Physique des Cellules et Cancers

This review summarizes theoretical progress in the field of active matter, placing it in the context of recent experiments. This approach offers a unified framework for the mechanical and statistical properties of living matter: biofilaments and molecular motors in vitro or in vivo, collections of motile microorganisms, animal flocks, and chemical or mechanical imitations. A major goal of this review is to integrate several approaches proposed in the literature, from semimicroscopic to phenomenological. In particular, first considered are ``dry'' systems, defined as those where momentum is not conserved due to friction with a substrate or an embedding porous medium. The differences and similarities between two types of orientationally ordered states, the nematic and the polar, are clarified. Next, the active hydrodynamics of suspensions or ``wet'' systems is discussed and the relation with and difference from the dry case, as well as various large-scale instabilities of these nonequilibrium states of matter, are highlighted. Further highlighted are various large-scale instabilities of these nonequilibrium states of matter. Various semimicroscopic derivations of the continuum theory are discussed and connected, highlighting the unifying and generic nature of the continuum model. Throughout the review, the experimental relevance of these theories for describing bacterial swarms and suspensions, the cytoskeleton of living cells, and vibrated granular material is discussed. Promising extensions toward greater realism in specific contexts from cell biology to animal behavior are suggested, and remarks are given on some exotic active-matter analogs. Last, the outlook for a quantitative understanding of active matter, through the interplay of detailed theory with controlled experiments on simplified systems, with living or artificial constituents, is summarized.

HiC-Pro is an optimized and flexible pipeline for processing Hi-C data from raw reads to normalized contact maps. HiC-Pro maps reads, detects valid ligation products, performs quality controls and generates intra- and inter-chromosomal contact maps. It includes a fast implementation of the iterative correction method and is based on a memory-efficient data format for Hi-C contact maps. In addition, HiC-Pro can use phased genotype data to build allele-specific contact maps. We applied HiC-Pro to different Hi-C datasets, demonstrating its ability to easily process large data in a reasonable time. Source code and documentation are available at http://github.com/nservant/HiC-Pro .

The authors present general considerations and simple models for the operation of isothermal motors at small scales, in asymmetric environments. Their work is inspired by recent observations on the behavior of molecular motors in the biological realm, where chemical energy is converted into mechanical energy. A generic Onsager-like description of the linear (close to equilibrium) regime is presented, which exhibits structural differences from the usual Carnot engines. Turning to more explicit models for a single motor, the authors show the importance of the time scales involved and of the spatial dependence of the motor's chemical activity. Considering the situation in which a large collection of such motors operates together. The authors exhibit new features among which are dynamical phase transitions formally similar to paramagnetic-ferromagnetic and liquid-vapor transitions.

Tight coupling between biochemical and mechanical properties of the actin cytoskeleton drives a large range of cellular processes including polarity establishment, morphogenesis, and motility. This is possible because actin filaments are semi-flexible polymers that, in conjunction with the molecular motor myosin, can act as biological active springs or "dashpots" (in laymen's terms, shock absorbers or fluidizers) able to exert or resist against force in a cellular environment. To modulate their mechanical properties, actin filaments can organize into a variety of architectures generating a diversity of cellular organizations including branched or crosslinked networks in the lamellipodium, parallel bundles in filopodia, and antiparallel structures in contractile fibers. In this review we describe the feedback loop between biochemical and mechanical properties of actin organization at the molecular level in vitro, then we integrate this knowledge into our current understanding of cellular actin organization and its physiological roles.

Using an original microfabrication-based technique, we experimentally study situations in which a virgin surface is presented to a confluent epithelium with no damage made to the cells. Although inspired by wound-healing experiments, the situation is markedly different from classical scratch wounding because it focuses on the influence of the free surface and uncouples it from the other possible contributions such as cell damage and/or permeabilization. Dealing with Madin-Darby canine kidney cells on various surfaces, we found that a sudden release of the available surface is sufficient to trigger collective motility. This migration is independent of the proliferation of the cells that mainly takes place on the fraction of the surface initially covered. We find that this motility is characterized by a duality between collective and individual behaviors. On the one hand, the velocity fields within the monolayer are very long range and involve many cells in a coordinated way. On the other hand, we have identified very active "leader cells" that precede a small cohort and destabilize the border by a fingering instability. The sides of the fingers reveal a pluricellular actin "belt" that may be at the origin of a mechanical signaling between the leader and the followers. Experiments performed with autocrine cells constitutively expressing hepatocyte growth factor (HGF) or in the presence of exogenous HGF show a higher average velocity of the border and no leader.

