A mass action model of a fibroblast growth factor signaling pathway and its simplification

We consider a kinetic law of mass action model for Fibroblast Growth Factor (FGF) signaling, focusing on the induction of the RAS-MAP kinase pathway via GRB2 binding. Our biologically simple model suffers a combinatorial explosion in the number of differential equations required to simulate the system. In addition to numerically solving the full model, we show that it can be accurately simplified. This requires combining matched asymptotics, the quasi-steady state hypothesis, and the fact subsets of the equations decouple asymptotically. Both the full and simplified models reproduce the qualitative dynamics observed experimentally and in previous stochastic models. The simplified model also elucidates both the qualitative features of GRB2 binding and the complex relationship between SHP2 levels, the rate SHP2 induces dephosphorylation and levels of bound GRB2. In addition to providing insight into the important and redundant features of FGF signaling, such work further highlights the usefulness of numerous simplification techniques in the study of mass action models of signal transduction, as also illustrated recently by Borisov and co-workers (Borisov et al. in Biophys. J. 89, 951–66, 2005, Biosystems 83, 152–66, 2006; Kiyatkin et al. in J. Biol. Chem. 281, 19925–9938, 2006). These developments will facilitate the construction of tractable models of FGF signaling, incorporating further biological realism, such as spatial effects or realistic binding stoichiometries, despite a more severe combinatorial explosion associated with the latter

Probabilistic model checking of complex biological pathways

Probabilistic model checking is a formal verification technique that has been successfully applied to the analysis of systems from a broad range of domains, including security and communication protocols, distributed algorithms and power management. In this paper we illustrate its applicability to a complex biological system: the FGF (Fibroblast Growth Factor) signalling pathway. We give a detailed description of how this case study can be modelled in the probabilistic model checker PRISM, discussing some of the issues that arise in doing so, and show how we can thus examine a rich selection of quantitative properties of this model. We present experimental results for the case study under several different scenarios and provide a detailed analysis, illustrating how this approach can be used to yield a better understanding of the dynamics of the pathway

A framework for modelling, simulation and control of integrated urban wastewater system

This paper is concerned with the integrated modelling, and control of urban wastewater systems (UWS) comprising the wastewater treatment plants (WTP), receiving waters (river) and the sewer networks. A unified framework is developed and simple models are used and implemented in Matlab/Simulink to produce a toolbox. Novel linear and nonlinear control structures are then proposed to design integrated control systems to improve the river water quality. A case study is simulated and simulation results are presented to demonstrate the possible improvement that can be achieved using a holistic integrated control system approac

Metabotropic Glutamate Receptor Activation in Cerebelar Purkinje Cells as Substrate for Adaptive Timing of the Classicaly Conditioned Eye Blink Response

To understand how the cerebellum adaptively times the classically conditioned nictitating membrane response (NMR), a model of the metabotropic glutamate receptor (mGluR) second messenger system in cerebellar Purkinje cells is constructed. In the model slow responses, generated postsynaptically by mGluR-mediated phosphoinositide hydrolysis, and calcium release from intracellular stores, bridge the interstimulus interval (ISI) between the onset of parallel fiber activity associated with the conditioned stimulus (CS) and climbing fiber activity associated with unconditioned stimulus (US) onset. Temporal correlation of metabotropic responses and climbing fiber signals produces persistent phosphorylation of both AMPA receptors and Ca2+-dependent K+ channels. This is responsible for long-term depression (LTD) of AMPA receptors. The phosphorylation of Ca2+-dependent K+ channels leads to a reduction in baseline membrane potential and a reduction of Purkinje cell population firing during the CS-US interval. The Purkinje cell firing decrease disinhibits cerebellar nuclear cells which then produce an excitatory response corresponding to the learned movement. Purkinje cell learning times the response, while nuclear cell learning can calibrate it. The model reproduces key features of the conditioned rabbit NMR: Purkinje cell population response is properly timed, delay conditioning occurs for ISIs of up to four seconds while trace conditioning occurs only at shorter ISIs, mixed training at two different ISis produces a double-peaked response, and ISIs of 200-400ms produce maximal responding. Biochemical similarities between timed cerebellar learning and photoreceptor transduction, and circuit similarities between the timed cerebellar circuit and a timed dentate-CA3 hippocampal circuit, are noted.Office of Naval Research (N00014- 92-J-4015, N00014-92-J-1309, N00014-95-1-0409); Air Force Office of Scientific Research (F49620-92-J-0225);National Science Foundation (IRI-90-24877

