulation in the model organism Drosophila melanogaster.

Breakdown of effective temperature, power law interactions, and self-propulsion in a momentum-conserving active fluid.

The simplest extensions of single-particle dynamics in a momentum-conserving active fluid-an active suspension of two colloidal particles or a single particle confined by a wall-exhibit strong departures from Boltzmann behavior, resulting in either a breakdown of an effective temperature description or a steady state with nonzero-entropy production rate. This is a consequence of hydrodynamic interactions that introduce multiplicative noise in the stochastic description of particle positions. This results in fluctuation-induced interactions that depend on distance as a power law. We find that the dynamics of activated colloids in a passive fluid, with stochastic forcing localized on the particle, is different from that of passive colloids in an active fluctuating fluid.

Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells.

Plasma membrane tension regulates many key cellular processes. It is modulated by, and can modulate, membrane trafficking. However, the cellular pathway(s) involved in this interplay is poorly understood. Here we find that, among a number of endocytic processes operating simultaneously at the cell surface, a dynamin independent pathway, the CLIC/GEEC (CG) pathway, is rapidly and specifically upregulated upon a sudden reduction of tension. Moreover, inhibition (activation) of the CG pathway results in lower (higher) membrane tension. However, alteration in membrane tension does not directly modulate CG endocytosis. This requires vinculin, a mechano-transducer recruited to focal adhesion in adherent cells. Vinculin acts by controlling the levels of a key regulator of the CG pathway, GBF1, at the plasma membrane. Thus, the CG pathway directly regulates membrane tension and is in turn controlled via a mechano-chemical feedback inhibition, potentially leading to homeostatic regulation of membrane tension in adherent cells.

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.

Soft inclusion in a confined fluctuating active gel.

We study stochastic dynamics of a point and extended inclusion within a one-dimensional confined active viscoelastic gel. We show that the dynamics of a point inclusion can be described by a Langevin equation with a confining potential and multiplicative noise. Using a systematic adiabatic elimination over the fast variables, we arrive at an overdamped equation with a proper definition of the multiplicative noise. To highlight various features and to appeal to different biological contexts, we treat the inclusion in turn as a rigid extended element, an elastic element, and a viscoelastic (Kelvin-Voigt) element. The dynamics for the shape and position of the extended inclusion can be described by coupled Langevin equations. Deriving exact expressions for the corresponding steady-state probability distributions, we find that the active noise induces an attraction to the edges of the confining domain. In the presence of a competing centering force, we find that the shape of the probability distribution exhibits a sharp transition upon varying the amplitude of the active noise. Our results could help understanding the positioning and deformability of biological inclusions, e.g., organelles in cells, or nucleus and cells within tissues.

Actomyosin pulsation and flows in an active elastomer with turnover and network remodeling.

Tissue remodeling requires cell shape changes associated with pulsation and flow of the actomyosin cytoskeleton. Here we describe the hydrodynamics of actomyosin as a confined active elastomer with turnover of its components. Our treatment is adapted to describe the diversity of contractile dynamical regimes observed in vivo. When myosin-induced contractile stresses are low, the deformations of the active elastomer are affine and exhibit spontaneous oscillations, propagating waves, contractile collapse and spatiotemporal chaos. We study the nucleation, growth and coalescence of actomyosin-dense regions that, beyond a threshold, spontaneously move as a spatially localized traveling front. Large myosin-induced contractile stresses lead to nonaffine deformations due to enhanced actin and crosslinker turnover. This results in a transient actin network that is constantly remodeling and naturally accommodates intranetwork flows of the actomyosin-dense regions. We verify many predictions of our study in Drosophila embryonic epithelial cells undergoing neighbor exchange during germband extension.

Universal lower bound on the free-energy cost of molecular measurements.

The living cell uses a variety of molecular receptors to read and process chemical signals that vary in space and time. We model the dynamics of such molecular level measurements as Markov processes in steady state, with a coupling between the receptor and the signal. We prove exactly that, when the signal dynamics is not perturbed by the receptors, the free energy consumed by the measurement process is lower bounded by a quantity proportional to the mutual information. Our result is completely independent of the receptor architecture and dependent on signal properties alone, and therefore holds as a general principle for molecular information processing.

Emergent Structures in an Active Polar Fluid: Dynamics of Shape, Scattering, and Merger.

Spatially localized defect structures emerge spontaneously in a hydrodynamic description of an active polar fluid comprising polar "actin" filaments and "myosin" motor proteins that (un)bind to filaments and exert active contractile stresses. These emergent defect structures are characterized by distinct textures and can be either static or mobile-we derive effective equations of motion for these "extended particles" and analyze their shape, kinetics, interactions, and scattering. Depending on the impact parameter and propulsion speed, these active defects undergo elastic scattering or merger. Our results are relevant for the dynamics of actomyosin-dense structures at the cell cortex, reconstituted actomyosin complexes, and 2D active colloidal gels.

Glassy swirls of active dumbbells.

Is an active glass different from a conventional passive glass? To address this, we study the dynamics of a dense binary mixture of soft dumbbells, each subject to an active propulsion force and thermal fluctuations. This dense assembly shows dynamical arrest, first to a translational and then to a rotational glass, as one reduces temperature T or the self-propulsion force f. We monitor the dynamics along an iso-relaxation-time contour in the (T-f) plane. We find dramatic differences both in the fragility and in the nature of dynamical heterogeneity, which characterize the onset of glass formation-the activity-induced glass exhibits large swirls or vortices, whose scale is set by activity, and it appears to diverge as one approaches the glass transition. This large collective swirling movement should have implications for collective cell migration in epithelial layers. We construct continuum hydrodynamic equations for the simulated system, and we show that the observed behavior of this growing dynamic length scale can be understood from these equations.