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arXiv2010

Immune System Inspired Strategies for Distributed Systems

Many components of the IS are constructed as modular units which do not need to communicate with each other such that the number of components increases but the size remains constant. However, a sub-modular IS architecture in which lymph node number and size both increase sublinearly with body size is shown to efficiently balance the requirements of communication and migration, consistent with experimental data. We hypothesize that the IS architecture optimizes the tradeoff between local search for pathogens and global response using antibodies. Similar to natural immune systems, physical space and resource are also important constraints on Artificial Immune Systems (AIS), especially distributed systems applications used to connect low-powered sensors using short-range wireless communication. AIS problems like distributed robot control will also require a sub-modular architecture to efficiently balance the tradeoff between local search for a solution and global response or proliferation of the solution between different components.

cs.DC↗

arXiv2010

Modeling the Intercelular Exchange of Signalling Molecules depending on Intra- and Inter-Cellular Environmental Parameters

Exchange of biochemical substances is essential way in establishing communication between bacterial cells. It is noticeable that all phases of the process are heavily influenced by perturbations of either internal or external parameters. Therefore, instead to develop an accurate quantitative model of substances exchange between bacterial cells, we are interested in formalization of the basic shape of the process, and creating the appropriate strategy that allows further investigation of synchronization. Using a form of coupled difference logistic equations we investigated synchronization of substances exchange between abstract cells and its sensitivity to fluctuations of environmental parameters using methods of nonlinear dynamics.

nlin.CD↗

arXiv2010

How is the Monoclonal Antibodies Kinetic Affected by Changes of Their Physical Parameters?

The study of monoclonal antibodies (MAb) is a field of great interest to science medicine, for example, anti-TNF agents (infliximab and adalimumab) represent an important tool for the management of autoimmune and inflammatory disorders. In this work we focus on the physical description of the transport kinetics of MAb in a fluid with laminar flow and parabolic profile. To simulate the kinetics of the MAb, standard equations were solved numerically (using The Verlet algorithm) to calculate the motion of a particle with a spherically symmetric inside of parabolic laminar flow, in order to find the time evolution of the antibody velocity in blood plasma in function of the increase of the radius, mass and density of the MAb, and the fluid pressure in blood vessels. In the case of we fixed the value of the antibody density, their kinetics increased when the pressure in the vessels increased. When we fixed the pressure in the vessels we found: if we reduce the antibody radius their kinetics increased, and when we increase antibody density we found that their kinetics also increased.

physics.bio-ph↗

arXiv2010

Analysis of a Mathematical Model of Apoptosis: Individual Differences and Malfunction in Programmed Cell Death

Apoptosis is an important area of research because of its role in keeping a mature multicellular organism's number of cells constant hence, ensuring that the organism does not have cell accumulation that may transform into cancer with additional hallmarks. Firstly, we have carried out sensitivity analysis on an existing mitochondria-dependent mathematical apoptosis model to find out which parameters have a role in causing monostable cell survival i.e., malfunction in apoptosis. We have then generated three healthy cell models by changing these sensitive parameters while preserving bistability i.e., healthy functioning. For each healthy cell, we varied the proapoptotic production rates, which were found to be among the most sensitive parameters, to yield cells that have malfunctioning apoptosis. We simulated caspase-3 activation, by numerically integrating the governing ordinary differential equations of a mitochondria-dependent apoptosis model, in a hypothetical malfunctioning cell which is treated by four potential treatments, namely: (i) proteasome inhibitor treatment, (ii) Bcl-2 inhibitor treatment, (iii) IAP inhibitor treatment, (iv) Bid-like synthetic peptides treatment. The simulations of the present model suggest that proteasome inhibitor treatment is the most effective treatment though it may have severe side effects. For this treatment, we observed that the amount of proteasome inhibitor needed for caspase-3 activation may be different for cells in individuals with a different proapoptotic protein deficiency. We also observed that caspase-3 can be activated by Bcl-2 inhibitor treatment only in those hypothetical malfunctioning cells with Bax deficiency but not in others. These support the view that molecular heterogeneity in individuals may be an important factor in determining the individuals' positive or negative responses to treatments.

q-bio.MN↗

arXiv2010

Intercellular spiral waves of calcium in a two dimensional network of cells

It is shown, by means of numerical simulations, that intercellular spiral waves of calcium can be initiated in a network of coupled cells as a result of a de-synchronization between Ca2+ oscillations in two domains. No artificial heterogeneities need to be imposed to the system for spontaneous formation of spiral waves. The de-synchronization occurs near the interface of the stimulated region (which acts as a pacemaker) and propagates over the entire network. We also find the outcome of the collision of two spiral waves.

q-bio.MN↗

arXiv2010

Subdiffusion, superdiffusion and chemotaxis

We propose two nonlinear random walk models which are suitable for the analysis of both chemotaxis and anomalous transport. We derive the balance equations for the population density for the case when the transition rate for a random walk depends on residence time, chemotactic substance and population density. We introduce the anomalous chemotactic sensitivity and find anomalous aggregation phenomenon. So we suggest a new explanation of the well-known effect of chemotactic collapse. We develop a non-Markovian "velocity-jump" model and obtain the superdiffusive behavior of bacteria with power law "run" time.

