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arXiv2015

MreB helical pitch angle determines cell diameter in Escherichia coli

Bacteria have remarkably robust cell shape control mechanisms. For example, cell diameter only varies by a few percent across a population. MreB is necessary for establishment and maintenance of rod shape although the mechanism of shape control remains unknown. We perturbed MreB in two complimentary ways to produce steady-state cell diameters over a wide range, from 790+/-30 nm to 1700+/-20 nm. To determine which properties of MreB are important for diameter control, we correlated structural characteristics of fluorescently-tagged MreB polymers with cell diameter by simultaneously analyzing 3-dimensional images of MreB and cell shape. Our results indicate that the pitch angle of MreB inversely correlates with cell diameter. Other correlations are not found to be significant. These results demonstrate that the physical properties of MreB filaments are important for shape control and support a model in which MreB dictates cell diameter and organizes cell wall growth to produce a chiral cell wall.

physics.bio-ph↗

arXiv2015

Optimal Chemotactic Responses in Stochastic Environments

Most of our understanding of bacterial chemotaxis comes from studies of Escherichia coli. However, recent evidence suggests significant departures from the E. coli paradigm in other bacterial species. This variation may stem from different species inhabiting distinct environments and thus adapting to specific environmental pressures. In particular, these complex and dynamic environments may be poorly represented by standard experimental and theoretical models. In this work, we study the performance of various chemotactic strategies under a range of stochastic time- and space-varying attractant distributions in silico. We describe a novel type of response in which the bacterium tumbles more when attractant concentration is increasing, in contrast to the response of E. coli, and demonstrate how this response explains the behavior of aerobically-grown Rhodobacter sphaeroides. In this "speculator" response, bacteria compare the current attractant concentration to the long-term average. By tumbling persistently when the current concentration is higher than the average, bacteria maintain their position in regions of high attractant concentration. If the current concentration is lower than the average, or is declining, bacteria swim away in search of more favorable conditions. When the attractant distribution is spatially complex but slowly-changing, this response is as effective as that of E. coli.

q-bio.CB↗

arXiv2016

A neuron inspired model for the time constant of dynamical systems

Emulate the gating mechanism of ionic channels in neurons, we present a mathematical model for the time constant of dynamical systems. Our model is an analytical continues function. The analyses give evidence that one can adjust the desirable morphology of the response of the dynamical system by adjusting the parameters of the proposed model.

q-bio.CB↗

arXiv2015

Fluctuations in growth rates determine the generation time and size distributions of E. coli cells

Isogenic Escherichia coli growing exponentially in a constant environment display large variation in growth-rates, division-sizes and generation-times. It is unclear how these seemingly random cell cycles can be reconciled with the precise regulation required under conditions where the generation time is shorter than the time to replicate the genome. Here we use single molecule microscopy to map the location of the replication machinery to the division cycle of individual cells. We find that the cell-to-cell variation in growth rate is sufficient to explain the corresponding variation in cell size and division timing assuming a simple mechanistic model. In the model, initiation of chromosome replication is triggered at a fixed volume per origin region, and associated with each initiation event is a division event at a growth rate dependent time later. The result implies that cell division in E. coli has no other regulation beyond what is needed to initiate DNA replication at the right volume.

q-bio.QM↗

arXiv2015

Surface deformation and shear flow in ligand mediated cell adhesion

We present a single, unified, multi-scale model to study the attachment\detachment dynamics of two deforming, near spherical cells, coated with binding ligands and subject to a slow, homogeneous shear flow in a viscous fluid medium. The binding ligands on the surface of the cells experience attractive and repulsive forces in an ionic medium and exhibit finite resistance to rotation via bond tilting. The macroscale drag forces and couples describing the fluid flow inside the small separation gap between the cells, are calculated using a combination of methods in lubrication theory and previously published numerical results. For a select range of material and fluid parameters, a hysteretic transition of the sticking probability curves between the adhesion and fragmentation domain is attributed to a nonlinear relation between the total microscale binding forces and the separation gap between the cells. We show that adhesion is favored in highly ionic fluids, increased deformability of the cells, elastic binders and a higher fluid shear rate (until a critical value). Continuation of the limit points predict a bistable region, indicating an abrupt switching between the adhesion and fragmentation regimes at critical shear rates, and suggesting that adhesion of two deformable surfaces in shearing fluids may play a significant dynamical role in some cell adhesion applications.

