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arXiv2012

A stochastic model for virus growth in a cell population

A stochastic model for the growth of a virus in a cell population is introduced. The virus has two ways of spreading: either by allowing its host cell to live on and duplicate, or else by multiplying in large numbers within the host cell such that the host cell finally bursts and the viruses then have the chance to enter new uninfected host cells. The model, and in particular the probability of the virus population surviving, is analyzed using the theory of Markov processes together with a coupling argument. Our analysis shows that the optimal strategy of the virus (in terms of survival) is obtained when the virus has no effect on the host cell's life-cycle, in agreement with experimental data about real viruses.

q-bio.CB↗

arXiv2011

Inducing phase-locking and chaos in cellular oscillators by modulating the driving stimuli

Inflammatory responses in eucaryotic cells are often associated with oscillations in the nuclear-cytoplasmic translocation of the transcription factor NF-kB. In most laboratory realizations, the oscillations are triggered by a cytokine stimulus, like the tumor necrosis factor alpha, applied as a step change to a steady level. Here we use a mathematical model to show that an oscillatory external stimulus can synchronize the NF-kB oscillations into states where the ratios of the internal to external frequency are close to rational numbers. We predict a specific response diagram of the TNF-driven NF-kB system which exhibits bands of synchronization known as "Arnold tongues". Our model also suggests that when the amplitude of the external stimulus exceeds a certain threshold there is the possibility of coexistence of multiple different synchronized states and eventually chaotic dynamics of the nuclear NF-kB concentration. This could be used as a way of externally controlling immune response, DNA repair and apoptotic pathways.

physics.bio-ph↗

arXiv2012

Symmetrical charge-charge interactions in ionic solutions: implications for biological interactions

As is well known in electrolyte theory, electrostatic fields are attenuated by the presence of mobile charges in the solution. This seems to limit the possibility of an electrostatic repulsion model of biological interactions such as cell division. Here, a system of two charges in an ionic solution is considered. It is found that in the context of the symmetries of the system, the electrostatic repulsion between the two is considerably increased as compared to the electrostatic repulsion between two bare charges in a dielectric. This increase in repulsion, directly resulting from interactions between the symmetrical parts of the system, was found to be dependent on the magnitude of the charges and the separation between them. It was also found that this increases reaches a steady state for separation greater than a solvent determined length scale related to the Debye length. These findings strongly suggest that electrostatic interactions can play a crucial part in the physical forces that are involved in biological interactions.

physics.bio-ph↗

arXiv2012

Finite Volume Model to Study the Effect of ER flux on Cytosolic Calcium Distribution in Astrocytes

Most of the intra-cellular events involved in the initiation and propagation phases of this process has now been identified astrocytes. The control of the spread of intracellular calcium signaling has been demonstrated to occur at several levels including IP3 receptors, intracellular Ca2+ stores like endoplasmic reticulum (ER) . In normal and pathological situations that affect one or several of these steps can be predicted to influence on astrocytic calcium waves. In view of above a mathematical model is developed to study interdependence of all the important parameters like diffusion coefficient and influx over [Ca2+] profile. Model incorporates the ER fluxes like, leak Pump Chan J J andJ . Finite volume method is employed to solve the problem. A program has been developed using in MATLAB 7.5 for the entire problem and simulated on an AMD-Turion 32-bite machine to compute the numerical results. In view of above a mathematical model is developed to study calcium transport between cytosol and ER.

q-bio.CB↗

arXiv2012

Mechanobiological regulation of bone remodeling -- Theoretical development of a coupled systems biology-micromechanical approach

