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

Value Iteration for Long-run Average Reward in Markov Decision Processes

Markov decision processes (MDPs) are standard models for probabilistic systems with non-deterministic behaviours. Long-run average rewards provide a mathematically elegant formalism for expressing long term performance. Value iteration (VI) is one of the simplest and most efficient algorithmic approaches to MDPs with other properties, such as reachability objectives. Unfortunately, a naive extension of VI does not work for MDPs with long-run average rewards, as there is no known stopping criterion. In this work our contributions are threefold. (1) We refute a conjecture related to stopping criteria for MDPs with long-run average rewards. (2) We present two practical algorithms for MDPs with long-run average rewards based on VI. First, we show that a combination of applying VI locally for each maximal end-component (MEC) and VI for reachability objectives can provide approximation guarantees. Second, extending the above approach with a simulation-guided on-demand variant of VI, we present an anytime algorithm that is able to deal with very large models. (3) Finally, we present experimental results showing that our methods significantly outperform the standard approaches on several benchmarks

Equilibria-based Probabilistic Model Checking for Concurrent Stochastic Games

Probabilistic model checking for stochastic games enables formal verification of systems that comprise competing or collaborating entities operating in a stochastic environment. Despite good progress in the area, existing approaches focus on zero-sum goals and cannot reason about scenarios where entities are endowed with different objectives. In this paper, we propose probabilistic model checking techniques for concurrent stochastic games based on Nash equilibria. We extend the temporal logic rPATL (probabilistic alternating-time temporal logic with rewards) to allow reasoning about players with distinct quantitative goals, which capture either the probability of an event occurring or a reward measure. We present algorithms to synthesise strategies that are subgame perfect social welfare optimal Nash equilibria, i.e., where there is no incentive for any players to unilaterally change their strategy in any state of the game, whilst the combined probabilities or rewards are maximised. We implement our techniques in the PRISM-games tool and apply them to several case studies, including network protocols and robot navigation, showing the benefits compared to existing approaches

Testing, Verification and Improvements of Timeliness in ROS Processes

This paper addresses the problem improving response times of robots implemented in the Robotic Operating System (ROS) using formal verification of computational-time feasibility. In order to verify the real time behaviour of a robot under uncertain signal processing times, methods of formal verification of timeliness properties are proposed for data flows in a ROS-based control system using Probabilistic Timed Programs (PTPs). To calculate the probability of success under certain time limits, and to demonstrate the strength of our approach, a case study is implemented for a robotic agent in terms of operational times verification using the PRISM model checker, which points to possible enhancements to the operation of the robotic agent

Physiotherapeutic management in the separation of the white borderline

Dissolution of the white border of the rectus abdominal muscle is a disruption of the functioning of the rectus muscle, which results in loosening of the white border. As a result, a characteristic muscle stretch is visible. This defect affects a significant number of pregnant women and is not just an aesthetic problem. There are many factors that contribute to the above-mentioned ailments. To get the best treatment results, it is important to diagnose the problem early. For this purpose, special tests are used. The ease with which they are made enables the patient to control the separation of the frontier by the patient. The implementation of therapy should take place already in the first days after delivery. It is important to start therapy with posture corrective exercises, breathing exercises and learning how to properly perform everyday activities. Then we implement exercises that involve the abdominal muscles. The exercise program can be supplemented with dynamic slicing. A holistic approach to the problem and combining different forms of therapy allows you to obtain optimal results

Local abstraction refinement for probabilistic timed programs

We consider models of programs that incorporate probability, dense real-time and data. We present a new abstraction refinement method for computing minimum and maximum reachability probabilities for such models. Our approach uses strictly local refinement steps to reduce both the size of abstractions generated and the complexity of operations needed, in comparison to previous approaches of this kind. We implement the techniques and evaluate them on a selection of large case studies, including some infinite-state probabilistic real-time models, demonstrating improvements over existing tools in several cases

Quantitative multi-objective verification for probabilistic systems

We present a verification framework for analysing multiple quantitative objectives of systems that exhibit both nondeterministic and stochastic behaviour. These systems are modelled as probabilistic automata, enriched with cost or reward structures that capture, for example, energy usage or performance metrics. Quantitative properties of these models are expressed in a specification language that incorporates probabilistic safety and liveness properties, expected total cost or reward, and supports multiple objectives of these types. We propose and implement an efficient verification framework for such properties and then present two distinct applications of it: firstly, controller synthesis subject to multiple quantitative objectives; and, secondly, quantitative compositional verification. The practical applicability of both approaches is illustrated with experimental results from several large case studies

When images work faster than words: The integration of content-based image retrieval with the Northumbria Watermark Archive

Information on the manufacture, history, provenance, identification, care and conservation of paper-based artwork/objects is disparate and not always readily available. The Northumbria Watermark Archive will incorporate such material into a database, which will be made freely available on the Internet providing an invaluable resource for conservation, research and education. The efficiency of a database is highly dependant on its search mechanism. Text based mechanisms are frequently ineffective when a range of descriptive terminologies might be used i.e. when describing images or translating from foreign languages. In such cases a Content Based Image Retrieval (CBIR) system can be more effective. Watermarks provide paper with unique visual identification characteristics and have been used to provide a point of entry to the archive that is more efficient and effective than a text based search mechanism. The research carried out has the potential to be applied to any numerically large collection of images with distinctive features of colour, shape or texture i.e. coins, architectural features, picture frame profiles, hallmarks, Japanese artists stamps etc. Although the establishment of an electronic archive incorporating a CBIR system can undoubtedly improve access to large collections of images and related data, the development is rarely trouble free. This paper discusses some of the issues that must be considered i.e. collaboration between disciplines; project management; copying and digitising objects; content based image retrieval; the Northumbria Watermark Archive; the use of standardised terminology within a database as well as copyright issues

Oral administration of Lactococcus lactis expressing synthetic genes of myelin antigens in decreasing experimental autoimmune encephalomyelitis in rats

ABSTRACT Background: Multiple sclerosis is a human autoimmunological disease that causes neurodegeneration. One of the potential ways to stop its development is induction of oral tolerance, whose effect lies in decreasing immune response to the fed antigen. It was shown on animal models that administration of specific epitopes of the three main myelin proteins, myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) results in induction of oral tolerance and suppression of disease symptoms. Application of bacterial cells to produce and deliver antigens to gut mucosa seems to be an attractive method for oral tolerance induction in treatment of diseases with autoimmune background. Material/Methods: Synthetic genes of MOG35-55, MBP85-97 and PLP139-151 myelin epitopes were generated and cloned in Lactococcus lactis under a CcpA-regulated promoter. The tolerogenic effect of bacterial preparations was tested on experimental autoimmune encephalomyelitis, the animal model of MS. EAE was induced in rats by intradermal injection of guinea pig homogenate into hind paws. Results: Rats were administered preparations containing whole-cell lysates of L. lactis producing myelin antigens using different feeding schemes. Our study demonstrates that 20-fold, but not 4-fold, intragastric administration of autoantigen-expressing L. lactis cells under specific conditions reduces the clinical symptoms of EAE in rats. Conclusions: The present study evaluates the use of myelin antigens produced in L. lactis in inhibiting the on-set of experimental autoimmune encephalomyelitis in rats. Obtained results indicate that application of such recombinant cells can be an attractive method of oral tolerance induction