q-bio.CB↗

arXiv2015

Entropy, Ergodicity and Stem Cell Multipotency

Populations of mammalian stem cells commonly exhibit considerable cell-cell variability. However, the functional role of this diversity is unclear. Here, we analyze expression fluctuations of the stem cell surface marker Sca1 in mouse hematopoietic progenitor cells using a simple stochastic model and find that the observed dynamics naturally lie close to a critical state, thereby producing a diverse population that is able to respond rapidly to environmental changes. We propose an information-theoretic interpretation of these results that views cellular multipotency as an instance of maximum entropy statistical inference.

q-bio.CB↗

arXiv2017

pH/$T$ duality - wall properties and time evolution of plant cells

We examined the pH/$T$ (or $μ$/$T$) duality of acidic pH and temperature ($T$) for the growth of grass shoots in order to determine the equation of state (EoS) for living plants. By considering non-meristematic growth as a dynamic series of 'state transitions' (STs) in the extending primary wall, we identified the critical (read: optimum) exponents for this phenomenon, which exhibit a singular behaviour at a critical temperature, critical pH and critical chemical potential ($μ$) in the form of four power laws: $F(τ)_π\propto|τ|^{β-1}$, $F(π)_τ\propto|π|^{1-α}$, $G(τ)_μ\propto|τ|^{-2-α+2β}$ and $G(μ)_τ\propto|μ|^{2-α}$. The power-law exponents $α$ and $β$ are numbers, which are independent of pH (or $μ$) and $T$ that are known as critical exponents, while $π$ and $τ$ represent a reduced pH and reduced temperature, respectively. Various 'scaling' predictions were obtained - a convexity relation $α+ β\ge 2$ for practical pH-based analysis and a $β\equiv 2$ identity in microscopic representation. In the presented scenario, the magnitude that is decisive is the chemical potential of H$^+$ ions (protons), enforcing subsequent STs and growth. The EoS span areas of the biological, physical, chemical and Earth sciences cross the borders with the language (adapted formalism) of phase transitions.

q-bio.CB↗

arXiv2015

A stochastic model of B cell affinity maturation and a network model of immune memory

Many events in the vertebrate immune system are influenced by some element of chance. The objective of the present work is to describe affinity maturation of B lymphocytes (in which random events are perhaps the most characteristic), and to study a possible network model of immune memory. In our model stochastic processes govern all events. A major novelty of this approach is that it permits studying random variations in the immune process. Four basic components are simulated in the model: non-immune self cells, nonself cells (pathogens), B lymphocytes, and bone marrow cells that produce naive B lymphocytes. A point in a generalized shape space plus the size of the corresponding population represents nonself and non-immune self cells. On the other hand, each individual B cell is represented by a disc that models its recognition region in the shape space. Infection is simulated by an "injection" of nonself cells into the system. Division of pathogens may instigate an attack of naive B cells, which in turn may induce clonal proliferation and hypermutation in the attacking B cells, and which eventually may slow down and stop the exponential growth of pathogens. Affinity maturation of newly produced B cells becomes expressed as a result of selection when the number of pathogens decreases. Under favorable conditions, the expanded primary B cell clones may stimulate the expansion of secondary B cell clones carrying complementary receptors to the stimulating B cells. Like in a hall of mirrors, the image of pathogens in the primary B cell clones then will be reflected in secondary B cell clones. This "ping-pong" game may survive for a long time even in the absence of the pathogen, creating a local network memory. This memory ensures that repeated infection by the same pathogen will be eliminated more efficiently.

q-bio.MN↗

arXiv2015

Metachronal waves in the flagellar beating of $Volvox$ and their hydrodynamic origin

Groups of eukaryotic cilia and flagella are capable of coordinating their beating over large scales, routinely exhibiting collective dynamics in the form of metachronal waves. The origin of this behaviour -- possibly influenced by both mechanical interactions and direct biological regulation -- is poorly understood, in large part due to lack of quantitative experimental studies. Here we characterise in detail flagellar coordination on the surface of the multicellular alga $Volvox~carteri$, an emerging model organism for flagellar dynamics. Our studies reveal for the first time that the average metachronal coordination observed is punctuated by periodic phase defects during which synchrony is partial and limited to specific groups of cells. A minimal model of hydrodynamically coupled oscillators can reproduce semi-quantitatively the characteristics of the average metachronal dynamics, and the emergence of defects. We systematically study the model's behaviour by assessing the effect of changing intrinsic rotor characteristics, including oscillator stiffness and the nature of their internal driving force, as well as their geometric properties and spatial arrangement. Our results suggest that metachronal coordination follows from deformations in the oscillators' limit cycles induced by hydrodynamic stresses, and that defects result from sufficiently steep local biases in the oscillators' intrinsic frequencies. Additionally, we find that random variations in the intrinsic rotor frequencies increase the robustness of the average properties of the emergent metachronal waves.

