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arXiv2015

Tiling solutions for optimal biological sensing

Biological systems, from cells to organisms, must respond to the ever changing environment in order to survive and function. This is not a simple task given the often random nature of the signals they receive, as well as the intrinsically stochastic, many body and often self-organized nature of the processes that control their sensing and response and limited resources. Despite a wide range of scales and functions that can be observed in the living world, some common principles that govern the behavior of biological systems emerge. Here I review two examples of very different biological problems: information transmission in gene regulatory networks and diversity of adaptive immune receptor repertoires that protect us from pathogens. I discuss the trade-offs that physical laws impose on these systems and show that the optimal designs of both immune repertoires and gene regulatory networks display similar discrete tiling structures. These solutions rely on locally non-overlapping placements of the responding elements (genes and receptors) that, overall, cover space nearly uniformly.

q-bio.QM↗

arXiv2015

In silico tumor control induced via alternating immunostimulating and immunosuppressive phases

Despite recent advances in the field of Oncoimmunology, the success potential of immunomodulatory therapies against cancer remains to be elucidated. One of the reasons is the lack of understanding on the complex interplay between tumor growth dynamics and the associated immune system responses. Towards this goal, we consider a mathematical model of vascularized tumor growth and the corresponding effector cell recruitment dynamics. Bifurcation analysis allows for the exploration of model's dynamic behavior and the determination of these parameter regimes that result in immune-mediated tumor control. Here, we focus on a particular tumor evasion regime that involves tumor and effector cell concentration oscillations of slowly increasing and decreasing amplitude, respectively. Considering a temporal multiscale analysis, we derive an analytically tractable mapping of model solutions onto a weakly negatively damped harmonic oscillator. Based on our analysis, we propose a theory-driven intervention strategy involving immunostimulating and immunosuppressive phases to induce long-term tumor control.

q-bio.TO↗

arXiv2015

Simultaneous regulation of cell size and chromosome replication in bacteria

Bacteria are able to maintain a narrow distribution of cell sizes by regulating the timing of cell divisions. In rich nutrient conditions, cells divide much faster than their chromosomes replicate. This implies that cells maintain multiple rounds of chromosome replication per cell division by regulating the timing of chromosome replications. Here, we show that both cell size and chromosome replication may be simultaneously regulated by the long-standing initiator accumulation strategy. The strategy proposes that initiators are produced in proportion to the volume increase and is accumulated at each origin of replication, and chromosome replication is initiated when a critical amount per origin has accumulated. We show that this model maps to the incremental model of size control, which was previously shown to reproduce experimentally observed correlations between various events in the cell cycle and explains the exponential dependence of cell size on the growth rate of the cell. Furthermore, we show that this model also leads to the efficient regulation of the timing of initiation and the number of origins consistent with existing experimental results.

q-bio.CB↗

arXiv2015

The Performance of Discrete Models of Low Reynolds Number Swimmers

Swimming by shape changes at low Reynolds number is widely used in biology and understanding how the efficiency of movement depends on the geometric pattern of shape changes is important to understand swimming of microorganisms and in designing low Reynolds number swimming models. The simplest models of shape changes are those that comprise a series of linked spheres that can change their separation and/or their size. Herein we compare the efficiency of three models in which these modes are used in different ways.

physics.flu-dyn↗

arXiv2015

Effective diffusion rates and cross-correlation analysis of "acid growth" data

We investigated the growth-temperature relationship in plants using a quantitative perspective of a recently derived growth functional. We showed that auxin-induced growth is achieved by the diffusion rate, which is almost constant or slowly ascending in temperature while the diffusion rate of fusicoccin-induced growth increases monotonically with temperature for the entire temperature range, though for some concentrations of IAA "super-diffusion" takes place for unperturbed growth. Furthermore, three kind of experiments were compared: for abraded coleoptiles, coleoptile segments and intact growing seedlings. From cross-correlation analysis it was found that the timing of IAA and FC-induced proton secretion and growth matches well. Unambiguous results, concerning fundamental conditions of the acid growth hypothesis, were obtained by cross- and auto-correlation analysis: (1) For abraded coleoptiles, because of the lowering of the cuticule potential barrier, auxin-induced cell wall pH decreases simultaneously with the change in growth rate; no advancement or retardation of pH (proton efflux rate) or growth rate takes place (2) Exogenous protons are able to substitute for auxin causing wall loosening and growth (3) Although the underlying molecular mechanisms vastly differ, a potent stimulator of proton secretion, the fungal toxin FC, promotes growth similar to auxin, however of much elevated intensity; as for auxin - no advancement or retardation takes place.

