Splitting Strategy for Simulating Genetic Regulatory Networks

The splitting approach is developed for the numerical simulation of genetic regulatory networks with a stable steady-state structure. The numerical results of the simulation of a one-gene network, a two-gene network, and a p53-mdm2 network show that the new splitting methods constructed in this paper are remarkably more effective and more suitable for long-term computation with large steps than the traditional general-purpose Runge-Kutta methods. The new methods have no restriction on the choice of stepsize due to their infinitely large stability regions

A subsystems approach for parameter estimation of ODE models of hybrid systems

We present a new method for parameter identification of ODE system descriptions based on data measurements. Our method works by splitting the system into a number of subsystems and working on each of them separately, thereby being easily parallelisable, and can also deal with noise in the observations.Comment: In Proceedings HSB 2012, arXiv:1208.315

Split histidine kinases enable ultrasensitivity and bistability in two-component signaling networks

Bacteria sense and respond to their environment through signaling cascades generally referred to as two-component signaling networks. These networks comprise histidine kinases and their cognate response regulators. Histidine kinases have a number of biochemical activities: ATP binding, autophosphorylation, the ability to act as a phosphodonor for their response regulators, and in many cases the ability to catalyze the hydrolytic dephosphorylation of their response regulator. Here, we explore the functional role of “split kinases” where the ATP binding and phosphotransfer activities of a conventional histidine kinase are split onto two distinct proteins that form a complex. We find that this unusual configuration can enable ultrasensitivity and bistability in the signal-response relationship of the resulting system. These dynamics are displayed under a wide parameter range but only when specific biochemical requirements are met. We experimentally show that one of these requirements, namely segregation of the phosphatase activity predominantly onto the free form of one of the proteins making up the split kinase, is met in Rhodobacter sphaeroides. These findings indicate split kinases as a bacterial alternative for enabling ultrasensitivity and bistability in signaling networks. Genomic analyses reveal that up 1.7% of all identified histidine kinases have the potential to be split and bifunctional

The Reasonable Effectiveness of Randomness in Scalable and Integrative Gene Regulatory Network Inference and Beyond

Gene regulation is orchestrated by a vast number of molecules, including transcription factors and co-factors, chromatin regulators, as well as epigenetic mechanisms, and it has been shown that transcriptional misregulation, e.g., caused by mutations in regulatory sequences, is responsible for a plethora of diseases, including cancer, developmental or neurological disorders. As a consequence, decoding the architecture of gene regulatory networks has become one of the most important tasks in modern (computational) biology. However, to advance our understanding of the mechanisms involved in the transcriptional apparatus, we need scalable approaches that can deal with the increasing number of large-scale, high-resolution, biological datasets. In particular, such approaches need to be capable of efficiently integrating and exploiting the biological and technological heterogeneity of such datasets in order to best infer the underlying, highly dynamic regulatory networks, often in the absence of sufficient ground truth data for model training or testing. With respect to scalability, randomized approaches have proven to be a promising alternative to deterministic methods in computational biology. As an example, one of the top performing algorithms in a community challenge on gene regulatory network inference from transcriptomic data is based on a random forest regression model. In this concise survey, we aim to highlight how randomized methods may serve as a highly valuable tool, in particular, with increasing amounts of large-scale, biological experiments and datasets being collected. Given the complexity and interdisciplinary nature of the gene regulatory network inference problem, we hope our survey maybe helpful to both computational and biological scientists. It is our aim to provide a starting point for a dialogue about the concepts, benefits, and caveats of the toolbox of randomized methods, since unravelling the intricate web of highly dynamic, regulatory events will be one fundamental step in understanding the mechanisms of life and eventually developing efficient therapies to treat and cure diseases

Spatio-Temporal Patterns act as Computational Mechanisms governing Emergent behavior in Robotic Swarms

open access articleOur goal is to control a robotic swarm without removing its swarm-like nature. In other words, we aim to intrinsically control a robotic swarm emergent behavior. Past attempts at governing robotic swarms or their selfcoordinating emergent behavior, has proven ineffective, largely due to the swarm’s inherent randomness (making it difficult to predict) and utter simplicity (they lack a leader, any kind of centralized control, long-range communication, global knowledge, complex internal models and only operate on a couple of basic, reactive rules). The main problem is that emergent phenomena itself is not fully understood, despite being at the forefront of current research. Research into 1D and 2D Cellular Automata has uncovered a hidden computational layer which bridges the micromacro gap (i.e., how individual behaviors at the micro-level influence the global behaviors on the macro-level). We hypothesize that there also lie embedded computational mechanisms at the heart of a robotic swarm’s emergent behavior. To test this theory, we proceeded to simulate robotic swarms (represented as both particles and dynamic networks) and then designed local rules to induce various types of intelligent, emergent behaviors (as well as designing genetic algorithms to evolve robotic swarms with emergent behaviors). Finally, we analysed these robotic swarms and successfully confirmed our hypothesis; analyzing their developments and interactions over time revealed various forms of embedded spatiotemporal patterns which store, propagate and parallel process information across the swarm according to some internal, collision-based logic (solving the mystery of how simple robots are able to self-coordinate and allow global behaviors to emerge across the swarm)

Comparison of evolutionary algorithms in gene regulatory network model inference

Background: The evolution of high throughput technologies that measure gene expression levels has created a data base for inferring GRNs (a process also known as reverse engineering of GRNs). However, the nature of these data has made this process very di±cult. At the moment, several methods of discovering qualitative causal relationships between genes with high accuracy from microarray data exist, but large scale quantitative analysis on real biological datasets cannot be performed, to date, as existing approaches are not suitable for real microarray data which are noisy and insu±cient. Results: This paper performs an analysis of several existing evolutionary algorithms for quantitative gene regulatory network modelling. The aim is to present the techniques used and o®er a comprehensive comparison of approaches, under a common framework. Algorithms are applied to both synthetic and real gene expression data from DNA microarrays, and ability to reproduce biological behaviour, scalability and robustness to noise are assessed and compared. Conclusions: Presented is a comparison framework for assessment of evolutionary algorithms, used to infer gene regulatory networks. Promising methods are identi¯ed and a platform for development of appropriate model formalisms is established

Behavior finding: Morphogenetic Designs Shaped by Function

Evolution has shaped an incredible diversity of multicellular living organisms, whose complex forms are self-made through a robust developmental process. This fundamental combination of biological evolution and development has served as an inspiration for novel engineering design methodologies, with the goal to overcome the scalability problems suffered by classical top-down approaches. Top-down methodologies are based on the manual decomposition of the design into modular, independent subunits. In contrast, recent computational morphogenetic techniques have shown that they were able to automatically generate truly complex innovative designs. Algorithms based on evolutionary computation and artificial development have been proposed to automatically design both the structures, within certain constraints, and the controllers that optimize their function. However, the driving force of biological evolution does not resemble an enumeration of design requirements, but much rather relies on the interaction of organisms within the environment. Similarly, controllers do not evolve nor develop separately, but are woven into the organism’s morphology. In this chapter, we discuss evolutionary morphogenetic algorithms inspired by these important aspects of biological evolution. The proposed methodologies could contribute to the automation of processes that design “organic” structures, whose morphologies and controllers are intended to solve a functional problem. The performance of the algorithms is tested on a class of optimization problems that we call behavior-finding. These challenges are not explicitly based on morphology or controller constraints, but only on the solving abilities and efficacy of the design. Our results show that morphogenetic algorithms are well suited to behavior-finding