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arXiv2011

Comparing System Dynamics and Agent-Based Simulation for Tumour Growth and its Interactions with Effector Cells

There is little research concerning comparisons and combination of System Dynamics Simulation (SDS) and Agent Based Simulation (ABS). ABS is a paradigm used in many levels of abstraction, including those levels covered by SDS. We believe that the establishment of frameworks for the choice between these two simulation approaches would contribute to the simulation research. Hence, our work aims for the establishment of directions for the choice between SDS and ABS approaches for immune system-related problems. Previously, we compared the use of ABS and SDS for modelling agents' behaviour in an environment with nomovement or interactions between these agents. We concluded that for these types of agents it is preferable to use SDS, as it takes up less computational resources and produces the same results as those obtained by the ABS model. In order to move this research forward, our next research question is: if we introduce interactions between these agents will SDS still be the most appropriate paradigm to be used? To answer this question for immune system simulation problems, we will use, as case studies, models involving interactions between tumour cells and immune effector cells. Experiments show that there are cases where SDS and ABS can not be used interchangeably, and therefore, their comparison is not straightforward.

cs.CE↗

arXiv2011

Collective Cell Migration: Leadership, Invasion and Segregation

A number of biological processes, such as embryo development, cancer metastasis or wound healing, rely on cells moving in concert. The mechanisms leading to the emergence of coordinated motion remain however largely unexplored. Although biomolecular signalling is known to be involved in most occurrences of collective migration, the role of physical and mechanical interactions has only been recently investigated. In this paper, a versatile framework for cell motility is implemented in-silico in order to study the minimal requirements for the coordination of a group of epithelial cells. We find that cell motility and cell-cell mechanical interactions are sufficient to generate a broad array of behaviours commonly observed in vitro and in vivo. Cell streaming, sheet migration and susceptibility to leader cells are examples of behaviours spontaneously emerging from these simple assumptions, which might explain why collective effects are so ubiquitous in nature. This analysis provides also new insights into cancer metastasis and cell sorting, suggesting in particular that collective invasion might result from an emerging coordination in a system where single cells are mechanically unable to invade.

q-bio.CB↗

arXiv2011

Collective mechanics of embryogenesis: Formation of ventral furrow in Drosophila

We propose a 2D mechanical model of the ventral furrow formation in Drosophila that is based on undifferentiated epithelial cells of identical properties whose energy resides in their membrane. Depending on the relative tensions of the apical, basal, and lateral sides, the minimal-energy states of the embryo cross-section includes circular, elliptical, biconcave, and buckled furrow shapes. We discuss the possible shape transformation consistent with reported experimental observations, arguing that generic collective mechanics may play an important role in the embryonic development in Drosophila.

q-bio.CB↗

arXiv2011

Reaction-Diffusion-Delay Model for EPO/TNF-$α$? Interaction in Articular Cartilage Lesion Abatement

Injuries to articular cartilage result in the development of lesions that form on the surface of the cartilage. Such lesions are associated with articular cartilage degeneration and osteoarthritis. The typical injury response often causes collateral damage, primarily an effect of inflammation, which results in the spread of lesions beyond the region where the initial injury occurs. We present a minimal mathematical model based on known mechanisms to investigate the spread and abatement of such lesions. In particular we represent the "balancing act" between pro-inflammatory and anti-inflammatory cytokines that is hypothesized to be a principal mechanism in the expansion properties of cartilage damage during the typical injury response. We present preliminary results of in vitro studies that confirm the anti-inflammatory activities of the cytokine erythropoietin (EPO). We assume that the diffusion of cytokines determine the spatial behaviour of injury response and lesion expansion so that a reaction-diffusion system involving chemical species and chondrocyte cell state population densities is a natural way to represent cartilage injury response. We present computational results using the mathematical model showing that our representation is successful in capturing much of the interesting spatial behaviour of injury associated lesion development and abatement in articular cartilage. Further, we discuss the use of this model to study the possibility of using EPO as a therapy for reducing the amount of inflammation induced collateral damage to cartilage during the typical injury response. The mathematical model presented herein suggests that not only are anti-inflammatory cytokines, such as EPO necessary to prevent chondrocytes signaled by pro-inflammatory cytokines from entering apoptosis, they may also influence how chondrocytes respond to signaling by pro-inflammatory cytokines.