We report experiments and modeling of translocation of double-strand DNA through a siliconoxide nanopore. Long DNA molecules with different lengths ranging from 6500 to 97000 base pairs have been electrophoretically driven through a 10 nm pore. We observe a power-law caling of the translocation time with the length, with an exponent of 1.27. This nonlinear scaling is strikingly different from the well-studied linear behavior observed in similar experiments performed on protein pores. We present a theoretical model where hydrodynamic drag on the ection of the polymer outside the pore is the dominant force counteracting the electrical driving force. We show that this applies to our experiments, and we derive a power-law scaling with an exponent of 1.22, in good agreement with the data.

The dramatic recent advances in molecular biology, which have opened a new era in medicine and biotechnology, rely on improved techniques to study large molecules. Electrophoresis is one of the most important of these. Separation of DNA by size, in particular, is at the heart of genome mapping and sequencing and is likely to play an increasing role in diagnosis. This article reviews, from the point of view of a physicist, the mechanisms responsible for electrophoretic separation of polyelectrolytes. This separation is mainly performed in gels, and a wide variety of migration mechanisms can come into play, depending on the polyelectrolyte's architecture, on the electric fields applied, and on the properties of the gel. After a brief review of the thermodynamic and electrohydrodynamic principles relating to polyelectrolyte solutions, the author treats the phenomenology of electrophoresis and describes the conceptual and theoretical tools in the field. The reptation mechanisms, by which large flexible polyelectrolytes thread their way through the pores of the gel matrix, play a prominent role. Biased reptation, the extension of this model to electrophoresis, provides a very intuitive framework within which numerous physical ideas can be introduced and discussed. It has been the most popular theory in this domain, and it remains an inspiring concept for current development. There have also been important advances in experimental techniques such as single-molecule viodeomicroscopy and the development of nongel separation media and mechanisms. These, in turn, form the basis for fast-developing and innovative technologies like capillary electrophoresis, electrophoresis on microchips, and molecular ratchets.

When a liquid drops impinges a hydrophobic rough surface it can either bounce off the surface (fakir droplets) or be impaled and strongly stuck on it (Wenzel droplets). The analysis of drop impact and quasi static ''loading'' experiments on model microfabricated surfaces allows to clearly identify the forces hindering the impalement transitions. A simple semi-quantitative model is proposed to account for the observed relation between the surface topography and the robustness of fakir non-wetting states. Motivated by potential applications in microfluidics and in the fabrication of self cleaning surfaces, we finally propose some guidelines to design robust superhydrophobic surfaces.

We develop a general theory for active viscoelastic materials made of polar filaments. This theory is motivated by the dynamics of the cytoskeleton. The continuous consumption of a fuel generates a nonequilibrium state characterized by the generation of flows and stresses. Our theory applies to any polar system with internal energy consumption such as active chemical gels and cytoskeletal networks which are set in motion by active processes at work in cells.

A range of monodomain nematic azo side‐on elastomers , containing different proportions of photoisomerizable azo mesogenic moieties, were prepared for the first time photochemically using a radical photoinitiator working at wavelengths above 600 nm. These elastomers exhibit a photomechanical contraction of up to 20 % upon irradiation with UV light. The Figure shows an elastomer film in its contracted form under UV irradiation.

Blebs are spherical membrane protrusions often observed during cell migration, cell spreading, cytokinesis, and apoptosis, both in cultured cells and in vivo. Bleb expansion is thought to be driven by the contractile actomyosin cortex, which generates hydrostatic pressure in the cytoplasm and can thus drive herniations of the plasma membrane. However, the role of cortical tension in bleb formation has not been directly tested, and despite the importance of blebbing, little is known about the mechanisms of bleb growth. In order to explore the link between cortical tension and bleb expansion, we induced bleb formation on cells with different tensions. Blebs were nucleated in a controlled manner by laser ablation of the cortex, mimicking endogenous bleb nucleation. Cortical tension was modified by treatments affecting the level of myosin activity or proteins regulating actin turnover. We show that there is a critical tension below which blebs cannot expand. Above this threshold, the maximal size of a bleb strongly depends on tension, and this dependence can be fitted with a model of the cortex as an active elastic material. Together, our observations and model allow us to relate bleb shape parameters to the underlying cellular mechanics and provide insights as to how bleb formation can be biochemically regulated during cell motility.