q-bio.CB↗

arXiv2017

Active Tension Network model reveals an exotic mechanical state realized in epithelial tissues

It is now widely recognized that mechanical interactions between cells play a crucial role in epithelial morphogenesis, yet understanding the mechanisms through which stress and deformation affect cell behavior remains an open problem due to the complexity inherent in the mechanical behavior of cells and the difficulty of direct measurement of forces within tissues. Theoretical models can help by focusing experimental studies and by providing the framework for interpreting measurements. To that end, "vertex models" have introduced an approximation of epithelial cell mechanics based on a polygonal tiling representation of planar tissue. Here we formulate and analyze an Active Tension Network (ATN) model, which is based on the same polygonal representation of epithelial tissue geometry, but in addition i) assumes that mechanical balance is dominated by cortical tension and ii) introduces tension dependent local remodeling of the cortex, representing the active nature of cytoskeletal mechanics. The tension-dominance assumption has immediate implications for the geometry of cells, which we demonstrate to hold in certain types of Drosophila epithelial tissues. We demonstrate that stationary configurations of an ATN form a manifold with one degree of freedom per cell, corresponding to "isogonal" - i.e. angle preserving - deformations of cells, which dominate the dynamic response to perturbations. We show that isogonal modes account for approximately 90% of experimentally observed deformation of cells during the process of ventral furrow formation in Drosophila. Other interesting properties of our model include the exponential screening of mechanical stress and a negative Poisson ratio response to external uniaxial stress. We also provide a new approach to the problem of inferring local cortical tensions from the observed geometry of epithelial cells in a tissue

q-bio.TO↗

arXiv2015

Collective Properties of a Transcription Initiation Model under Varying Environment

The dynamics of gene transcription is tightly regulated in eukaryotes. Recent experiments have revealed various kinds of transcriptional dynamics, such as RNA polymerase II pausing, that involves regulation at the transcription initiation stage, and the choice of different regulation pattern is closely related to the physiological functions of the target gene. Here we consider a simplified model of transcription initiation, a process including the assembly of transcription complex and the pausing and releasing of the RNA polymerase II. Focusing on the collective behaviors on a population level, we explore potential regulatory functions this model can offer. These functions include fast and synchronized response to environmental change, or long-term memory about the transcriptional status. As a proof of concept we also show that, by selecting different control mechanisms cells can adapt to different environments. These findings may help us better understand the design principles of transcriptional regulation.

q-bio.CB↗

arXiv2015

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential In HLA-Matched and Mismatched Donor-Recipient Pairs

Stem cell transplants may be considered as dynamical systems to allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response. Whole exome sequencing was performed on HLA matched stem cell transplant donor-recipient pairs, and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each pair was determined. The resulting array of peptide-HLA binding affinity values in each patient was used to simulate an alloreactive donor derived T cell repertoire. This simulated T cell repertoire reproduces a number of features of clinically observed T cell repertoire. The simulated, alloreactive T cell repertoire was markedly different in HLA matched stem cell transplant donors and recipients and demonstrates a possible correlation with survival.

q-bio.CB↗

arXiv2015

ERK/p38 MAPK inhibition reduces radio-resistance to pulsed proton beam in breast cancer stem cells cells

Recent studies have identified highly tumorigenic cells with stem cell-like characteristics in human cancers, termed cancer stem cells (CSCs). CSCs are resistant to conventional radiotherapy and chemotherapy owing to their high DNA repair ability and oncogene overexpression. However, the mechanisms regulating CSC radio-resistance, particularly proton beam resistance, remain unclear. We isolated CSCs from the breast cancer cell lines MCF-7 and MDA-MB-231, which expressed the characteristic breast CSC membrane protein markers CD44+/CD24-/low, and irradiated the CSCs with pulsed proton beams. We confirmed that CSCs are resistant to pulsed proton beams and showed that treatment with p38 and ERK inhibitors reduced CSC radioresistance. Based on these results, BCSC radio-resistance can be reduced during proton beam therapy by co-treatment with ERK1/2 or p38 inhibitors, representing a novel approach for breast cancer therapy.

