Genetic switch systems with mutual repression of two transcription factors are studied using deterministic and stochastic methods. Numerous studies have concluded that cooperative binding is a necessary condition for the emergence of bistability in these systems. Here we show that for a range of biologically relevant conditions, a suitable combination of network structure and stochastic effects gives rise to bistability even without cooperative binding.

SUMMARY Shape is an indicator of cell health. But how is the information in shape decoded? We hypothesize that decoding occurs by modulation of signaling through changes in plasma membrane curvature. Using analytical approaches and numerical simulations, we studied how elongation of cell shape affects plasma membrane signaling. Mathematical analyses reveal transient accumulation of activated receptors at regions of higher curvature with increasing cell eccentricity. This distribution of activated receptors is periodic, following the Mathieu function, and it arises from local imbalance between reaction and diffusion of soluble ligands and receptors in the plane of the membrane. Numerical simulations show that transient microdomains of activated receptors amplify signals to downstream protein kinases. For growth factor receptor pathways, increasing cell eccentricity elevates the levels of activated cytoplasmic Src and nuclear MAPK1,2. These predictions were experimentally validated by changing cellular eccentricity, showing that shape is a locus of retrievable information storage in cells.

The recombination of hydrogen in the interstellar medium, taking place on surfaces of microscopic dust grains, is an essential process in the evolution of chemical complexity in interstellar clouds. Molecular hydrogen plays an important role in absorbing the heat that emerges during gravitational collapse, thus enabling the formation of structure in the universe. The H2 formation process has been studied theoretically, and in recent years also by laboratory experiments. The experimental results were analyzed using a rate equation model. The parameters of the surface that are relevant to H2 formation were obtained and used in order to calculate the recombination rate under interstellar conditions. However, it turned out that, due to the microscopic size of the dust grains and the low density of H atoms, the rate equations may not always apply. A master equation approach that provides a good description of the H2 formation process was proposed. It takes into account both the discrete nature of the H atoms and the fluctuations in the number of atoms on a grain. In this paper we present a comprehensive analysis of the H2 formation process, under steady state conditions, using an exact solution of the master equation. This solution provides an exact result for the hydrogen recombination rate and its dependence on the flux, the surface temperature, and the grain size. The results are compared with those obtained from the rate equations. The relevant length scales in the problem are identified and the parameter space is divided into two domains. One domain, characterized by first order kinetics, exhibits high efficiency of H2 formation. In the other domain, characterized by second order kinetics, the efficiency of H2 formation is low. In each of these domains we identify the range of parameters in which, due to the small size of the grains, the rate equations do not account correctly for the recombination rate and the master equation is needed.

Cell motility is important for many developmental and physiological processes. Motility arises from interactions between physical forces at the cell surface membrane and the biochemical reactions that control the actin cytoskeleton. To computationally analyze how these factors interact, we built a three-dimensional stochastic model of the experimentally observed isotropic spreading phase of mammalian fibroblasts. The multiscale model is composed at the microscopic levels of three actin filament remodeling reactions that occur stochastically in space and time, and these reactions are regulated by the membrane forces due to membrane surface resistance (load) and bending energy. The macroscopic output of the model (isotropic spreading of the whole cell) occurs due to the movement of the leading edge, resulting solely from membrane force-constrained biochemical reactions. Numerical simulations indicate that our model qualitatively captures the experimentally observed isotropic cell-spreading behavior. The model predicts that increasing the capping protein concentration will lead to a proportional decrease in the spread radius of the cell. This prediction was experimentally confirmed with the use of Cytochalasin D, which caps growing actin filaments. Similarly, the predicted effect of actin monomer concentration was experimentally verified by using Latrunculin A. Parameter variation analyses indicate that membrane physical forces control cell shape during spreading, whereas the biochemical reactions underlying actin cytoskeleton dynamics control cell size (i.e., the rate of spreading). Thus, during cell spreading, a balance between the biochemical and biophysical properties determines the cell size and shape. These mechanistic insights can provide a format for understanding how force and chemical signals together modulate cellular regulatory networks to control cell motility.