Many natural and social systems develop complex networks that are usually modeled as random graphs. The eigenvalue spectrum of these graphs provides information about their structural properties. While the semicircle law is known to describe the spectral densities of uncorrelated random graphs, much less is known about the spectra of real-world graphs, describing such complex systems as the Internet, metabolic pathways, networks of power stations, scientific collaborations, or movie actors, which are inherently correlated and usually very sparse. An important limitation in addressing the spectra of these systems is that the numerical determination of the spectra for systems with more than a few thousand nodes is prohibitively time and memory consuming. Making use of recent advances in algorithms for spectral characterization, here we develop methods to determine the eigenvalues of networks comparable in size to real systems, obtaining several surprising results on the spectra of adjacency matrices corresponding to models of real-world graphs. We find that when the number of links grows as the number of nodes, the spectral density of uncorrelated random matrices does not converge to the semicircle law. Furthermore, the spectra of real-world graphs have specific features, depending on the details of the corresponding models. In particular, scale-free graphs develop a trianglelike spectral density with a power-law tail, while small-world graphs have a complex spectral density consisting of several sharp peaks. These and further results indicate that the spectra of correlated graphs represent a practical tool for graph classification and can provide useful insight into the relevant structural properties of real networks.

We show that the formation of membrane tubes (or membrane tethers), which is a crucial step in many biological processes, is highly nontrivial and involves first-order shape transitions. The force exerted by an emerging tube is a nonmonotonic function of its length. We point out that tubes attract each other, which eventually leads to their coalescence. We also show that detached tubes behave like semiflexible filaments with a rather short persistence length. We suggest that these properties play an important role in the formation and structure of tubular organelles.

Polymer vesicles, commonly called polymersomes, are spherical shell structures in which an aqueous compartment is enclosed by a bilayer membrane made from amphiphilic block copolymers. Compared to liposomes, their low molecular weight analogues, polymersomes have many superior properties (higher toughness, better stability, tailorable membrane properties), which make them attractive candidates for applications including encapsulation, drug delivery, nanoreactors and templates for micro- or nano-structured materials. Many potential applications require the ability to control the release of substances encapsulated in the interior compartment and/or in the hydrophobic core of membrane. To address this goal, polymersomes have to be developed in which a specific stimulus destabilises the vesicle structure. In this article we review the most promising approaches to make stimuli-responsive polymer vesicles that permit the controlled release of encapsulated contents. Stimuli including hydrolysis, oxidation, reduction, pH, temperature and light are discussed and their effect on the chemical and physical structure of the amphiphilic copolymers is also described.

The deposition of organic monolayers containing quaternary ammonium groups has been shown by many authors to confer biocidal properties on a large variety of solid surfaces. In a search for the controlling factors, the authors have grafted quaternized poly(vinylpyridine) chains on glass surfaces by two different methods and varied the charge density within the organic layer between 10(12) and 10(16) positive charges per cm2. The measurements show that this parameter has a large influence on the killing efficiency. Bacterial death occurs in less than 10 min in the quiescent state above a threshold value. The value is smaller for bacteria in the growth state. It also depends on the bacterial type. An electrostatic mechanism based on the exchange of counterions between the functionalized cationic surface and the bacterial membrane is proposed and appears consistent with the results.

Many essential phenomena in biology involve changes in cell shape. Cell deformation occurs in response to physical forces either coming from the external environment or intracellularly generated. In most tests of cell rheology, an external constraint is usually superimposed on an already mechanically active cell, thus the measurements may reflect both active motion and passive viscoelastic deformation. To show that active and passive processes could be distinguished on a time scale basis, we designed a novel piezo-controlled micromanipulation system to impose dynamic mechanical deformations on individual cells. Chick fibroblasts were seized between two glass microplates; one of the plates, more flexible, served as a sensor of the applied force. Controlled amounts of unidirectional compression and traction in the range of 10(-8)-10(-7) N were applied, using either step functions or sinusoidal signals at chosen frequencies. These tests allowed identification of three time scale dependent regimes. (1) A dominant elastic response, characterized by a linear stress-strain relationship, was especially apparent at short times (seconds); (2) A viscous behavior, characterized by force relaxation and irreversible cell deformation, was noticeable at intermediate times (minutes). Data from traction and oscillatory excitation tests were well fitted by a three-element Kelvin viscoelastic model, allowing the calculation of two elastic moduli in the range of 600-1,000 N/m2 and an apparent viscosity of about 10(4) Pa.s. (3) A contractile regime, in which actin-dependent traction forces were developed in response to uniaxial load was apparent at longer times (several tens of minutes). These forces were in the order of 4 x 10(-8) N above viscous relaxation. Thus we could distinguish, on a time scale basis, the specific contributions of passive viscoelasticity and active traction, and evaluate their mechanical characteristics within one experiment on a single cell.