cond-mat.stat-mech↗

arXiv2010

The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape

Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood. Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor FcyRIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes. This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.

q-bio.CB↗

arXiv2010

System Level Numerical Analysis of a Monte Carlo Simulation of the E. Coli Chemotaxis

Over the past few years it has been demonstrated that "coarse timesteppers" establish a link between traditional numerical analysis and microscopic/ stochastic simulation. The underlying assumption of the associated lift-run-restrict-estimate procedure is that macroscopic models exist and close in terms of a few governing moments of microscopically evolving distributions, but they are unavailable in closed form. This leads to a system identification based computational approach that sidesteps the necessity of deriving explicit closures. Two-level codes are constructed; the outer code performs macroscopic, continuum level numerical tasks, while the inner code estimates -through appropriately initialized bursts of microscopic simulation- the quantities required for continuum numerics. Such quantities include residuals, time derivatives, and the action of coarse slow Jacobians. We demonstrate how these coarse timesteppers can be applied to perform equation-free computations of a kinetic Monte Carlo simulation of E. coli chemotaxis. Coarse-grained contraction mappings, system level stability analysis as well as acceleration of the direct simulation, are enabled through this computational multiscale enabling technology.

physics.bio-ph↗

arXiv2010

A computational model of cell polarization and motility coupling mechanics and biochemistry

The motion of a eukaryotic cell presents a variety of interesting and challenging problems from both a modeling and a computational perspective. The processes span many spatial scales (from molecular to tissue) as well as disparate time scales, with reaction kinetics on the order of seconds, and the deformation and motion of the cell occurring on the order of minutes. The computational difficulty, even in 2D, resides in the fact that the problem is inherently one of deforming, non-stationary domains, bounded by an elastic perimeter, inside of which there is redistribution of biochemical signaling substances. Here we report the results of a computational scheme using the immersed boundary method to address this problem. We adopt a simple reaction-diffusion system that represents an internal regulatory mechanism controlling the polarization of a cell, and determining the strength of protrusion forces at the front of its elastic perimeter. Using this computational scheme we are able to study the effect of protrusive and elastic forces on cell shapes on their own, the distribution of the reaction-diffusion system in irregular domains on its own, and the coupled mechanical-chemical system. We find that this representation of cell crawling can recover important aspects of the spontaneous polarization and motion of certain types of crawling cells.

q-bio.CB↗

arXiv2010

Noisy-threshold control of cell death

Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies. Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-xL and directly links adaptation with noise in an ATP threshold below which cells die. These results indicate that oncogenes like Bcl-xL, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.

q-bio.CB↗

arXiv2010

Asymptotic and bifurcation analysis of wave-pinning in a reaction-diffusion model for cell polarization

We describe and analyze a bistable reaction-diffusion (RD) model for two interconverting chemical species that exhibits a phenomenon of wave-pinning: a wave of activation of one of the species is initiated at one end of the domain, moves into the domain, decelerates, and eventually stops inside the domain, forming a stationary front. The second ("inactive") species is depleted in this process. This behavior arises in a model for chemical polarization of a cell by Rho GTPases in response to stimulation. The initially spatially homogeneous concentration profile (representative of a resting cell) develops into an asymmetric stationary front profile (typical of a polarized cell). Wave-pinning here is based on three properties: (1) mass conservation in a finite domain, (2) nonlinear reaction kinetics allowing for multiple stable steady states, and (3) a sufficiently large difference in diffusion of the two species. Using matched asymptotic analysis, we explain the mathematical basis of wave-pinning, and predict the speed and pinned position of the wave. An analysis of the bifurcation of the pinned front solution reveals how the wave-pinning regime depends on parameters such as rates of diffusion and total mass of the species. We describe two ways in which the pinned solution can be lost depending on the details of the reaction kinetics: a saddle-node or a pitchfork bifurcation.

q-bio.CB↗

arXiv2010

Some thoughts on the ontogenesis in B-cell immune networks

We are interested in modeling theoretical immunology within a statistical mechanics flavor: focusing on the antigen-independent maturation process of B-cells, in this paper we try to revise the problem of self vs non-self discrimination by mature B lymphocytes. We consider only B lymphocytes: despite this is of course an oversimplification, however such a toy model may help to highlight features of their interactions otherwise shadowed by main driven mechanisms due to i.e. helper T-cell signalling. By analyzing possible influences of the ontogenesis of the immune system on the final behavior of B lymphocytes, we try to merge over the purely negative selection mechanism at their birth with the adult self-regulation process. The final goal is a "thermodynamical picture" by which both the scenarios can exist and, actually, be synergically complementary: Trough numerical simulations we impose on a recent scheme for B-cell interactions, that part of self-reactive lymphocytes are killed during the ontogenesis by which two observations stem: At first the so built system is able to show anergy with respect to the previously encountered self even in its mature life, then this naturally leads to an increasing variance (and average) in the connectivity distribution of the resulting idiotypic network. As a consequence, following Varela perspective, this shift may contribute to push to anergy those self-directed cells which are free to explore the body: identifying the latter as the highly connected ones, anergy is imposed even via the B-network regulation, and its strength is influenced by the negative selection.

