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arXiv2012

The DNA Single-Strand Break Repair Machinery Facilitates CAF-1-Mediated Histone Deposition at Oxidative DNA Strand Breaks

Oxidative DNA single strand breaks arise continuously in cells and defects in their repair have been implicated in neurological disease. While much progress has been made in understanding how chromosomal single strand breaks are repaired little is known about the changes chromatin structure that accompany this process. Here, we show that nascent recombinant histone H3.1 protein accumulates and is deposited into chromatin at sites of DNA strand breakage in quiescent human cells following oxidative stress, and that core components of the single-strand break repair machinery are required for this process. We show that the SSBR sensor and scaffold proteins poly (ADP-ribose) polymerase and XRCC1 facilitate accumulation of chromatin assembly factor-1 (CAF-1) at sites of oxidative DNA strand breakage, which in turn mediates the deposition of Histone H3.1. We also demonstrate that depletion of CAF-1 slows global rates of DNA strand break repair in quiescent cells following oxidative stress, demonstrating that single-strand break repair and histone deposition are tightly coordinated processes. These data describe a novel role for the DNA singlestrand break repair machinery and implicate histone turnover as a core component of the cellular response of quiescent cells to oxidative damage.

q-bio.SC↗

arXiv2009

Simulation of mitochondrial metabolism using multi-agents system

Metabolic pathways describe chains of enzymatic reactions. Their modelling is a key point to understand living systems. An enzymatic reaction is an interaction between one or several metabolites (substrates) and an enzyme (simple protein or enzymatic complex build of several subunits). In our Mitochondria in Silico Project, MitoScop, we study the metabolism of the mitochondria, an intra-cellular organelle. Many ordinary differential equation models are available in the literature. They well fit experimental results on flux values inside the metabolic pathways, but many parameters are di$\pm$cult to transcribe with such models: localization of enzymes, rules about the reactions scheduler, etc Moreover, a model of a significant part of mitochondrial metabolism could become very complex and contain more than 50 equations. In this context, the multi-agents systems appear as an alternative to model the metabolic pathways. Firstly, we have looked after membrane design. The mitochondria is a particular case because the inner mitochondrial space, ie matricial space, is delimited by two membranes: the inner and the outer one. In addition to matricial enzymes, other enzymes are located inside the membranes or in the inter-membrane space. Analysis of mitochondrial metabolism must take into account this kind of architecture.

q-bio.SC↗

arXiv2012

Changes in chromatin state in donors subjected to physical stress

The purpose of the present study is to evaluate changes in chromatin of human buccal epithelium under the influence of stressing factor - dosed physical activity. Investigations were performed in a group of students (13 men) of age 19-23. Cells were stained on a slide by a 2% orcein solution in 45% acetic acid during 1 h. The following physiological indexes were determined: arterial blood pressure, pulse frequency, and frequency of breathing. The physical stress produced by the dosed physical activity causes the considerable increase of degree of heterochromatinization in the cell nuclei of human buccal epithelium. As a rule, the level of heterochromatinization increases after first stage of training, but in some donors it increases significantly only after the second stage of training.

q-bio.CB↗

arXiv2009

Phospholipid demixing and the birth of a lipid droplet

The biogenesis of lipid droplets (LD) in the yeast Saccharomyces cerevisiae was theoretically investigated on basis of a biophysical model. In accordance with the prevailing model of LD formation, we assumed that neutral lipids oil-out between the membrane leaflets of the endoplasmic reticulum (ER), resulting in LD that bud-off when a critical size is reached. Mathematically, LD were modeled as spherical protuberances in an otherwise planar ER membrane. We estimated the local phospholipid composition, and calculated the change in elastic free energy of the membrane caused by nascent LD. Based on this model calculation, we found a gradual demixing of lipids in the membrane leaflet that goes along with an increase in surface curvature at the site of LD formation. During demixing, the phospholipid monolayer was able to gain energy during LD growth, which suggested that the formation of curved interfaces was supported by or even driven by lipid demixing. In addition, we show that demixing is thermodynamically necessary as LD cannot bud-off otherwise. In the case of Saccharomyces cerevisiae our model predicts a LD bud-off diameter of about 13 nm. This diameter is far below the experimentally determined size of typical yeast LD. Thus, we concluded that if the standard model of LD formation is valid, LD biogenesis is a two step process. Small LD are produced from the ER, which subsequently ripe within the cytosol through a series of fusions.