Sorting of lipids and proteins is a key process allowing eukaryotic cells to execute efficient and accurate intracellular transport and to maintain membrane homeostasis. It occurs during the formation of highly curved transport intermediates that shuttle between cell compartments. Protein sorting is reasonably well described, but lipid sorting is much less understood. Lipid sorting has been proposed to be mediated by a physical mechanism based on the coupling between membrane composition and high curvature of the transport intermediates. To test this hypothesis, we have performed a combination of fluorescence and force measurements on membrane tubes of controlled diameters pulled from giant unilamellar vesicles. A model based on membrane elasticity and nonideal solution theory has also been developed to explain our results. We quantitatively show, using 2 independent approaches, that a difference in lipid composition can build up between a curved and a noncurved membrane. Importantly, and consistent with our theory, lipid sorting occurs only if the system is close to a demixing point. Remarkably, this process is amplified when even a low fraction of lipids is clustered upon cholera toxin binding. This can be explained by the reduction of the entropic penalty of lipid sorting when some lipids are bound together by the toxin. Our results show that curvature-induced lipid sorting results from the collective behavior of lipids and is even amplified in the presence of lipid-clustering proteins. In addition, they suggest a generic mechanism by which proteins can facilitate lipid segregation in vivo.

Increasing evidence suggests that mechanical cues inherent to the extracellular matrix may be as important as its chemical nature in regulating cell behavior. Here, the response of cells to the mechanical properties of the substrate is examined by culturing 3T3 fibroblastic cells and epithelial cells on surfaces composed of a dense array of flexible microfabricated pillars. We focus on the influence of substrate rigidity on the traction forces exerted by cells, and on cell adhesion and migration. We first measure these forces by monitoring the deflection of the pillars. Then, by varying their geometric parameters, we control the substrate stiffness over a large range from 1 to 200 nN μm−1. We show that the force–rigidity relationship exhibits a similar behavior for both cell types. Two distinct regimes are evidenced: first, a linear increase of the force with the rigidity and then a saturation plateau for the largest rigidities. We observe that the cell spreading area increases with increasing rigidity, as well as the size of focal adhesions. Substrates with an anisotropic rigidity allow us to determine that the migration paths of 3T3 cells are oriented in the stiffest direction in correlation with maximal traction forces. Finally, to compare the force measurements on micro-textured surfaces and continuous flexible gels, we propose an elastic model that estimates the equivalent Young's modulus of a micropillar substrate. This qualitative model gives comparable results for both experimental approaches.

We image macroscopic transient pores in mechanically stretched giant vesicles. Holes open above a critical radius r(c1), grow up to a radius r(c2), and close. We interpret the upper limit r(c2) by a relaxation of the membrane tension as the holes expand. The closing of the holes is caused by a further relaxation of the surface tension when the internal liquid leaks out. A dynamic model fits our data for the growth and closure of pores.

During animal development, several planar cell polarity (PCP) pathways control tissue shape by coordinating collective cell behavior. Here, we characterize by means of multiscale imaging epithelium morphogenesis in the Drosophila dorsal thorax and show how the Fat/Dachsous/Four-jointed PCP pathway controls morphogenesis. We found that the proto-cadherin Dachsous is polarized within a domain of its tissue-wide expression gradient. Furthermore, Dachsous polarizes the myosin Dachs, which in turn promotes anisotropy of junction tension. By combining physical modeling with quantitative image analyses, we determined that this tension anisotropy defines the pattern of local tissue contraction that contributes to shaping the epithelium mainly via oriented cell rearrangements. Our results establish how tissue planar polarization coordinates the local changes of cell mechanical properties to control tissue morphogenesis.