A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes.

We present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. Starting from an approximate mathematical model, we employ a "cycle of knowledge" strategy, identifying the steps with most control over flux. Kinetic parameters of the individual isoenzymes within these steps are measured experimentally under a standardised set of conditions.

Components of the neural signal underlying congenital nystagmus.

Congenital nystagmus is an involuntary bilateral horizontal oscillation of the eyes that develops soon after birth. In this study, the time constants of each of the components of the neural signal underlying congenital nystagmus were obtained by time series analysis and interpreted by comparison with those of the normal oculomotor system. In the neighbourhood of the fixation position, the system generating the neural signal is approximately linear with 3 degrees of freedom.

A max-plus model of ribosome dynamics during mRNA translation.

We examine the dynamics of the translation stage of cellular protein production, in which ribosomes move uni-directionally along an mRNA strand, building amino acid chains as they go. We describe the system using a timed event graph-a class of Petri net useful for studying discrete events, which have to satisfy constraints. We use max-plus algebra to describe a deterministic version of the model, where the constraints represent steric effects which prevent more than one ribosome reading a given codon at a given time and delays associated with the availability of the different tRNAs.

A systematic survey of the response of a model NF-κB signalling pathway to TNFα stimulation.

White's lab established that strong, continuous stimulation with tumour necrosis factor-α (TNFα) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor κB (NF-κB). But the intensity of the TNFα signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of TNFα stimulation and the existence of sustained NF-κB oscillations.

Interactions among oscillatory pathways in NF-kappa B signaling.

Background: Sustained stimulation with tumour necrosis factor alpha (TNF-alpha) induces substantial oscillations--observed at both the single cell and population levels--in the nuclear factor kappa B (NF-kappa B) system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer) and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways.

Systematic integration of experimental data and models in systems biology.

Background: The behaviour of biological systems can be deduced from their mathematical models. However, multiple sources of data in diverse forms are required in the construction of a model in order to define its components and their biochemical reactions, and corresponding parameters. Automating the assembly and use of systems biology models is dependent upon data integration processes involving the interoperation of data and analytical resources.

Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription.

The nuclear factor kappaB (NF-kappaB) transcription factor regulates cellular stress responses and the immune response to infection. NF-kappaB activation results in oscillations in nuclear NF-kappaB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor-alpha at various intervals to mimic pulsatile inflammatory signals.

A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology.

Genomic data allow the large-scale manual or semi-automated assembly of metabolic network reconstructions, which provide highly curated organism-specific knowledge bases. Although several genome-scale network reconstructions describe Saccharomyces cerevisiae metabolism, they differ in scope and content, and use different terminologies to describe the same chemical entities. This makes comparisons between them difficult and underscores the desirability of a consolidated metabolic network that collects and formalizes the 'community knowledge' of yeast metabolism.

Dynamics of saccadic oscillations.

The brainstem circuitry underlying saccades is symmetrical with respect to the midline. The oculomotor behaviour generated by the circuitry depends on a combination of signals passed along fibre tracts and less easily identifiable connections, such as those across the midline. The midline crossing connections are often affected by developmental disorders which give rise to unstable eye movements (see J.

Something from nothing: bridging the gap between constraint-based and kinetic modelling.

Two divergent modelling methodologies have been adopted to increase our understanding of metabolism and its regulation. Constraint-based modelling highlights the optimal path through a stoichiometric network within certain physicochemical constraints. Such an approach requires minimal biological data to make quantitative inferences about network behaviour; however, constraint-based modelling is unable to give an insight into cellular substrate concentrations.

Information-theoretic sensitivity analysis: a general method for credit assignment in complex networks.

Most systems can be represented as networks that couple a series of nodes to each other via one or more edges, with typically unknown equations governing their quantitative behaviour. A major question then pertains to the importance of each of the elements that act as system inputs in determining the output(s). We show that any such system can be treated as a 'communication channel' for which the associations between inputs and outputs can be quantified via a decomposition of their mutual information into different components characterizing the main effect of individual inputs and their interactions.

Bridging the gap between in silico and cell-based analysis of the nuclear factor-kappaB signaling pathway by in vitro studies of IKK2.

Previously, we have shown by sensitivity analysis, that the oscillatory behavior of nuclear factor (NF-kappaB) is coupled to free IkappaB kinase-2 (IKK2) and IkappaBalpha(IkappaBalpha), and that the phosphorylation of IkappaBalpha by IKK influences the amplitude of NF-kappaB oscillations. We have performed further analyses of the behavior of NF-kappaB and its signal transduction network to understand the dynamics of this system. A time lapse study of NF-kappaB translocation in 10,000 cells showed discernible oscillations in levels of nuclear NF-kappaB amongst cells when stimulated with interleukin (IL-1alpha), which suggests a small degree of synchronization amongst the cell population.

Insights into the behaviour of systems biology models from dynamic sensitivity and identifiability analysis: a case study of an NF-kappaB signalling pathway.

Mathematical modelling offers a variety of useful techniques to help in understanding the intrinsic behaviour of complex signal transduction networks. From the system engineering point of view, the dynamics of metabolic and signal transduction models can always be described by nonlinear ordinary differential equations (ODEs) following mass balance principles. Based on the state-space formulation, many methods from the area of automatic control can conveniently be applied to the modelling, analysis and design of cell networks.

A new framework for investigating both normal and abnormal eye movements.

Any comprehensive framework for understanding eye movements has to include both normal and abnormal eye movement behaviour. One approach which is applicable to the entire range of oculomotor behaviour is provided by the techniques of nonlinear dynamics. The stability of models of the oculomotor system can be analysed in terms of the characteristics of their fixed points and periodic orbits, and the method of delays can be used to recover such parameters from measurements of eye position.

Characterisation of congenital nystagmus waveforms in terms of periodic orbits.

Because the oscillatory eye movements of congenital nystagmus vary from cycle to cycle, there is no clear relationship between the waveform produced and the underlying abnormality of the ocular motor system. We consider the durations of successive cycles of nystagmus which could be (1) completely determined by the lengths of the previous cycles, (2) completely independent of the lengths of the previous cycles or (3) a mixture of the two. The behaviour of a deterministic system can be characterised in terms of a collection of (unstable) oscillations, referred to as periodic orbits, which make up the system.