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At least 109 records · Page 6Linked to original sources

arXiv2009

Self-organization of the MinE ring in subcellular Min oscillations

We model the self-organization of the MinE ring that is observed during subcellular oscillations of the proteins MinD and MinE within the rod-shaped bacterium {\it Escherichia coli}. With a steady-state approximation, we can study the MinE-ring generically -- apart from the other details of the Min oscillation. Rebinding of MinE to depolymerizing MinD filament tips controls MinE ring formation through a scaled cell shape parameter $\tilde{r}$. We find two types of E-ring profiles near the filament tip: a strong plateau-like E-ring controlled by 1D diffusion of MinE along the bacterial length, or a weak cusp-like E-ring controlled by 3D diffusion near the filament tip. While the width of a strong E-ring depends on $\tilde{r}$, the occupation fraction of MinE at the MinD filament tip is saturated and hence the depolymerization speed do not depend strongly on $\tilde{r}$. Conversely, for weak E-rings both $\tilde{r}$ and the MinE to MinD stoichiometry strongly control the tip occupation and hence the depolymerization speed. MinE rings {\em in vivo} are close to the threshold between weak and strong, and so MinD-filament depolymerization speed should be sensitive to cell shape, stoichiometry, and the MinE-rebinding rate. We also find that the transient to MinE-ring formation is quite long in the appropriate open geometry for assays of ATPase activity {\it in vitro}, explaining the long delays of ATPase activity observed for smaller MinE concentrations in those assays without the need to invoke cooperative MinE activity.

q-bio.SC↗

arXiv2009

Accuracy of direct gradient sensing by cell-surface receptors

Chemotactic cells of eukaryotic organisms are able to accurately sense shallow chemical concentration gradients using cell-surface receptors. This sensing ability is remarkable as cells must be able to spatially resolve small fractional differences in the numbers of particles randomly arriving at cell-surface receptors by diffusion. An additional challenge and source of uncertainty is that particles, once bound and released, may rebind the same or a different receptor, which adds to noise without providing any new information about the environment. We recently derived the fundamental physical limits of gradient sensing using a simple spherical-cell model, but not including explicit particle-receptor kinetics. Here, we use a method based on the fluctuation-dissipation theorem (FDT) to calculate the accuracy of gradient sensing by realistic receptors. We derive analytical results for two receptors, as well as two coaxial rings of receptors, e.g. one at each cell pole. For realistic receptors, we find that particle rebinding lowers the accuracy of gradient sensing, in line with our previous results.

q-bio.CB↗

arXiv2009

In Vivo Localization of Fas-Associated Death Domain Protein in the Nucleus and Cytoplasm of Normal Thyroid and Liver Cells

FADD (Fas-associated death domain) is the main death receptor adaptor molecule that transmits apoptotic signal. Recently, FADD protein was shown to be expressed both in the cytoplasm and nucleus of in vitro cell lines. In contrast to the cytoplasmic FADD, the nuclear FADD was shown to protect cells from apoptosis. However, in vivo subcellular localization of FADD was still unknown. Here, we demonstrated that FADD protein was expressed in both cytoplasmic and nuclear compartment in ex vivo thyroid cells demonstrating that nuclear sublocalization of FADD protein was a relevant phenomenon occurring in vivo. Moreover, we showed that in the nucleus of untransformed thyroid cells FADD localized mainly on euchromatin. We confirmed the nuclear localization of FADD in ex vivo liver and showed that in this organ FADD and MBD4 interact together. These results demonstrate that FADD is physiologically expressed in the nucleus of cells in at least two mouse organs. This particular localization opens new possible role of FADD in vivo either asan inhibitor of cell death, or as a transcription factor, or as a molecular link between apoptosis and genome surveillance.

q-bio.SC↗

arXiv2009

Modeling and simulation of Ran-mediated nuclear import

We present here a detailed description of the model of ran-driven nuclear transduction in living cells to be published elswere. The mathematical model presented is the first to account for the active transport of molecules along the cytoplasmic microtubules. All parameters entering the models are thoroughly discussed. The simulations reproduce the behavior observed experimentally.

math.NA↗

arXiv2009

Emergent Network Structure, evolvable Robustness and non-linear Effects of Point Mutations in an Artificial Genome Model