Power quality and electromagnetic compatibility: special report, session 2

The scope of Session 2 (S2) has been defined as follows by the Session Advisory Group and the Technical Committee: Power Quality (PQ), with the more general concept of electromagnetic compatibility (EMC) and with some related safety problems in electricity distribution systems. Special focus is put on voltage continuity (supply reliability, problem of outages) and voltage quality (voltage level, flicker, unbalance, harmonics). This session will also look at electromagnetic compatibility (mains frequency to 150 kHz), electromagnetic interferences and electric and magnetic fields issues. Also addressed in this session are electrical safety and immunity concerns (lightning issues, step, touch and transferred voltages). The aim of this special report is to present a synthesis of the present concerns in PQ&EMC, based on all selected papers of session 2 and related papers from other sessions, (152 papers in total). The report is divided in the following 4 blocks: Block 1: Electric and Magnetic Fields, EMC, Earthing systems Block 2: Harmonics Block 3: Voltage Variation Block 4: Power Quality Monitoring Two Round Tables will be organised: - Power quality and EMC in the Future Grid (CIGRE/CIRED WG C4.24, RT 13) - Reliability Benchmarking - why we should do it? What should be done in future? (RT 15

The Effects of Neurosteroids, such as Pregnenolone Sulfate and its receptor, TrpM3 in the Retina.

Pregnenolone sulfate (PregS) is the precursor to all steroid hormones and is produced in neurons in an activity dependent manner. Studies have shown that PregS production is upregulated during certain critical periods of development, such as in the first year of life in humans, during adolescence, and during pregnancy. Conversely, PregS is decreased during aging, as well as in several neurodevelopmental and neurodegenerative conditions. There are several known targets of PregS, such as a positive allosteric modulator NMDA receptors, sigma1 receptor, and as a negative allosteric modulator of GABA-A receptors. Recently a transient receptor potential channel, TrpM3 has been shown to be activated by PregS. TrpM3 is a heat sensitive (between 33-40oC), non-selective cation channel that is outwardly rectifying. PregS has been shown to increase the frequency of post-synaptic currents in the hippocampus and developing cerebellum, induce calcium transients in a subset of retinal ganglion cells, and enhance memory formation in rodents. Furthermore, PregS mediated TrpM3 activation induces calcium dependent transcription of early immediate genes, suggesting that activation of this channel may produce lasting effects on cells and systems in which it is activated. Because PregS is abundant during critical periods of development, we hypothesized that it may play a significant role during development. Furthermore, the role of PregS or its receptor TrpM3, has not previously been well characterized in the retina. To address this question, in this dissertation, we examine the role of the neurosteroid PregS and its receptor, TrpM3, on retinal waves, which are characteristic of specific stages of synaptic development and connectivity. Briefly, we show that PregS induces a TrpM3 dependent prolonged calcium transient, which is absent in the TrpM3-/- animals and increases the correlation of cell participation in waves. We also show that TrpM3 increases the frequency of post-synaptic currents, indicating a mechanism of action presynaptic to retinal ganglion cells, but that TrpM3 is expressed primarily in RGCs and Müller glia. Taken together, our results indicate that both PregS and TrpM3 are important in modulating spontaneous synaptic activity during development

Time domain analysis of switching transient fields in high voltage substations

Switching operations of circuit breakers and disconnect switches generate transient currents propagating along the substation busbars. At the moment of switching, the busbars temporarily acts as antennae radiating transient electromagnetic fields within the substations. The radiated fields may interfere and disrupt normal operations of electronic equipment used within the substation for measurement, control and communication purposes. Hence there is the need to fully characterise the substation electromagnetic environment as early as the design stage of substation planning and operation to ensure safe operations of the electronic equipment. This paper deals with the computation of transient electromagnetic fields due to switching within a high voltage air-insulated substation (AIS) using the finite difference time domain (FDTD) metho