q-bio.SC↗

arXiv2009

Quantitative interpretation of binding reactions of rapidly diffusing species using fluorescence recovery after photobleaching

Fluorescence recovery after photobleaching (FRAP) measurements offer an important tool for analyzing diffusion and binding processes. Confocal scanning laser microscopes that are used in FRAP experiments bleach regions with a radially Gaussian distributed profile. Previous attempts to derive analytical expressions in the case of processes governed by fast diffusion have overlooked the characteristics of the instruments used to perform FRAP measurements and therefore led to approximating solutions. In the present paper, bleaching laser beam characteristics are incorporated into an improved model to provide a more rigorous and accurate method. The proposed model simulates binding inside bounded regions, and it leads to FRAP curves that depend on the on and off rates that can be employed to determine the rate constants. It can be used in conjunction with experimental data acquired with confocal scanning laser microscopes to investigate the biophysical properties of proteins in living cells. The model aims to improve the accuracy when determining rate constants by taking into account amore realistic scenario of the light-matter interaction.

q-bio.SC↗

arXiv2009

Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.

q-bio.SC↗

arXiv2009

Strong cooperativity and inhibitory effects in DNA multi-looping processes

We show the existence of a high interrelation between the different loops that may appear in a DNA segment. Conformational changes in a chain segment caused by the formation of a particular loop may either promote or prevent the appearance of another. The underlying loop selection mechanism is analyzed by means of a Hamiltonian model from which the looping free energy and the corresponding repression level can be computed. We show significant differences between the probability of single and multiple loop formation. The consequences that these collective effects might have on gene regulation processes are outlined.

q-bio.BM↗

arXiv2011

Quantification of Biological Robustness at the Systemic Level

Biological systems possess negative entropy. In them, one form of order produces another, more organized form of order. We propose a formal scheme to calculate robustness of an entire biological system by quantifying the negative entropy present in it. Our Methodology is based upon a computational implementation of two-person non-cooperative finite zero-sum game between positive (physico-chemical) and negative (biological) entropy, present in the system(TCA cycle, for this work). Biochemical analogue of Nash equilibrium, proposed here, could measure the robustness in TCA cycle in exact numeric terms, whereas the mixed strategy game between these entropies could quantitate the progression of stages of biological adaptation. Synchronization profile amongst macromolecular concentrations (even under environmental perturbations) is found to account for negative entropy and biological robustness. Emergence of synchronization profile was investigated with dynamically varying metabolite concentrations. Obtained results were verified with that from the deterministic simulation methods. Categorical plans to apply this algorithm in Cancer studies and anti-viral therapies are proposed alongside. From theoretical perspective, this work proposes a general, rigorous and alternative view of immunology.

q-bio.SC↗

arXiv2011

A first-passage-time theory for search and capture of chromosomes by microtubules in mitosis

The mitotic spindle is an important intermediate structure in eukaryotic cell division, in which each of a pair of duplicated chromosomes is attached through microtubules to centrosomal bodies located close to the two poles of the dividing cell. Several mechanisms are at work towards the formation of the spindle, one of which is the `capture' of chromosome pairs, held together by kinetochores, by randomly searching microtubules. Although the entire cell cycle can be up to 24 hours long, the mitotic phase typically takes only less than an hour. How does the cell keep the duration of mitosis within this limit? Previous theoretical studies have suggested that the chromosome search and capture is optimized by tuning the microtubule dynamic parameters to minimize the search time. In this paper, we examine this conjecture. We compute the mean search time for a single target by microtubules from a single nucleating site, using a systematic and rigorous theoretical approach, for arbitrary kinetic parameters. The result is extended to multiple targets and nucleating sites by physical arguments. Estimates of mitotic time scales are then obtained for different cells using experimental data. In yeast and mammalian cells, the observed changes in microtubule kinetics between interphase and mitosis are beneficial in reducing the search time. In {\it Xenopus} extracts, by contrast, the opposite effect is observed, in agreement with the current understanding that large cells use additional mechanisms to regulate the duration of the mitotic phase.