Bone remodeling involves the coordinated removal of bone by osteoclasts and addition of bone by osteoblasts, a process that is modulated by the prevailing mechanical environment. In this paper a fully coupled model of bone remodeling is developed, based on coupling a bone cell population model with a micromechanical homogenization scheme of bone stiffness. While the former model considers biochemical regulatory mechanisms between bone cells such as the RANK-RANKL-OPG pathway and action of TGF-β, the latter model allows for accurate upscaling of the mechanical properties of bone. Importantly, we consider bone remodeling as being controlled proportionally to the microscopic strain energy density, on the observation scale where the sensing of the mechanical loading takes place, estimated by means of continuum micromechanics-based strain concentration. This approach allows to address two fundamental questions of bone biology: (i) How do biochemical changes influence bone remodeling and so affect the composition and mechanical properties of bone? and (ii) What mechanisms are responsible for mechanoregulation of bone remodeling? Numerical studies highlight the conceptual advantage of this new approach compared to conventional phenomenological models. It is demonstrated that the proposed model is able to simulate changes of the bone constituent volume fractions that are in qualitative agreement with experimental observations for osteoporotic and disuse syndromes.

q-bio.TO↗

arXiv2012

Bridging the gap between the micro- and the macro-world of tumors

At present it is still quite difficult to match the vast knowledge on the behavior of individual tumor cells with macroscopic measurements on clinical tumors. On the modeling side, we already know how to deal with many molecular pathways and cellular events, using systems of differential equations and other modeling tools, and ideally, we should be able to extend such a mathematical description up to the level of large tumor masses. An extended model should thus help us forecast the behavior of large tumors from our basic knowledge of microscopic processes. Unfortunately, the complexity of these processes makes it very difficult -- probably impossible -- to develop comprehensive analytical models. We try to bridge the gap with a simulation program which is based on basic biochemical and biophysical processes -- thereby building an effective computational model -- and in this paper we describe its structure, endeavoring to make the description sufficiently detailed and yet understandable.

q-bio.TO↗

arXiv2012

Model of pathogenesis of psoriasis. Part 2. Local processes

Analytical research of results of experimental and theoretical studies on pathogenesis of psoriatic disease is carried out. The new model of pathogenesis - skin reaction to systemic psoriatic process SPP is formulated. ... Psoriatic inflammation is regarded as a reaction of the skin immune system to activity of Mo-R and DC-R involved in derma from blood flow. They contain Y-antigen and, getting to derma, can be transformed in mature maDC-Y and present this antigen to Y-specific T-lymphocytes as well as activate them. Y-antigen is a part of the interpeptide bridge IB-Y. Therefore, the skin immune system can incorrectly interpret Y-antigen presentation as a sign of external PsB-infection and switch one of mechanisms of protection against bacterial infection - epidermal hyperproliferation. Psoriatic plaque can be initiated only during action of local inflammatory process LP2 in derma causing not only innate, but also adaptive response. In particular, it is possible at LP2(IN) - open trauma of derma or at LP2(HPV) - HPV-carriage of keratinocytes. The level of Y-priming (presence and concentration of Y-specific T-lymphocytes in prepsoriatic derma and in lymph nodes) also determines possibility of psoriatic plaque initiation. Existence and severity of psoriatic plaque is determined by intensity of Y-antigen income into derma (inside Mo-R and DC-R). ... Severity of plaque is aggravated by LP2-inflammation if it persists after this plaque initiation. New Mo-T, DC-T (incl. Mo-R, DC-R) and Y-specific T-lymphocytes are constantly attracted into plaques from blood flow, and so support vicious cycles. Only at decrease of SPP severity, these vicious cycles weaken and natural remission of plaques takes place, up to their complete disappearance. The detailed analysis comparing the new model of pathogenesis with five other previously published models is carried out. Part 1. arXiv:1110.0584