Genetic regulation is a key component in development, but a clear understanding of the structure and dynamics of genetic networks is not yet at hand. In this paper we investigate these properties within an artificial genome model originally introduced by Reil (1999). We analyze statistical properties of randomly generated genomes both on the sequence- and network level, and show that this model correctly predicts the frequency of genes in genomes as found in experimental data. Using an evolutionary algorithm based on stabilizing selection for a phenotype, we show that dynamical robustness against single base mutations, as well as against random changes in initial states of regulatory dynamics that mimic stochastic fluctuations in environmental conditions, can emerge in parallel. Point mutations at the sequence level have strongly non-linear effects on network wiring, including as well structurally neutral mutations and simultaneous rewiring of multiple connections, which occasionally lead to strong reorganization of the attractor landscape and metastability of evolutionary dynamics. Evolved genomes exhibit characteristic patterns on both sequence and network level.

q-bio.MN↗

arXiv2009

The Gated Narrow Escape Time for molecular signaling

The mean time for a diffusing ligand to activate a target protein located on the surface of a microdomain can regulate cellular signaling. When the ligand switches between various states induced by chemical interactions or conformational changes, while target activation occurs in only one state, this activation time is affected. We investigate this dynamics using new equations for the sojourn times spent in each state. For two states, we obtain exact solutions in dimension one, and asymptotic ones confirmed by Brownian simulations in dimension 3. We find that the activation time is quite sensitive to changes of the switching rates, which can be used to modulate signaling. Interestingly, our analysis reveals that activation can be fast although the ligand spends most of the time 'hidden' in the non-activating state. Finally, we obtain a new formula for the narrow escape time in the presence of switching.

q-bio.SC↗

arXiv2010

Modeling the formation of in vitro filopodia

Filopodia are bundles of actin filaments that extend out ahead of the leading edge of a crawling cell to probe its upcoming environment. {\it In vitro} experiments [D. Vignjevic {\it et al.}, J. Cell Biol. {\bf 160}, 951 (2003)] have determined the minimal ingredients required for the formation of filopodia from the dendritic-like morphology of the leading edge. We model these experiments using kinetic aggregation equations for the density of growing bundle tips. In mean field, we determine the bundle size distribution to be broad for bundle sizes smaller than a characteristic bundle size above which the distribution decays exponentially. Two-dimensional simulations incorporating both bundling and cross-linking measure a bundle size distribution that agrees qualitatively with mean field. The simulations also demonstrate a nonmonotonicity in the radial extent of the dendritic region as a function of capping protein concentration, as was observed in experiments, due to the interplay between percolation and the ratcheting of growing filaments off a spherical obstacle.

q-bio.SC↗

arXiv2009

Coherent and Noncoherent Photonic Communications in Biological Systems

The possible mechanisms of communications between distant bio-systems by means of optical and UV photons are studied. It is argued that their main production mechanism is owed to the biochemical reactions, occurring during the cell division.. In the proposed model the bio-systems perform such communications, radiating the photons in form of short periodic bursts, which were observed experimentally for fish and frog eggs1. For experimentally measured photon rates the communication algorithm is supposedly similar to the exchange of binary encoded data in computer net via optical channels

q-bio.OT↗

arXiv2009

Dynamics of Enzyme Digestion of a Single Elastic Fiber Under Tension: An Anisotropic Diffusion Model

We study the enzymatic degradation of an elastic fiber under tension using an an isotropic random-walk model, coupled with binding-unbinding reactions that weaken the fiber. The fiber is represented by a chain of elastic springs in series, surrounded by two layers of sites along which enzyme molecules can diffuse. Through numerical simulations we show that the fiber stiffness decreases exponentially with two distinct regimes. The time constant associated with the first regime decreases with increasing applied force, which is in agreement with published experimental data. In addition, a simple mean field calculation allows us to partition the time constant into geometrical, chemical and externally controllable factors, which is corroborated by the simulations.