q-bio.TO↗

arXiv2015

A continuum model for nematic alignment of self-propelled particles

A continuum model for a population of self-propelled particles interacting through nematic alignment is derived from an individual-based model. The methodology consists of introducing a hydrodynamic scaling of the corresponding mean-field kinetic equation. The resulting perturbation problem is solved thanks to the concept of generalized collision invariants. It yields a hyperbolic but non-conservative system of equations for the nematic mean direction of the flow and the densities of particles flowing parallel or anti-parallel to this mean direction. Diffusive terms are introduced under a weakly non-local interaction assumption and the diffusion coefficient is proven to be positive. An application to the modeling of myxobacteria is outlined.

math.AP↗

arXiv2015

Computational Analysis of Amoeboid Swimming at Low Reynolds Number

Recent experimental work has shown that eukaryotic cells can swim in a fluid as well as crawl on a substrate. We investigate the swimming behavior of Dictyostelium discoideum amoebae who swim by initiating traveling protrusions at the front that propagate rearward. In our model we prescribe the velocity at the surface of the swimming cell, and use techniques of complex analysis to develop 2D models that enable us to study the fluid-cell interaction. Shapes that approximate the protrusions used by Dictyostelium discoideum can be generated via the Schwarz-Christoffel transformation, and the boundary- value problem that results for swimmers in the Stokes flow regime is then reduced to an integral equation on the boundary of the unit disk. We analyze the swimming characteristics of several varieties of swimming Dictyostelium discoideum amoebae, and discuss how the slenderness of the cell body and the shapes of the protrusion effect the swimming of these cells. The results may provide guidance in designing low Reynolds number swimming models.

q-bio.CB↗

arXiv2015

The impact of microfibril orientations on the biomechanics of plant cell walls and tissues: modelling and simulations

It is known that the orientation of cellulose microfibrils within plant cell walls has an important impact on the morphogenesis of plant cells and tissues. Viewing the shape of a plant cell as a square prism or cylinder with the axis aligning with the primary direction of expansion and growth, the orientation of the microfibrils within the cell wall on the sides of the cell is known. However, not much is known about their orientation at the ends of the cell. Here we investigate the impact of the orientation of cellulose microfibrils within a plant cell wall at the ends of the cell by solving the equations of linear elasticity numerically. Three different scenarios for the orientation of the microfibrils are considered. The macroscopic elastic properties of the cell wall are obtained using homogenization theory from the microscopic description of the elastic properties of the cell wall microfibrils and wall matrix. It is found that the orientation of the microfibrils in the upper and lower parts of cell walls do not affect the expansion of the cell in the direction of its axis but do affect its expansion in the lateral directions. The arrangement of the microfibrils in the upper and lower parts of cell walls is especially important in the case of directed forces acting on plant cell walls and tissues.

q-bio.CB↗

arXiv2015

A theoretical model of soma-to-germline transmission of transposable elements to build new gene regulatory sequences

Transposable elements are DNA sequences that can move around to different positions in the genome. During this process, they can cause mutations, and lead to an increase in genome size. Despite representing a large genomic fraction, transposable elements have no clear biological function. This work builds upon a previous model, to propose a new concept of natural selection which combines Lamarckian and Darwinian elements. Transposable elements are hypothesised to be the vector of a flow of genetic information from soma to germline, that shapes gene regulatory regions across the genome. The paper introduces the concept, presents and discusses the body of evidence in support of this hypothesis, and suggests an experiment to test it.

q-bio.CB↗

arXiv2015

A biophysical model of cell evolution after cytotoxic treatments: damage, repair and cell response