q-bio.SC↗

arXiv2009

On the Influence of Weak Magnetic and Electric Fields on the Fluctuations of Ionic Electric Currents in Blood Circulation

An analysis of a variety of existing experimental data leads to the conclusion on the existence of a resonance mechanism allowing weak magnetic fields to affect biological processes. These fields may either be static magnetic fields comparable in magnitude with the magnetic field of the earth or weak ultra-low frequency time-dependent fields. So far, a generally accepted theoretical model allowing one to understand the effect of magnetic and electric fields on biological processes is not available. By this reason, it is not clear which characteristics of the fields, like magnetic and electric field strength, frequency of change of the field, shape of the electromagnetic wave, the duration of the magnetic or electric influence or some particular combination of them, are responsible for the biological effect. In the present analysis it is shown that external time-independent magnetic fields may cause a resonance amplification of ionic electric currents in biological tissues and, in particular, in the vasculature system due to a Brownian motion of charges. These resonance electric currents may cause necrotic changes in the tissues or blood circulation and in this way significantly affect the biological organism. The magnitude of the magnetic fields leading to resonance effects is estimated, it is shown that it depends significantly on the radius of the blood capillaries.

physics.bio-ph↗

arXiv2009

Analytical description of anomalous diffusion in living cells

We propose a stochastic model for intracellular transport processes associated with the activity of molecular motors. This out-of-equilibrium model, based on a generalized Langevin equation, considers a particle immersed in a viscoelastic environment and simultaneously driven by an external random force that models the motors activity. An analytical expression for the mean square displacement is derived, which exhibits a subdiffusive to superdiffusive transition. We show that the experimentally accessible statistical properties of the diffusive particle motion can be reproduced by this model.

physics.bio-ph↗

arXiv2009

Boolean Network Approach to Negative Feedback Loops of the p53 Pathways: Synchronized Dynamics and Stochastic Limit Cycles

Deterministic and stochastic Boolean network models are build for the dynamics of negative feedback loops of the p53 pathways. It is shown that the main function of the negative feedback in the p53 pathways is to keep p53 at a low steady state level, and each sequence of protein states in the negative feedback loops, is globally attracted to a closed cycle of the p53 dynamics after being perturbed by outside signal (e.g. DNA damage). Our theoretical and numerical studies show that both the biological stationary state and the biological oscillation after being perturbed are stable for a wide range of noise level. Applying the mathematical circulation theory of Markov chains, we investigate their stochastic synchronized dynamics and by comparing the network dynamics of the stochastic model with its corresponding deterministic network counterpart, a dominant circulation in the stochastic model is the natural generalization of the deterministic limit cycle in the deterministic system. Moreover, the period of the main peak in the power spectrum, which is in common use to characterize the synchronized dynamics, perfectly corresponds to the number of states in the main cycle with dominant circulation. Such a large separation in the magnitude of the circulations, between a dominant, main cycle and the rest, gives rise to the stochastic synchronization phenomenon.

q-bio.MN↗

arXiv2009

Stochastic Control Analysis for Biochemical Reaction Systems

In this paper, we investigate how stochastic reaction processes are affected by external perturbations. We describe an extension of the deterministic metabolic control analysis (MCA) to the stochastic regime. We introduce stochastic sensitivities for mean and covariance values of reactant concentrations and reaction fluxes and show that there exist MCA-like summation theorems among these sensitivities. The summation theorems for flux variances are shown to depend on the size of the measurement time window ($ε$), within which reaction events are counted for measuring a single flux. The degree of the $ε$-dependency can become significant for processes involving multi-time-scale dynamics and is estimated by introducing a new measure of time scale separation. This $ε$-dependency is shown to be closely related to the power-law scaling observed in flux fluctuations in various complex networks. We propose a systematic way to control fluctuations of reactant concentrations while minimizing changes in mean concentration levels. Such orthogonal control is obtained by introducing a control vector indicating the strength and direction of parameter perturbations leading to a sensitive control. We also propose a possible implication in the control of flux fluctuation: The control distribution for flux fluctuations changes with the measurement time window size, $ε$. When a control engineer applies a specific control operation on a reaction system, the system can respond contrary to what is expected, depending on the time window size $ε$.

