Local and global modes of drug action in biochemical networks

It becomes increasingly accepted that a shift is needed from the traditional target-based approach of drug development to an integrated perspective of drug action in biochemical systems. We here present an integrative analysis of the interactions between drugs and metabolism based on the concept of drug scope. The drug scope represents the set of metabolic compounds and reactions that are potentially affected by a drug. We constructed and analyzed the scopes of all US approved drugs having metabolic targets. Our analysis shows that the distribution of drug scopes is highly uneven, and that drugs can be classified into several categories based on their scopes. Some of them have small scopes corresponding to localized action, while others have large scopes corresponding to potential large-scale systemic action. These groups are well conserved throughout different topologies of the underlying metabolic network. They can furthermore be associated to specific drug therapeutic properties

Bridging topological and functional information in protein interaction networks by short loops profiling

Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to AP, ACCC and FF, and BB/J016284/1 to NSBT) and by the Leukaemia & Lymphoma Research (to NSBT and FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

The phase transition in random catalytic sets

The notion of (auto) catalytic networks has become a cornerstone in understanding the possibility of a sudden dramatic increase of diversity in biological evolution as well as in the evolution of social and economical systems. Here we study catalytic random networks with respect to the final outcome diversity of products. We show that an analytical treatment of this longstanding problem is possible by mapping the problem onto a set of non-linear recurrence equations. The solution of these equations show a crucial dependence of the final number of products on the initial number of products and the density of catalytic production rules. For a fixed density of rules we can demonstrate the existence of a phase transition from a practically unpopulated regime to a fully populated and diverse one. The order parameter is the number of final products. We are able to further understand the origin of this phase transition as a crossover from one set of solutions from a quadratic equation to the other.Comment: 7 pages, ugly eps files due to arxiv restriction

Evidential Label Propagation Algorithm for Graphs

Community detection has attracted considerable attention crossing many areas as it can be used for discovering the structure and features of complex networks. With the increasing size of social networks in real world, community detection approaches should be fast and accurate. The Label Propagation Algorithm (LPA) is known to be one of the near-linear solutions and benefits of easy implementation, thus it forms a good basis for efficient community detection methods. In this paper, we extend the update rule and propagation criterion of LPA in the framework of belief functions. A new community detection approach, called Evidential Label Propagation (ELP), is proposed as an enhanced version of conventional LPA. The node influence is first defined to guide the propagation process. The plausibility is used to determine the domain label of each node. The update order of nodes is discussed to improve the robustness of the method. ELP algorithm will converge after the domain labels of all the nodes become unchanged. The mass assignments are calculated finally as memberships of nodes. The overlapping nodes and outliers can be detected simultaneously through the proposed method. The experimental results demonstrate the effectiveness of ELP.Comment: 19th International Conference on Information Fusion, Jul 2016, Heidelber, Franc

Lifeguard: Local Health Awareness for More Accurate Failure Detection

SWIM is a peer-to-peer group membership protocol with attractive scaling and robustness properties. However, slow message processing can cause SWIM to mark healthy members as failed (so called false positive failure detection), despite inclusion of a mechanism to avoid this. We identify the properties of SWIM that lead to the problem, and propose Lifeguard, a set of extensions to SWIM which consider that the local failure detector module may be at fault, via the concept of local health. We evaluate this approach in a precisely controlled environment and validate it in a real-world scenario, showing that it drastically reduces the rate of false positives. The false positive rate and detection time for true failures can be reduced simultaneously, compared to the baseline levels of SWIM