q-bio.CB↗

arXiv2012

Immunity to Plasmodium knowlesi H strain malaria in olive baboons

Malaria disease is a major global health and economic development threat. It results in approximately 2.7 million deaths annually. There is currently no vaccine that has been licensed for use against malaria. Studies in animal models, especially non-human primates can lead to the revelation of possible immunological mechanisms that can lead to protection or predisposition of the host to malaria. Plasmodium knowlesi, a simian and human malaria parasite, is an attractive experimental parasite for malaria research since it can infect olive baboons (Papio anubis), non-human primates that have similar host-pathogen interactions to humans. This study was carried out to determine host immunological profiles provoked in olive baboons during the course of an infection with Plasmodium knowlesi. A total of eight adult baboons were intravenously inoculated with overnight cultured blood stage P. knowlesi H strain parasites. Five of these baboons became acutely infected while the other three became chronically infected. The immunological basis of this dual outcome of the infection was determined by measuring circulating cytokine (T helper 1 and T helper 2) and antibody (immunoglobulin G and immunoglobulin M) responses elicited in the infected baboons on a weekly basis by Enzyme Linked Immunosorbent Assay (ELISA) for up to six weeks post infection. Generated data for the first time indicated that acute P. knowlesi malaria is accompanied by increased concentrations of interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha) and IL 6 and reduced levels of circulating interleukin 10 (IL 10), IL 4, IL 12, immunoglobulin G (IgG) and IgM in the baboon host. These results are largely agreeable with data from human studies, thereby increasing the relevance of the olive baboon - P. knowlesi experimental infection system for future malaria studies.

q-bio.CB↗

arXiv2013

Effects of electropermeabilization and gene electrotransfert on the lateral mobility of a GPi anchored protein

Electropermeabilization is a method by which molecules can be introduced in living cells through the plasma membrane. Here, we show that electropermeabilization affects the lateral mobility of Rae-1, a GPi anchored protein. Our results shows that 10 to 20 % of the membrane surface is occupied by defaults or pores. Gene electrotransfert also affects the lateral mobility of Rae-1. Furthermore, we clearly show that once inserted into the plasma membrane, DNA totaly excludes Rae-1, indicating that DNA molecules are tightly packed together to forms huge aggregates.

q-bio.BM↗

arXiv2012

Formation of BCR Oligomers Provides a Mechanism for B cell Affinity Discrimination

B cells encounter antigen over a wide affinity range. The strength of B cell signaling in response to antigen increases with affinity, a process known as "affinity discrimination". In this work, we use a computational simulation of B cell surface dynamics and signaling to show that affinity discrimination can arise from the formation of BCR oligomers. It is known that BCRs form oligomers upon encountering antigen, and that the size and rate of formation of these oligomers increase with affinity. In our simulation, we have introduced a requirement that only BCR-antigen complexes that are part of an oligomer can engage cytoplasmic signaling molecules such as Src-family kinases. Our simulation shows that as affinity increases, not only does the number of collected antigen increases, but so does signaling activity. Our results are also consistent with the existence of an experimentally-observed threshold affinity of activation (no signaling activity below this affinity value) and affinity discrimination ceiling (no affinity discrimination above this affinity value). Comparison with experiments shows that the time scale of dimer formation predicted by our model (less than 10 s) is well within the time scale of experimentally observed association of BCR with Src-family kinases (10-20 s).

q-bio.CB↗

arXiv2012

Human sperm cells swimming in micro-channels

The migratory abilities of motile human spermatozoa in vivo are essential for natural fertility, but it remains a mystery what properties distinguish the tens of cells which find an egg from the millions of cells ejaculated. To reach the site of fertilization, sperm must traverse narrow and convoluted channels, filled with viscous fluids. To elucidate individual and group behaviors that may occur in the complex three-dimensional female tract environment, we examine the behavior of migrating sperm in assorted micro-channel geometries. Cells rarely swim in the central part of the channel cross-section, instead traveling along the intersection of the channel walls (`channel corners'). When the channel turns sharply, cells leave the corner, continuing ahead until hitting the opposite wall of the channel, with a distribution of departure angles, the latter being modulated by fluid viscosity. If the channel bend is smooth, cells depart from the inner wall when the curvature radius is less than a threshold value close to 150 micron. Specific wall shapes are able to preferentially direct motile cells. As a consequence of swimming along the corners, the domain occupied by cells becomes essentially 1-dimensional. This leads to frequent collisions and needs to be accounted for when modeling the behavior of populations of migratory cells and considering how sperm populate and navigate the female tract. The combined effect of viscosity and three-dimensional architecture should be accounted for in future in vitro studies of sperm chemoattraction.

physics.bio-ph↗

arXiv2012

Fixed-points in Random Boolean Networks: The impact of parallelism in the scale-free topology case