q-bio.TO↗

arXiv2012

An analysis of overall network architecture reveals an infinite-period bifurcation underlying oscillation arrest in the segmentation clock

Unveiling the mechanisms through which the somitogenesis regulatory network exerts spatiotemporal control of the somitic patterning has required a combination of experimental and mathematical modeling strategies. Significant progress has been made for the zebrafish clockwork. However, due to its complexity, the clockwork of the amniote segmentation regulatory network has not been fully elucidated. Here, we address the question of how oscillations are arrested in the amniote segmentation clock. We do this by constructing a minimal model of the regulatory network, which privileges architectural information over molecular details. With a suitable choice of parameters, our model is able to reproduce the oscillatory behavior of the Wnt, Notch and FGF signaling pathways in presomitic mesoderm (PSM) cells. By introducing positional information via a single Wnt3a gradient, we show that oscillations are arrested following an infinite-period bifurcation. Notably: the oscillations increase their amplitude as cells approach the anterior PSM and remain in an upregulated state when arrested; the transition from the oscillatory regime to the upregulated state exhibits hysteresis; and an opposing distribution of the Fgf8 and RA gradients in the PSM arises naturally in our simulations. We hypothesize that the interaction between a limit cycle (originated by the Notch delayed-negative feedback loop) and a bistable switch (originated by the Wnt-Notch positive cross-regulation) is responsible for the observed segmentation patterning. Our results agree with previously unexplained experimental observations and suggest a simple plausible mechanism for spatiotemporal control of somitogenesis in amniotes.

q-bio.CB↗

arXiv2012

Two models of protoplasm microstructure of the living cell in resting state

In order to develop the methods of thermodynamic analysis for the living cell, two models of protoplasm microstructure of the living cell in resting state were suggested. Both models are based on the assumption that the Ling's cell as a statistical mechanics system is non-ergodic. In the first, Van der Waals model, the protein-protein interactions, which form the physical basis for the cell functioning, are considered as a interactions of key importance. It is postulated that protein molecules are situated in points of some space lattice (the Ling model of a cell) they assemble to aggregates at equilibrium state, corresponding to the dead protoplasm. In the second model we consider protein conformation at the resting state and conformation changes while the cell is passing from the resting state to the equilibrium state (dead protoplasm). The investigation of the models and comparison of their characteristics showed that the convenient tool to define the energy minimum of the system under consideration is a Hamiltonian describing the superfluid Bose gas on protein configuration space. Our approach allows us to define the thermodynamic features of the living (at resting state) and dead protoplasm in a new way: in the first case the system is characterized by the unfolded state of proteins, in the second case proteins are folded and aggregated. Obtained results prove the applicability of our approaches for thermodynamic characteristics of the Ling model of a cell.

cond-mat.stat-mech↗

arXiv2011

Growth of bioluminescent bacteria under modelled gravity of different astronomical bodies in the Solar system

Spaceflights and clinostats have been used extensively to study the effects of microgravity on various biological systems ranging from microbes to plants. Similarly hypergravity studies have been carried out using centrifuges where growth retardation has been observed. However, no studies have been carried out yet on how the gravity of astronomical bodies, e.g. Moon having 1/6th the gravity of Earth, affects biological systems. Such studies are important with missions to Moon and Mars to be carried out in future. Also, a comparative study to see the effects of gravity that exists on astronomical bodies such as Moon, Mars and Jupiter on any organism using simulation have not been reported so far. This paper discusses the effects of modelled gravity on the growth of Vibrio harveyi using the clinostat-centrifuge system designed and developed in-house. Results showed that though growth as measured by optical density was significantly higher for simulated microgravity and lunar and Martian gravities, there was no significant difference in viable counts. This is because the relative death rate is also higher for these gravities. Jovian gravity was found to slightly retard the growth. This study also shows that simulated lunar gravity is relatively most suited for the growth of Vibrio harveyi.