Genetic switch systems with mutual repression of two transcription factors are studied using deterministic methods (rate equations) and stochastic methods (the master equation and Monte Carlo simulations). These systems exhibit bistability, namely two stable states such that spontaneous transitions between them are rare. Induced transitions may take place as a result of an external stimulus. We study several variants of the genetic switch and examine the effects of cooperative binding, exclusive binding, protein-protein interactions and degradation of bound repressors. We identify the range of parameters in which bistability takes place, enabling the system to function as a switch. Numerous studies have concluded that cooperative binding is a necessary condition for the emergence of bistability in these systems. We show that a suitable combination of network structure and stochastic effects gives rise to bistability even without cooperative binding. The average time between spontaneous transitions is evaluated as a function of the biological parameters.

Motivated by recent observations of deuterated molecules in the interstellar medium, we examine the production of HD and D 2 molecules on dust grain surfaces. A mechanism for the enhanced production of these deuterated molecules is studied. This mechanism applies on grain surfaces on which D atoms stick more strongly than H atoms, under conditions of low flux and within a suitable range of temperatures. It is shown that under these conditions the production rates of HD and D 2 are greatly enhanced (vs. the H 2 production rate) compared with the expected rates based on the adsorption of gas-phase atomic abundances of D and H. The enhancement in the formation rate of HD is comparable with the enhancement due to gas-phase ion-molecule reactions in diffuse clouds.

Abstract. While most chemical reactions in the interstellar medium take place in the gas phase, those occurring on the surfaces of dust grains play an essential role. Such surface reactions include the catalytic production of molecular hydrogen as well as more complex reaction networks producing ice mantles and various organic molecules. Chemical models based on rate equations including both gas phase and grain surface reactions have been used in order to simulate the formation of chemical complexity in interstellar clouds. For reactions in the gas phase and on large grains, rate equations, which are highly efficient to simulate, are an ideal tool. However, for small grains under low flux, the typical number of atoms or molecules of certain reactive species on a grain may go down to order one or less. In this case the discrete nature of the populations of reactive species as well as the fluctuations become dominant, thus the mean-field approximation on which the rate equations are based does not apply. Recently, a master equation approach that provides a good description of chemical reactions on interstellar dust grains was proposed. Here we present a related approach based on moment equations that can be obtained from the master equation. These equations describe the time evolution of the moments of the distribution of the population of the various chemical species on the grain. An advantage of this approach is the fact that the production rates of molecular species are expressed directly in terms of these moments. Here we use the moment equations to calculate the rate of molecular hydrogen formation on small grains. It is shown that the moment equation approach is efficient in this case in which only a single reactive species is involved. The set of equations for the case of two species is presented and the difficulties in implementing this approach for complex reaction networks involving multiple species are discussed.

Cells often mount ultrasensitive (switch-like) responses to stimuli. The design principles underlying many switches are not known. We computationally studied the switching behavior of GTPases, and found that this first-order kinetic system can show ultrasensitivity. Analytical solutions indicate that ultrasensitive first-order reactions can yield switches that respond to signal amplitude or duration. The three-component GTPase system is analogous to the physical fermion gas. This analogy allows for an analytical understanding of the functional capabilities of first-order ultrasensitive systems. Experiments show amplitude-and time-dependent Rap GTPase switching in response to Cannabinoid-1 receptor signal. This firstorder switch arises from relative reaction rates and the concentrations ratios of the activator and deactivator of Rap. First-order ultrasensitivity is applicable to many systems where threshold for transition between states is dependent on the duration, amplitude, or location of a distal signal. We conclude that the emergence of ultrasensitivity from coupled first-order reactions provides a versatile mechanism for the design of biochemical switches.GTPase | signaling | ultrasensitivity