cond-mat.stat-mech↗

arXiv2009

Mechanics and Dynamics of X-Chromosome Pairing at X Inactivation

At the onset of X Chromosomes Inactivation, the vital process whereby female mammal cells equalize X products with respect to males, the X chromosomes are colocalized along their Xic (X-Inactivation Center) regions. The mechanism inducing recognition and pairing of the X's remains, though, elusive. Starting from recent discoveries on the molecular factors and on the DNA sequences (the so-called ``pairing sites'') involved, we dissect the mechanical basis of Xic colocalization by using a Statistical Physics model. We show that soluble DNA specific binding molecules, as those experimentally identified, can be indeed sufficient to induce the spontaneous colocalization of the homologous chromosomes, but only when their concentration, or chemical affinity, rises above a threshold value, as a consequence of a thermodynamic phase transition. We derive the likelihood of pairing and its probability distribution. Chromosome dynamics has two stages: an initial independent Brownian diffusion followed, after a characteristic time scale, by recognition and pairing. Finally, we investigate the effects of DNA deletion/insertions in the region of pairing sites and compare model predictions to available experimental data.

q-bio.GN↗

arXiv2009

Stop-and-go kinetics in amyloid fibrillation

Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermittent fashion, with periods of growth followed by long pauses. The observed exponential distributions of stop and growth times support a Markovian model, in which fibrils shift between the two states with specific rates. Remarkably, the probability of being in the growing (stopping) state is very close to 1/4 (3/4) in all experiments, even if the rates vary considerably. This finding suggests the presence of 4 independent conformations of the fibril tip; we discuss this possibility in terms of the existing structural knowledge.

physics.bio-ph↗

arXiv2009

Investigating the robustness of the classical enzyme kinetic equations in small intracellular compartments

Classical descriptions of enzyme kinetics ignore the physical nature of the intracellular environment. Main implicit assumptions behind such approaches are that reactions occur in compartment volumes which are large enough so that molecular discreteness can be ignored and that molecular transport occurs via diffusion. Starting from a master equation description of enzyme reaction kinetics and assuming metabolic steady-state conditions, we derive novel mesoscopic rate equations which take into account (i) the intrinsic molecular noise due to the low copy number of molecules in intracellular compartments (ii) the physical nature of the substrate transport process, i.e. diffusion or vesicle-mediated transport. These equations replace the conventional macroscopic and deterministic equations in the context of intracellular kinetics. The latter are recovered in the limit of infinite compartment volumes. We find that deviations from the predictions of classical kinetics are pronounced (hundreds of percent in the estimate for the reaction velocity) for enzyme reactions occurring in compartments which are smaller than approximately 200nm, for the case of substrate transport to the compartment being mediated principally by vesicle or granule transport and in the presence of competitive enzyme inhibitors. This has implications for the common approach of modelling large intracellular reaction networks using ordinary differential equations and also for the calculation of the effective dosage of competitive inhibitor drugs.

q-bio.SC↗

arXiv2009

Analysis of interaction partners of H4 histone by a new proteomics approach

We describe a modification of the TAP method for purification and analysis of multiprotein complexes, termed here DEF-TAP (for Differential Elution Fractionation after Tandem Affinity Purification). Its essential new feature is the use for last purification step of 6XHis-Ni++ interaction, which is resistant to a variety of harsh washing conditions, including high ionic strength and presence of organic solvents. This allows us to use various fractionation schemes before the protease digestion, which is expected to improve the coverage of the analysed protein mixture and also to provide an additional insight into the structure of the purified macromolecular complex and the nature of protein-protein interactions involved. We illustrate our new approach by analysis of soluble nuclear complexes containing histone H4 purified from HeLa cells. In particular, we observed different fractionation patterns of HAT1 and RbAp46 proteins as compared to RbAp48 protein, all identified as interaction partners of H4 histone. In addition, we report all components of the licensing MCM2-7 complex and the apoptosis-related DAXX protein among the interaction partners of the soluble H4. Finally, we show that HAT1 requires N-terminal tail of H4 for its stable association with this histone.

q-bio.MN↗

arXiv2009

Mapping Complex Networks: Exploring Boolean Modeling of Signal Transduction Pathways

In this study, we explored the utility of a descriptive and predictive bionetwork model for phospholipase C-coupled calcium signaling pathways, built with non-kinetic experimental information. Boolean models generated from these data yield oscillatory activity patterns for both the endoplasmic reticulum resident inositol-1,4,5-trisphosphate receptor (IP3R) and the plasma-membrane resident canonical transient receptor potential channel 3 (TRPC3). These results are specific as randomization of the Boolean operators ablates oscillatory pattern formation. Furthermore, knock-out simulations of the IP3R, TRPC3, and multiple other proteins recapitulate experimentally derived results. The potential of this approach can be observed by its ability to predict previously undescribed cellular phenotypes using in vitro experimental data. Indeed our cellular analysis of the developmental and calcium-regulatory protein, DANGER1a, confirms the counter-intuitive predictions from our Boolean models in two highly relevant cellular models. Based on these results, we theorize that with sufficient legacy knowledge and/or computational biology predictions, Boolean networks provide a robust method for predictive-modeling of any biological system.