cond-mat.soft↗

arXiv2015

Numerical treatment of the Filament Based Lamellipodium Model (FBLM)

We describe in this work the numerical treatment of the Filament Based Lamellipodium Model (FBLM). The model itself is a two-phase two-dimensional continuum model, describing the dynamics of two interacting families of locally parallel F-actin filaments. It includes, among others, the bending stiffness of the filaments, adhesion to the substrate, and the cross-links connecting the two families. The numerical method proposed is a Finite Element Method (FEM) developed specifically for the needs of these problem. It is comprised of composite Lagrange-Hermite two dimensional elements defined over two dimensional space. We present some elements of the FEM and emphasise in the numerical treatment of the more complex terms. We also present novel numerical simulations and compare to in-vitro experiments of moving cells.

q-bio.CB↗

arXiv2015

A mathematical insight in the epithelial-mesenchymal-like transition in cancer cells and its effect in the invasion of the extracellular matrix

Current biological knowledge supports the existence of a secondary group of cancer cells within the body of the tumour that exhibits stem cell-like properties. These cells are termed Cancer Stem Cells (CSCs}, and as opposed to the more usual Differentiated Cancer Cells (DCCs), they exhibit higher motility, they are more resilient to therapy, and are able to metastasize to secondary locations within the organism and produce new tumours. The origin of the CSCs is not completely clear; they seem to stem from the DCCs via a transition process related to the Epithelial-Mesenchymal Transition (EMT) that can also be found in normal tissue. In the current work we model and numerically study the transition between these two types of cancer cells, and the resulting "ensemble" invasion of the extracellular matrix. This leads to the derivation and numerical simulation of two systems: an algebraic-elliptic system for the transition and an advection-reaction-diffusion system of Keller-Segel taxis type for the invasion.

q-bio.CB↗

arXiv2015

Implications of the hybrid epithelial/mesenchymal phenotype in metastasis

Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes - epithelial and mesenchymal - cells can also attain a hybrid epithelial/mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g. adhesion) and mesenchymal (e.g. migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor Cells (CTCs). If these clusters enter the circulation, they can be more apoptosis-resistant and more capable of initiating metastatic lesions than cancer cells moving individually with wholly mesenchymal phenotypes, having undergo a complete EMT. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a three-way switch giving rise to three distinct phenotypes - epithelial, mesenchymal and hybrid epithelial/mesenchymal. We further characterize this hybrid E/M phenotype in terms of its capabilities in terms of collective cell migration, tumor-initiation, cell-cell communication, and drug resistance. We elucidate how the highly interconnected coupling between these modules coordinates cell-fate decisions among a population of cancer cells in the dynamic tumor, hence facilitating tumor-stoma interactions, formation of CTC clusters, and consequently cancer metastasis. Finally, we discuss the multiple advantages that the hybrid epithelial/mesenchymal phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary 'bad actors' of metastasis.

q-bio.CB↗

arXiv2015

Frequency landscape of tip-growing plants

It has been interesting that nearly all of the ion activities that have been analysed thus far have exhibited oscillations that are tightly coupled to growth. Here, we present discrete Fourier transform (DFT) spectra with a finite sampling of tip-growing cells and organs that were obtained from voltage measurements of the elongating coleoptiles of maize in situ. The electromotive force (EMF) oscillations (~ 0.1 μV) were measured in a simple but highly sensitive RL circuit, in which the solenoid was initially placed at the tip of the specimen and then was moved thus changing its position in relation to growth (EMF can be measured first at the tip, then at the sub-apical part and finally at the shank). The influx- and efflux-induced oscillations of Ca$^{2+}$, along with H$^{+}$, K$^{+}$ and Cl$^{-}$ were densely sampled (preserving the Nyquist theorem in order to 'grasp the structure' of the pulse), the logarithmic amplitude of pulse spectrum was calculated, and the detected frequencies, which displayed a periodic sequence of pulses, were compared with the literature data. A band of life vital individual pulses was obtained in a single run of the experiment, which not only allowed the fundamental frequencies (and intensities of the processes) to be determined but also permitted the phase relations of the various transport processes in the plasma membrane and tonoplast to be established. A discrete frequency spectrum (like the hydrogen spectrum in quantum physics) was achieved for a growing plant for the first time, while all of the metabolic and enzymatic functions of the life cell cycle were preserved using this totally non-invasive treatment.

