Epigenetics as a first exit problem

We develop a framework to discuss stability of epigenetic states as first exit problems in dynamical systems with noise. We consider in particular the stability of the lysogenic state of the lambda prophage, which is known to exhibit exceptionally large stability. The formalism defines a quantative measure of robustness of inherited states. In contrast to Kramers' well-known problem of escape from a potential well, the stability of inherited states in our formulation is not a numerically trivial problem. The most likely exit path does not go along a steepest decent of a potential -- there is no potential. Instead, such a path can be described as a zero-energy trajectory between two equilibria in an auxiliary classical mechanical system. Finding it is similar to e.g. computing heteroclinic orbits in celestial mechanics. The overall lesson of this study is that an examination of equilibria and their bifurcations with changing parameter values allow us to quantify both the stability and the robustness of particular states of a genetic control system.Comment: 6 pages, 3 figures, in REVTe

Navigating Networks with Limited Information

We study navigation with limited information in networks and demonstrate that many real-world networks have a structure which can be described as favoring communication at short distance at the cost of constraining communication at long distance. This feature, which is robust and more evident with limited than with complete information, reflects both topological and possibly functional design characteristics. For example, the characteristics of the networks studied derived from a city and from the Internet are manifested through modular network designs. We also observe that directed navigation in typical networks requires remarkably little information on the level of individual nodes. By studying navigation, or specific signaling, we take a complementary approach to the common studies of information transfer devoted to broadcasting of information in studies of virus spreading and the like.Comment: 6 pages, 6 figures. For associated Java applet, see http://cmol.nbi.dk/models/bit/bit.htm

Time delay as a key to Apoptosis Induction in the p53 Network

A feedback mechanism that involves the proteins p53 and mdm2, induces cell death as a controled response to severe DNA damage. A minimal model for this mechanism demonstrates that the respone may be dynamic and connected with the time needed to translate the mdm2 protein. The response takes place if the dissociation constant k between p53 and mdm2 varies from its normal value. Although it is widely believed that it is an increase in k that triggers the response, we show that the experimental behaviour is better described by a decrease in the dissociation constant. The response is quite robust upon changes in the parameters of the system, as required by any control mechanism, except for few weak points, which could be connected with the onset of cancer

Networks and Cities: An Information Perspective

Traffic is constrained by the information involved in locating the receiver and the physical distance between sender and receiver. We here focus on the former, and investigate traffic in the perspective of information handling. We re-plot the road map of cities in terms of the information needed to locate specific addresses and create information city networks with roads mapped to nodes and intersections to links between nodes. These networks have the broad degree distribution found in many other complex networks. The mapping to an information city network makes it possible to quantify the information associated with locating specific addresses.Comment: 4 pages, 4 figure

Searchability of Networks

We investigate the searchability of complex systems in terms of their interconnectedness. Associating searchability with the number and size of branch points along the paths between the nodes, we find that scale-free networks are relatively difficult to search, and thus that the abundance of scale-free networks in nature and society may reflect an attempt to protect local areas in a highly interconnected network from nonrelated communication. In fact, starting from a random node, real-world networks with higher order organization like modular or hierarchical structure are even more difficult to navigate than random scale-free networks. The searchability at the node level opens the possibility for a generalized hierarchy measure that captures both the hierarchy in the usual terms of trees as in military structures, and the intrinsic hierarchical nature of topological hierarchies for scale-free networks as in the Internet.Comment: 9 pages, 10 figure

Oscillations and temporal signalling in cells

The development of new techniques to quantitatively measure gene expression in cells has shed light on a number of systems that display oscillations in protein concentration. Here we review the different mechanisms which can produce oscillations in gene expression or protein concentration, using a framework of simple mathematical models. We focus on three eukaryotic genetic regulatory networks which show "ultradian" oscillations, with time period of the order of hours, and involve, respectively, proteins important for development (Hes1), apoptosis (p53) and immune response (NFkB). We argue that underlying all three is a common design consisting of a negative feedback loop with time delay which is responsible for the oscillatory behaviour

Hide and seek on complex networks

Signaling pathways and networks determine the ability to communicate in systems ranging from living cells to human society. We investigate how the network structure constrains communication in social-, man-made and biological networks. We find that human networks of governance and collaboration are predictable on teat-a-teat level, reflecting well defined pathways, but globally inefficient. In contrast, the Internet tends to have better overall communication abilities, more alternative pathways, and is therefore more robust. Between these extremes the molecular network of Saccharomyces cerevisea is more similar to the simpler social systems, whereas the pattern of interactions in the more complex Drosophilia melanogaster, resembles the robust Internet.Comment: 5 pages, 5 figure

Corrections to Universal Fluctuations in Correlated Systems: the 2D XY-model

Generalized universality, as recently proposed, postulates a universal non-Gaussian form of the probability density function (PDF) of certain global observables for a wide class of highly correlated systems of finite volume N. Studying the 2D XY -model, we link its validity to renormalization group properties. It would be valid if there were a single dimension 0 operator, but the actual existence of several such operators leads to T-dependent corrections. The PDF is the Fourier transform of the partition function Z(q) of an auxiliary theory which differs by a dimension 0 perturbation with a very small imaginary coefficient iq/N from a theory which is asymptotically free in the infrared. We compute the PDF from a systematic loop expansion of ln Z(q).Comment: To be published in Phys. Rev.

Efficient chromosomal-scale DNA looping in Escherichia coli using multiple DNA-looping elements

Genes are frequently regulated by interactions between proteins that bind to the DNA near the gene and proteins that bind to DNA sites located far away, with the intervening DNA looped out. But it is not understood how efficient looping can occur when the sites are very far apart. We develop a simple theoretical framework that relates looping efficiency to the energetic cost and benefit of looping, allowing prediction of the efficiency of single or multiple nested loops at different distances. Measurements of absolute loop efficiencies for Lac repressor and λ CI using gene expression reporters in Escherichia coli cells show that, as predicted by the model, long-range DNA looping between a pair of sites can be strongly enhanced by the use of nested DNA loops or by the use of additional protein-binding sequences. A combination of these approaches was able to generate efficient DNA looping at a 200 kb distance.Nan Hao, Kim Sneppen, Keith E. Shearwin, Ian B. Dod