physics.bio-ph↗

arXiv2012

Model of pathogenesis of psoriasis. Part 1. Systemic psoriatic process

Analytical study of results of experimental and theoretical works on pathogenesis of psoriatic disease was conducted. Psoriasis is dermal implication of systemic psoriatic process (SPP). New SPP model explaining results of clinical and laboratory experiments was formulated. According to Y-model there are two main factors: hyperpermeability of small intestine for bacterial products and colonization of its walls by Gram+ bacteria (incl. psoriagenic bacteria PsB) and Gram(-) TLR4-active bacteria. Inside SPP there is a vicious cycle which is supported by disturbance of production and-or circulation of bile acids. SPP central subprocess is PAMP-nemia, namely chronic kPAMP-load on blood phagocytes (neutrophiles, monocytes and dendritic cells). The load results in increase of blood kPAMP level. The major key PAMP (kPAMP) are LPS and PG (incl. PG-Y - peptidoglycan of psoriagenic bacteria). Chronically increased kPAMP-load possibly provides tolerization of some neutrophils Neu, monocytes Mo and dendritic cells DC in blood flow. The chemostatus of tolerized blood Neu-T in process of their aging changes similarly to chemostatus nonactivated Neu and, hence, they carry endocytosed content from blood flow into the bone marrow. Chemostatuses of tolerized Mo-T and DC-T are similar to nonactivated ones. So they don't bring endocytosed content to lymph nodes or spleen and remain in blood. Tolerized phagocytes degrade endocytosed fragments of bacterial products containing kPAMP slowly and incompletely, Tolerized phagocytes appeared to be (PG-Y)-carriers are named by R-phagocytes and are designated as Neu-R, Mo-R and DC-R. SPP severity predetermines possibility of psoriasis initialization and maintenance because Mo-R and DC-R along with normal Mo and DC participate in homeostatic and inflammatory renewal of pool of dermal macrophages and DC of non-resident origin. Part 2 - arXiv:1201.2900

q-bio.TO↗

arXiv2011

Prospects of using Antagonist Histamine H2-Receptor (Cimetidinum) as Adjuvant for Melanoma Biotherapy Treatment

Improvement of anti-tumor biotherapy effectiveness by modification of immune response with histamine H2 receptor Cimetidinum (CM) was studied using the experimental murine model of B16 F10 melanoma in vivo. It is shown that skin melanoma biotherapy by antitumor whole-cell GM-CSF-producing vaccine with the addition of CM (in dose of 25 mg/kg, daily for 5 days) increases preventive effects of vaccination. 33 % of mice did not have tumor growth within 60 days of observation. Average life span of animals exceeded those of the control group up to 68 %. Using CM-combined bio-chemotherapy doesn't improve therapeutic effect, however in the case of a monotherapeutic approach tendency for increased average life-time and decreased metastatic processes in mice with the developed tumors was noticed. Aquired data provides expediency to study the further application of CM as adjuvant for skin melanoma vaccinotherapy, and also the necessity to verify the immune status of an organism against the complex bio-chemotherapy.

q-bio.TO↗

arXiv2011

Dependence of MAPK mediated signaling on Erk isoforms and differences in nuclear shuttling