q-bio.QM↗

arXiv2009

Wave and quantum properties of peptide strings: defining a helix in spacetime

Previous studies have described the concept of peptide strings in qualitative terms and illustrated it by applying its corrolaries in order to elucidate basic questions in oncology and rheumatology. The present investigation is the first to quantify these potential sub- and transcellular phenomena. Accordingly, the propagation of peptide strings is proposed here to occur by way of waves that in turn are subject to the energy equation established by Planck. As a result of these insights, widespread future applications can now be envisaged for peptide strings both in molecular medicine and quantum optics.

q-bio.SC↗

arXiv2009

Discrete- versus continuous-state descriptions of the F1-ATPase molecular motor

A discrete-state model of the F1-ATPase molecular motor is developed which describes not only the dependences of the rotation and ATP consumption rates on the chemical concentrations of ATP, ADP, and inorganic phosphate, but also on mechanical control parameters such as the friction coefficient and the external torque. The dependence on these mechanical parameters is given to the discrete-state model by fitting its transition rates to the continuous-angle model of P. Gaspard and E. Gerritsma [J. Theor. Biol. 247 (2007) 672-686]. This discrete-state model describes the behavior of the F1 motor in the regime of tight coupling between mechanical motion and chemical reaction. In this way, kinetic and thermodynamic properties of the F1 motor are obtained such as the Michaelis-Menten dependence of the rotation and ATP consumption rates on ATP concentration and its extension in the presence of ADP and Pi, their dependences on friction and external torque, as well as the chemical and mechanical thermodynamic efficiencies.

q-bio.SC↗

arXiv2009

A mathematical model for period-memorizing behavior in Physarum plasmodium

A mathematical model to describe period-memorizing behavior in Physarum plasmodium are reported. In constructing the model, we first examine the basic characteristics required for the class of models, then create a minimal linear model to fulfill these requirements. We also propose two modifications of the minimal model, nonlinearization and noise addition, which improve the reproducibility of experimental evidences. Differences in the mechanisms and in the reproducibility of experiments between our models and the previous models are discussed.

q-bio.CB↗

arXiv2009

Lipid Domain Order and the Algebra of Morphology

Lipid membranes regulate the flow of materials and information between cells and their organelles. Further, lipid composition and morphology can play a key role in regulating a variety of biological processes. For example, viral uptake, plasma membrane tension regulation, and the formation of caveolae all require the creation and control of groups of lipids that adopt specific morphologies. In this paper, we use a simplified model mixture of lipids and cholesterol to examine the interplay between lipid phase-separation and bilayer morphology. We observe and theoretically analyze three main features of phase-separated giant unilamellar vesicles. First, by tracking the motion of `dimpled' domains, we measure repulsive, elastic interactions that create short--range translational and orientational order, leading to a stable distribution of domain sizes, and hence maintaining lateral heterogeneity on relatively short length scales and long time scales. Second, we examine the transition to `budded' domain morphologies, showing that the transition is size-selective, and has two kinetic regimes, as revealed by a calculated phase diagram. Finally, using observations of the interactions between dimpled and budded domains, we build a theoretical framework with an elastic model that maps the free energies and allowed transitions in domain morphology upon coalescence, to serve as an interpretive tool for understanding the algebra of domain morphology. In all three cases, the two major factors that regulate domain morphology and morphological transitions are the domain size and membrane tension.

q-bio.BM↗

arXiv2009

Taking the reaction-diffusion master equation to the microscopic limit

The reaction-diffusion master equation (RDME) is commonly used to model processes where both the spatial and stochastic nature of chemical reactions need to be considered. We show that the RDME in many cases is inconsistent with a microscopic description of diffusion limited chemical reactions and that this will result in unphysical results. We describe how the inconsistency can be reconciled if the association and dissociation rates used in the RDME are derived from the underlying microscopic description. These rate constants will however necessarily depend on the spatial discretization. At fine spatial resolution the rates approach the microscopic rate constants defined at the reaction radius. At low resolution the rates converge to the macroscopic diffusion limited rate constants in 3D, whereas there is no limiting value in 2D. Our results make it possible to develop spatially discretized reaction-diffusion models that correspond to a well-defined microscopic description. We show that this is critical for a correct description of 2D systems and systems that require high spatial resolution in 3D.

q-bio.QM↗