We present a theoretical agent-based model of cell evolution under the action of cytotoxic treatments, such as radioteraphy or chemoteraphy. The major features of cell cycle and proliferation, cell damage and repair, and chemical diffusion are included. Cell evolution is based on a discrete Markov chain, with cells stepping along a sequence of discrete internal states from 'normal' to 'inactive'. Probabilistic laws are introduced for each type of event a cell can undergo during its life cycle: duplication, arrest, apoptosis, senescence, damage, healing. We adjust the model parameters on a series of cell irradiation experiments, carried out in a clinical LINAC at 20 MV, in which the damage and repair kinetics of single- and double-strand breaks are followed. Two showcase applications of the model are then presented. In the first one, we reconstruct the cell survival curves from a number of published low- and high-dose irradiation experiments. We reobtain a very good description of the data without assuming the well-known linear-quadratic model, but instead including a variable DSB repair probability, which is found to spontaneously saturate with an exponential decay at increasingly high doses. As a second test, we attempt to simulate the two extreme possibilities of the so-called 'bystander' effect in radiotherapy: the 'local' effect versus a 'global' effect, respectively activated by the short-range or long-range diffusion of some factor, presumably secreted by the irradiated cells. Even with an oversimplified simulation, we could demonstrate a sizeable difference in the proliferation rate of non-irradiated cells, the proliferation acceleration being much larger for the global than the local effect, for relatively small fractions of irradiated cells in the colony.

q-bio.CB↗

arXiv2015

Decay to equilibrium of the filament end density along the leading edge of the lamellipodium

A model for the dynamics of actin filament ends along the leading edge of the lamellipodium is analyzed. It contains accounts of nucleation by branching, of deactivation by capping, and of lateral flow along the leading edge by polymerization. A nonlinearity arises from a Michaelis-Menten type modeling of the branching process. For branching rates large enough compared to capping rates, the existence and stability of nontrivial steady states is investigated. The main result is exponential convergence to nontrivial steady states, proven by investigating the decay of an appropriate Lyapunov functional.

math.AP↗

arXiv2015

Phase Diagram of Collective Motion of Bacterial Cells in a Shallow Circular Pool

The collective motion of bacterial cells in a shallow circular pool is systematically studied using the bacterial species $Bacillus$ $subtilis$. The ratio of cell length to pool diameter (i.e., the reduced cell length) ranges from 0.06 to 0.43 in our experiments. Bacterial cells in a circular pool show various types of collective motion depending on the cell density in the pool and the reduced cell length. The motion is classified into six types, which we call random motion, turbulent motion, one-way rotational motion, two-way rotational motion, random oscillatory motion, and ordered oscillatory motion. Two critical values of reduced cell lengths are evaluated, at which drastic changes in collective motion are induced. A phase diagram is proposed in which the six phases are arranged.

physics.bio-ph↗

arXiv2015

Ligand mediated adhesive mechanics of two deformed spheres

A self-consistent model is developed to investigate attachment / detachment kinetics of two soft, deformable microspheres with irregular surface and coated with flexible binding ligands. The model highlights how the microscale binding kinetics of these ligands as well as the attractive/repulsive potential of the charged surface affects the static deformed configuration of the spheres. It is shown that in the limit of smooth, neutral charged surface (i.e., the Debye length, $κ\rightarrow \infty $), interacting via elastic binders (i.e., the stiffness coefficient, $λ\rightarrow 0$) the adhesion mechanics approaches the regime of application of the JKR theory, and in this particular limit, the contact radius scales with the particle radius, according to the scaling law, $R_c\propto R^{\frac{2}{3}}$. We show that adhesion dominates in larger particles with highly charged surface and with resilient binders. Normal stress distribution within the contact area fluctuates with the binder stiffness coefficient, from a maximum at the center to a maximum at the periphery of the region. Surface heterogeneities result in a diminished adhesion with a distinct reduction in the pull off force, larger separation gap, weaker normal stress and limited area of adhesion. These results are in agreement with the published experimental findings.

q-bio.CB↗

arXiv2015

A physical description of the adhesion and aggregation of platelets

The early stages of clot formation in blood vessels involve platelets adhesion-aggregation. Although these mechanisms have been extensively studied, gaps in their understanding still persist. We have performed detailed in-vitro experiments and developed a numerical model to better describe and understand this phenomenon. Unlike previous studies, we took into account both activated and non-activated platelets, as well as the 3D nature of the aggregation process. Our investigation reveals that blood albumin is a major parameter limiting platelet adhesion and aggregation. Our results also show that the well accepted Zydney-Colton shear-induced diffusivity is much too low to explain the observed deposition rate. Simulations are in very good agreement with observations and provide quantitative estimates of the adhesion and aggregation rates that are hard to measure experimentally.

physics.bio-ph↗