Fixed points are fundamental states in any dynamical system. In the case of gene regulatory networks (GRNs) they correspond to stable genes profiles associated to the various cell types. We use Kauffman's approach to model GRNs with random Boolean networks (RBNs). We start this paper by proving that, if we fix the values of the source nodes (nodes with in-degree 0), the expected number of fixed points of any RBN is one (independently of the topology we choose). For finding such fixed points we use the α-asynchronous dynamics (where every node is updated independently with probability 0 < α < 1). In fact, it is well-known that asynchrony avoids the cycle attractors into which parallel dynamics tends to fall. We perform simulations and we show the remarkable property that, if for a given RBN with scale-free topology and α-asynchronous dynamics an initial configuration reaches a fixed point, then every configuration also reaches a fixed point. By contrast, in the parallel regime, the percentage of initial configurations reaching a fixed point (for the same networks) is dramatically smaller. We contrast the results of the simulations on scale-free networks with the classical Erdos-Renyi model of random networks. Everything indicates that scale-free networks are extremely robust. Finally, we study the mean and maximum time/work needed to reach a fixed point when starting from randomly chosen initial configurations.

q-bio.CB↗

arXiv2012

A Unified Term for Directed and Undirected Motility in Collective Cell Invasion

In this paper we develop mathematical models for collective cell motility. Initially we develop a model using a linear diffusion-advection type equation and fit the parameters to data from cell motility assays. This approach is helpful in classifying the results of cell motility assay experiments. In particular, this model can determine degrees of directed versus undirected collective cell motility. Next we develop a model using a nonlinear diffusion term that is able capture in a unified way directed and undirected collective cell motility. Finally we apply the nonlinear diffusion approach to a problem in tumor cell invasion, noting that neither chemotaxis or haptotaxis are present in the system under consideration in this article.

q-bio.CB↗

arXiv2012

Routing Physarum with electrical flow/current

Plasmodium stage of Physarum polycephalum behaves as a distributed dynamical pattern formation mechanism who's foraging and migration is influenced by local stimuli from a wide range of attractants and repellents. Complex protoplasmic tube network structures are formed as a result, which serve as efficient `circuits' by which nutrients are distributed to all parts of the organism. We investigate whether this `bottom-up' circuit routing method may be harnessed in a controllable manner as a possible alternative to conventional template-based circuit design. We interfaced the plasmodium of Physarum polycephalum to the planar surface of the spatially represented computing device, (Mills' Extended Analog Computer, or EAC), implemented as a sheet of analog computing material whose behaviour is input and read by a regular 5x5 array of electrodes. We presented a pattern of current distribution to the array and found that we were able to select the directional migration of the plasmodium growth front by exploiting plasmodium electro-taxis towards current sinks. We utilised this directional guidance phenomenon to route the plasmodium across its habitat and were able to guide the migration around obstacles represented by repellent current sources. We replicated these findings in a collective particle model of Physarum polycephalum which suggests further methods to orient, route, confine and release the plasmodium using spatial patterns of current sources and sinks. These findings demonstrate proof of concept in the low-level dynamical routing for biologically implemented circuit design.

physics.bio-ph↗

arXiv2012

Plasmodium knowlesi H strain pregnancy malaria immune responses in olive baboons (Papio anubis)

Approximately 24 million pregnant women in Sub-Saharan Africa are at risk of suffering from pregnancy malaria complications. Mechanisms responsible for increased susceptibility to malaria in pregnant women are not fully understood. Baboons are susceptible to Plasmodium knowlesi and their reproductive physiology and host pathogen interactions are similar to those in humans, making them attractive for development as a model for studying mechanisms underlying pregnancy malaria. This study exploited the susceptibility of baboons to Plasmodium knowlesi infection to characterize cytokine and peripheral blood mononuclear cell recall proliferation responses underlying the pathogenesis of pregnancy malaria in baboons infected with Plasmodium knowlesi. The pregnancies of three time mated adult female baboons and their gestational levels were confirmed by ultrasonography. On the 150th day of gestation, the pregnant baboons together with four non pregnant controls were infected with Plasmodium knowlesi H strain parasites. Collection of peripheral sera, and mononuclear cells was then done on a weekly basis. Sera cytokine concentrations were measured by Enzyme Linked Immunosorbent Assay (ELISA) using respective enzyme conjugated antibodies. Peripheral blood mononuclear cell recall proliferation assays were also done on a weekly basis. Results indicate that pregnancy malaria in this model is associated with suppression of interferon gamma and interleukin 6 (IL-6) responses. Tumour necrosis factor alpha responses were upregulated while IL-4, IL-12 and recall proliferation responses were not different from controls. These data to a great extent are consistent with some findings from human studies, showing the feasibility of this model for studying mechanisms underlying pregnancy malaria.