q-bio.MN↗

arXiv2010

Transient Pulse Formation in Jasmonate Signaling Pathway

The jasmonate (JA) signaling pathway in plants is activated as defense response to a number of stresses like attacks by pests or pathogens and wounding by animals. Some recent experiments provide significant new knowledge on the molecular detail and connectivity of the pathway. The pathway has two major components in the form of feedback loops, one negative and the other positive. We construct a minimal mathematical model, incorporating the feedback loops, to study the dynamics of the JA signaling pathway. The model exhibits transient gene expression activity in the form of JA pulses in agreement with experimental observations. The dependence of the pulse amplitude, duration and peak time on the key parameters of the model is determined computationally. The deterministic and stochastic aspects of the pathway dynamics are investigated using both the full mathematical model as well as a reduced version of it. We also compare the mechanism of pulse formation with the known mechanisms of pulse generation in some bacterial and viral systems.

q-bio.SC↗

arXiv2010

DNA heats up : Energetics of genome ejection from phage revealed by isothermal titration calorimetry

Most bacteriophages are known to inject their double-stranded DNA into bacteria upon receptor binding in an essentially spontaneous way. This downhill thermodynamic process from the intact virion toward the empty viral capsid plus released DNA is made possible by the energy stored during active packaging of the genome into the capsid. Only indirect measurements of this energy have been available until now using either single-molecule or osmotic suppression techniques. In this paper, we describe for the first time the use of isothermal titration calorimetry to directly measure the heat released (or equivalently the enthalpy) during DNA ejection from phage lambda, triggered in solution by a solubilized receptor. Quantitative analyses of the results lead to the identification of thermodynamic determinants associated with DNA ejection. The values obtained were found to be consistent with those previously predicted by analytical models and numerical simulations. Moreover, the results confirm the role of DNA hydration in the energetics of genome confinement in viral capsids.

physics.bio-ph↗

arXiv2011

The mechanical creep compliance of tissue cells is gamma distributed

Investigations of natural variation among cells within a population are essential for understanding the stochastic nature of tissue cell deformation under applied load. In the existing literature, the population variation of single-cell creep compliance has so far been modeled universally by using a log-normal distribution. Here we use optical stretching, a non-contact and relatively high-throughput technique for probing cell mechanics, to accumulate a sufficient data set that demonstrates robustly that cell compliance varies according to the similar but distinct gamma distribution. Additionally, we re-examine existing simulations that were originally proposed to justify a log-normal fit, and show that in fact these simulation data also correspond to the gamma distribution. Finally, we propose a general stochastic differential equation that analytically predicts a gamma distribution of creep compliance during cell stretching, as well as the Gaussian distribution of cell recovery that we observe experimentally upon removal of applied load. The population variation is well characterized by just a single parameter in each of the creep and recovery regimes. We expect our correction of a phenomenological distribution fit, enabled by an expansive data set for mesenchymal stem cells, to enable the development of more accurate constitutive laws to describe cytoskeletal deformation. These findings thus serve to replace an empirical distribution with a better-fitting model that rests on a more solid experimental and theoretical foundation, and also provides a basis to predict and understand the stochastic nature of the mechanical response of individual cells within populations.

q-bio.CB↗

arXiv2010

Continuum Electrostatics in Cell Biology

Recent experiments revealing possible nanoscale electrostatic interactions in force generation at kinetochores for chromosome motions have prompted speculation regarding possible models for interactions between positively charged molecules in kinetochores and negative charge on C-termini near the plus ends of microtubules. A clear picture of how kinetochores establish and maintain a dynamic coupling to microtubules for force generation during the complex motions of mitosis remains elusive. The current paradigm of molecular cell biology requires that specific molecules, or molecular geometries, for force generation be identified. However, it is possible to account for mitotic motions within a classical electrostatics approach in terms of experimentally known cellular electric charge interacting over nanometer distances. These charges are modeled as bound surface and volume continuum charge distributions. Electrostatic consequences of intracellular pH changes during mitosis may provide a master clock for the events of mitosis.

q-bio.CB↗