q-bio.CB↗

arXiv2010

Discrimination of Membrane Antigen Affinity by B cells Requires Dominance of Kinetic Proofreading over Serial Triggering

B cells receptor (BCR) signaling in response to membrane-bound antigen increases with antigen affinity, a process known as affinity discrimination. We use computational modeling to show that B cell affinity discrimination requires that kinetic proofreading predominate over serial engagement. We find that if BCR molecules become signaling-capable immediately upon binding antigen, the loss in serial engagement as affinity increases results in weaker signaling with increasing affinity. A threshold time for antigen to stay bound to BCR for several seconds before the latter becomes signaling-capable, similar to kinetic proofreading, is needed to overcome the loss in serial engagement due to increasing antigen affinity, and replicate the monotonic increase in B cell signaling with affinity observed in B cell activation experiments. This finding matches well with the experimentally observed time (~ 20 seconds) required for the BCR signaling domains to undergo antigen and lipid raft-mediated conformational changes that lead to Src-family kinase recruitment. We hypothesize that the physical basis of the threshold time of antigen binding may lie in the formation timescale of BCR dimers. The latter decreases with increasing affinity, resulting in shorter threshold antigen binding times as affinity increases. Such an affinity-dependent kinetic proofreading requirement results in affinity discrimination very similar to that observed in biological experiments. B cell affinity discrimination is critical to the process of affinity maturation and the production of high affinity antibodies, and thus our results here have important implications in applications such as vaccine design.

q-bio.CB↗

arXiv2011

Effective temperature of active complex matter

We use molecular dynamics simulations to study the dynamics of an ensemble of interacting self-propelled semi-flexible polymers in contact with a thermal bath. Our intention is to model complex systems of biological interest. We find that an effective temperature allows one to rationalize the out of equilibrium dynamics of the system. This parameter is measured in several independent ways -- from fluctuation-dissipation relations and by using tracer particles -- and they all yield equivalent results. The effective temperature takes a higher value than the temperature of the bath when the effect of the motors is not correlated with the structural rearrangements they induce. We show how to use this concept to interpret experimental results and suggest possible innovative research directions.

cond-mat.soft↗

arXiv2010

Measurement of phase synchrony of coupled segmentation clocks

The temporal behaviour of segmentation clock oscillations show phase synchrony via mean field like coupling of delta protein restricting to nearest neighbours only, in a configuration of cells arranged in a regular three dimensional array. We found the increase of amplitudes of oscillating dynamical variables of the cells as the activation rate of delta-notch signaling is increased, however, the frequencies of oscillations are decreased correspondingly. Our results show the phase transition from desynchronized to synchronized behaviour by identifying three regimes, namely, desynchronized, transition and synchronized regimes supported by various qualitative and quantitative measurements.

physics.comp-ph↗

arXiv2010

Intercellular synchronization of diffusively coupled astrocytes

We examine the synchrony of the dynamics of localized [Ca^{2+}]_i oscillations in internal pool of astrocytes via diffusing coupling of a network of such cells in a certain topology where cytosolic Ca^{2+} and inositol 1,4,5-triphosphate (IP3) are coupling molecules; and possible long range interaction among the cells. Our numerical results claim that the cells exhibit fairly well coordinated behaviour through this coupling mechanism. It is also seen in the results that as the number of coupling molecular species is increased, the rate of synchrony is also increased correspondingly. Apart from the topology of the cells taken, as the number of coupled cells around any one of the cells in the system is increased, the cell process information faster.

physics.comp-ph↗

arXiv2010

Dynamical quorum-sensing and synchronization of nonlinear oscillators coupled through an external medium

Many biological and physical systems exhibit population-density dependent transitions to synchronized oscillations in a process often termed "dynamical quorum sensing". Synchronization frequently arises through chemical communication via signaling molecules distributed through an external media. We study a simple theoretical model for dynamical quorum sensing: a heterogenous population of limit-cycle oscillators diffusively coupled through a common media. We show that this model exhibits a rich phase diagram with four qualitatively distinct mechanisms fueling population-dependent transitions to global oscillations, including a new type of transition we term "dynamic death". We derive a single pair of analytic equations that allows us to calculate all phase boundaries as a function of population density and show that the model reproduces many of the qualitative features of recent experiments of BZ catalytic particles as well as synthetically engineered bacteria.

q-bio.CB↗

arXiv2011

Competing HIV Strains and Immune System Response

We consider a simple deterministic model which describes an asymmetric competition between an immune system with a specific and powerful response, and a virus with a broad toxicity and fast mutations. Interest in this model relies on the fact that in spite of it simplicity, it reproduces some of the features of the asymptomatic phase of the infection by HIV-1. In particular, there is a domain of parameters in which the dynamics is characterized by the apparition of \blips", associated here to an instability which develops at high virus reproduction rate. Various possible extensions of this simple model are discussed, in particular in view of its applications in the context of HAART therapy.

q-bio.QM↗