q-bio.CB↗

arXiv2012

Characterisation of placental malaria in olive baboons (Papio anubis) infected with Plasmodium knowlesi H strain

Pregnant women have increased susceptibility to malaria infection. In these women, malaria parasites are frequently found sequestered in the placental intervillous spaces, a condition referred to as placental malaria (PM). Placental malaria threatens the health of the mother and the child's life by causing still births and reduction in gestational age. An estimated 24 million pregnant women in Sub-Saharan Africa are at risk. Mechanisms responsible for increased susceptibility in pregnant women are not fully understood. Pregnancy malaria studies have been limited by the lack of a suitable animal model. This research aimed to develop a baboon (Papio anubis) model for studying PM. The pregnancies of three adult female baboons were synchronized and their gestational levels confirmed by ultrasonography. On the 150th day of gestation the pregnant baboons were infected with Plasmodium knowlesi H strain parasites together with four nulligravid control baboons. Parasitaemia was monitored from two days post inoculation until the 159th day of gestation when caesarean section was done on one baboon in order to obtain the placenta. Two baboons aborted their conceptus. Smears prepared from placental blood demonstrated the presence of Plasmodium knowlesi parasites in all the three sampled placentas. These new findings show that P. knowlesi sequesters in the baboon placenta. In addition, this study has characterized haemoglobin, eosinophil, Immunoglobulin G and Immunoglobulin M profiles in this model. Thus a non human primate (baboon) model for studying PM has been established. The established baboon - P. knowlesi model for studying human placental/pregnancy malaria now offers an opportunity for circumventing the obstacles experienced during human studies like having inadequate tissue for analysis, inaccurate estimation of gestational age, moral, ethical and financial limitations.

q-bio.CB↗

arXiv2012

Modelling of light driven CO2 concentration gradient and photosynthetic carbon assimilation flux distribution at the chloroplast level

The steady state of the two-substance model of light driven carbon turnover for the photosynthetic CO2 assimilation rate is presented. The model is based on the nonlinear diffusion equation for a single chloroplast in the elliptical geometry by assuming light driven Ribulose-1,5-bisphosphate (RuBP) regeneration and CO2 assimilation reaction of carboxilation coupled with the photosynthetic sink strength. The detailed analysis of 3 -dimensional CO2 concentration and flux on the chloroplast level is made. It is shown that under intense light irradiation there exists a boundary layer of chloroplasts with a high value of CO2 assimilation flux. The presented simplified model can be used for the calculations and experimental estimations of the CO2 assimilation rate for environmental applications.

q-bio.CB↗

arXiv2012

The receptor-toxin-antibody interaction: Mathematical model and numerical simulation

A reaction-diffusion model of receptor-toxin-antibody (RTA) interaction is studied numerically. The protective properties of an antibody against a given toxin are evaluated for a spherical cell placed into a toxin-antibody solution. The selection of parameters for numerical simulation approximately corresponds to the practically relevant values reported in the literature (ricin and monoclonal antibody 2B11) with the significant ranges in variation to allow demonstration of different regimes of intracellular transport. The proposed refinement of the RTA model may become important for the consistent evaluation of protective potential of an antibody and for the estimation of the time period during which the application of this antibody becomes the most effective. It can be a useful tool for in vitro selection of potential protective antibodies for progression to in vivo evaluation.

q-bio.CB↗