q-bio.CB↗

arXiv2015

Spatial Effects of Delay-induced Stochastic Oscillations in a Multi-Cellular System

We explore the joint effect of the intrinsic noise and time delay on the spatial pattern formation within a multi-scale mobile lattice model of the epithelium. The protein fluctuations are driven by transcription/translation processes in epithelial cells exchanging chemical and mechanical signals and are described by a single-gene auto-repressor model with constant delay. Both deterministic and stochastic descriptions are given. We found that time delay, noise and spatial signaling can result in the protein pattern formation even when deterministic description exhibits no patterns.

nlin.AO↗

arXiv2015

Alterations in cell surface area and deformability of individual human red blood cells in stored blood

The functionality and viability of stored human red blood cells (RBCs) is an important clinical issue in transfusion. To systematically investigate changes in stored whole blood, the hematological properties of individual RBCs were quantified in blood samples stored for various periods with and without a preservation solution called CPDA-1. With 3-D quantitative phase imaging techniques, the optical measurements of the 3-D refractive index (RI) distributions and membrane fluctuations were done at the individual cell level. From the optical measurements, the morphological (volume, surface area and sphericity), biochemical (hemoglobin content and concentration), and mechanical parameters (dynamic membrane fluctuation) were simultaneously quantified to investigate the functionalities and their progressive alterations in stored RBCs. Our results show that the stored RBCs without CPDA-1 had a dramatic morphological transformation from discocytes to spherocytes within 2 weeks which was accompanied with significant decreases in cell deformability and cell surface area, and increases in sphericity. However, the stored RBCs with CPDA-1 maintained their morphology and deformability for up to 6 weeks.

physics.med-ph↗

arXiv2015

The effects of MAPK activity on cell-cell adhesion during wound healing

The mechanisms underlying collective migration, or the coordinated movement of a population of cells, are not well understood despite its ubiquitous nature. As a means to investigate collective migration, we consider a wound healing scenario in which a population of cells fills in the empty space left from a scratch wound. Here we present a simplified mathematical model that uses reaction-diffusion equations to model collective migration during wound healing with an emphasis on cell movement and its response to both cell signaling and cell-cell adhesion. We use the model to investigate the effect of the MAPK signaling cascade on cell-cell adhesion during wound healing after EGF treatment. Our results suggest that activation of the MAPK signaling cascade stimulates collective migration through increases in the pulling strength of leader cells. We further use the model to suggest that treating a cell population with EGF converts the time to wound closure (as function of wound area) from parabolic to linear.

q-bio.CB↗

arXiv2015

Myosin-II dependent cell contractility contributes to spontaneous nodule formation of mesothelioma cells

We demonstrate that characteristic nodules emerge in cultures of several malignant pleural mesothelioma (MPM) cell lines. Instead of excessive local cell proliferation, the nodules arise by Myosin II-driven cell contractility. The aggregation process can be prevented or reversed by suitable pharmacological inhibitors of acto-myosin contractility. A cell-resolved elasto-plastic model of the multicellular patterning process indicates that the morphology and size of the nodules as well as the speed of their formation is determined by the mechanical tension cells exert on their neighbors, and the stability of cell-substrate adhesion complexes. A linear stability analysis of a homogenous, self-tensioned Maxwell fluid indicates the unconditional presence of a patterning instability.

physics.bio-ph↗

arXiv2015

Superdiffusion dominates intracellular particle motion in the supercrowded space of pathogenic Acanthamoeba castellanii

Acanthamoebae are free-living protists and human pathogens, whose cellular functions and pathogenicity strongly depend on the transport of intracellular vesicles and granules through the cytosol. Using high-speed live cell imaging in combination with single-particle tracking analysis, we show here that the motion of endogenous intracellular particles in the size range from a few hundred nanometers to several micrometers in Acanthamoeba castellanii is strongly superdiffusive and influenced by cell locomotion, cytoskeletal elements, and myosin II. We demonstrate that cell locomotion significantly contributes to intracellular particle motion, but is clearly not the only origin of superdiffusivity. By analyzing the contribution of microtubules, actin, and myosin II motors we show that myosin II is a major driving force of intracellular motion in A. castellanii. The cytoplasm of A. castellanii is supercrowded with intracellular vesicles and granules, such that significant intracellular motion can only be achieved by actively driven motion, while purely thermally driven diffusion is negligible.

physics.bio-ph↗