The mitogen activated protein kinase (MAPK) family of proteins is involved in regulating cellular fate activities such as proliferation, differentiation and apoptosis. Their fundamental importance has attracted considerable attention on different aspects of the MAPK signaling dynamics; this is particularly true for the Erk/Mek system, which has become the canonical example for MAPK signaling systems. Erk exists in many different isoforms, of which the most widely studied are Erk1 and Erk2. Until recently, these two kinases were considered equivalent as they differ only subtly at the sequence level; however, these isoforms exhibit radically different trafficking between cytoplasm and nucleus. Here we use spatially resolved data on Erk1/2 to develop and analyze spatio-temporal models of these cascades; and we discuss how sensitivity analysis can be used to discriminate between mechanisms. We are especially interested in understanding why two such similar proteins should co-exist in the same organism, as their functional roles appear to be different. Our models elucidate some of the factors governing the interplay between processes and the Erk1/2 localization in different cellular compartments, including competition between isoforms. This methodology is applicable to a wide range of systems, such as activation cascades, where translocation of species occurs via signal pathways. Furthermore, our work may motivate additional emphasis for considering potentially different roles for isoforms that differ subtly at the sequence level.

q-bio.CB↗

arXiv2011

About the Neuronal Mechanism of Lateral Hypothalamic Self-Stimulation Response

The experimental part of this study has shown that hunger motivation may be evoked by a long-term (10=180 s) continuous electrical stimulation of the "hunger center" at a current of 133.6{\pm}8.1 mkA. Positive emotions were caused by electrostimulation at the same current intensity but short-term duration (0.3-0.5 s). A positive feeling elicited by electrostimulation of the motivation center can be explained in terms of the adaptation (polarization) theory of motivation and emotion (Murik, 2001, 2005).

q-bio.NC↗

arXiv2011

Phenomenological understanding of aggregation and dispersion of chemotactic cells

We present a simple model that describes the motion of a single chemotactic cell exposed to a traveling wave of the chemoattractant. The model incorporates two types of responses to stimulation by the chemoattractant, i.e., change in polarity and change in motility of the cell. The periodic change in motility is assumed to be induced by the periodic stimulation by the chemoattractant on the basis of previous observations. Consequently, net migration of the cell occurs in a particular direction with respect to wave propagation, which explains the migration of Dictyostelium cells in aggregation processes. The difference between two time delays from the stimulation to the two responses and the wave frequency determined by the frequency of the secretion of the chemoattractant are important parameters that determine the direction of migration and the effective interaction between cells in a population. This result explains the dispersed state of a population of vegetative cells and cells in preaggregation without the assumption of a chemorepellent, and also explains the commencement of the aggregation. The result is extended to a general fact as follows: the temporal oscillation of the magnitude of the random motion for gradient-sensing particles induces spontaneous movement, even when the particles are exposed to a periodic wave of the chemoattractant, which results in the aggregation or dispersion of the particles communicating via their attractant.

physics.bio-ph↗

arXiv2012

A chemotactic model for interaction of antagonistic microflora colonies: front asymptotics and numerical simulations

This paper studies a two-dimensional chemotactic model for two species in which one of them produces a chemo-repellent for the other. It is shown asymptotically and numerically how the chemical inhibits the invasion of a moving front for the second species and how stable steady states, which depend on the chemical concentration, can be reached. The results qualitatively explain experimental observations by Swain and Ray (Microbiol. Res. 164(2), 2009), where colonies of bacteria produce metabolite agents which prevent the invasion of fungi.

math.AP↗

arXiv2011

Cancer Networks: A general theoretical and computational framework for understanding cancer

We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of the architecture and function of developmental control networks which guide the formation of multicellular organisms. Cancer networks are special cases of developmental control networks. Cancer results from transformations of normal developmental networks. Our theory generates a natural classification of all possible cancers based on their network architecture. Each cancer network has a unique topology and semantics and developmental dynamics that result in distinct clinical tumor phenotypes. We apply this new theory with a series of proof of concept cases for all the basic cancer types. These cases have been computationally modeled, their behavior simulated and mathematically described using a multicellular systems biology approach. There are fascinating correspondences between the dynamic developmental phenotype of computationally modeled {\em in silico} cancers and natural {\em in vivo} cancers. The theory lays the foundation for a new research paradigm for understanding and investigating cancer. The theory of cancer networks implies that new diagnostic methods and new treatments to cure cancer will become possible.

q-bio.MN↗

arXiv2012

Thermodynamics of pharmacological action for electron-accepting compounds on activated or damaged cell in the context of Ling's model of the living cell

The theory describing action of medicines explored in this paper is based on assumption that vital activity of the cell may be described in terms of the model of two states: resting state and excitation. According to available physiological data excitation state is dangerous for cell and may cause different pathological changes, including "conformational" diseases, due to protein aggregation. Normally, the excitation is completely reversible and the key role is played here by ATP (adenosine-5'-triphosphate) which disaggregates proteins of cytomatrix. The same effect ATP exerts during cell injury by eliciting a "healing" effect. Damage of cell structures we consider as "illness", whereas removal of pathological consequences caused by protein aggregation of any origin we will call "a cure". The latter is considered as physical process of cell recovering from excitation/injury to resting state, which is analyzed in terms of our generalized thermodynamics. "Cure" results in reduction of effective temperature of cell proteins due to binding intracellular water which is present in the cell at concentration of approximately 44 M. As a result of the sorption processes mobility of both water and proteins is greatly reduced, and the corresponding reduction of the effective temperature seen by us as a measure of treatment effect.

physics.bio-ph↗

arXiv2013

Ag-dependent (in silico) approach implies a deterministic kinetics for homeostatic memory cell turnover

Verhulst-like mathematical modeling has been used to investigate several complex biological issues, such as immune memory equilibrium and cell-mediated immunity in mammals. The regulation mechanisms of both these processes are still not sufficiently understood. In a recent paper, Choo et al. [J. Immunol., v. 185, pp. 3436-44, 2010], used an Ag-independent approach to quantitatively analyze memory cell turnover from some empirical data, and concluded that immune homeostasis behaves stochastically, rather than deterministically. In the paper here presented, we use an in silico Ag-dependent approach to simulate the process of antigenic mutation and study its implications for memory dynamics. Our results have suggested a deterministic kinetics for homeostatic equilibrium, what contradicts the Choo et al. findings. Accordingly, our calculations are an indication that a more extensive empirical protocol for studying the homeostatic turnover should be considered.

q-bio.CB↗

arXiv2011

Measuring the viscous and elastic properties of single cells using video particle tracking microrheology

We present a simple and \emph{non-invasive} experimental procedure to measure the linear viscoelastic properties of cells by passive video particle tracking microrheology. In order to do this, a generalised Langevin equation is adopted to relate the time-dependent thermal fluctuations of a bead, chemically bound to the cell's \emph{exterior}, to the frequency-dependent viscoelastic moduli of the cell. It is shown that these moduli are related to the cell's cytoskeletal structure, which in this work is changed by varying the solution osmolarity from iso- to hypo-osmotic conditions. At high frequencies, the viscoelastic moduli frequency dependence changes from $\propto ω^{3/4}$ found in iso-osmotic solutions to $\propto ω^{1/2}$ in hypo--osmotic solutions; the first situation is typical of bending modes in isotropic \textit{in vitro} reconstituted F--actin networks, and the second could indicate that the restructured cytoskeleton behaves as a gel with "\textit{dangling branches}". The insights gained from this form of rheological analysis could prove to be a valuable addition to studies that address cellular physiology and pathology.

physics.bio-ph↗

arXiv2011

The stochastic evolution of a protocell. The Gillespie algorithm in a dynamically varying volume

In the present paper we propose an improvement of the Gillespie algorithm allowing us to study the time evolution of an ensemble of chemical reactions occurring in a varying volume, whose growth is directly related to the amount of some specific molecules, belonging to the reactions set. This allows us to study the stochastic evolution of a protocell, whose volume increases because of the production of container molecules. Several protocells models are considered and compared with the deterministic models.

physics.bio-ph↗