This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.tbiomed.com The latest articles from Theoretical Biology and Medical Modelling (ISSN 1742-4682) published by BioMed Central Background: Glutathione (GSH) plays an important role in anti-oxidant defense and detoxification reactions. It is primarily synthesized in the liver by the transulfuration pathway and exported to provide precursors for in situ GSH synthesis by other tissues. Deficits in glutathione have been implicated in aging and a host of diseases including Alzheimeras disease, Parkinsonas disease, cardiovascular disease, cancer, Down syndrome and autism. Approach: We explore the properties of glutathione metabolism in the liver by experimenting with a mathematical model of one-carbon metabolism, the transsulfuration pathway, and glutathione synthesis, transport, and breakdown. The model is based on known properties of the enzymes and the regulation of those enzymes by oxidative stress. We explore the regulation of glutathione synthesis and its sensitivity to fluctuations in amino acid input. We use the model to simulate the metabolic profiles previously observed in Down syndrome and autism and compare the model results to clinical data. Conclusions: We show that the glutathione pools in hepatic cells and in the blood are quite insensitive to fluctuations in amino acid input and offer an explanation based on model predictions. In contrast, we show that hepatic glutathione pools are highly sensitive to the level of oxidative stress. The model shows that trisomy 21, an increase in oxidative stress, and subsequent increased transport of GSH precursors by peripheral cells can explain the metabolic profile of Down syndrome. The model also correctly simulates the metabolic profile of autism when oxidative stress is substantially increased, the adenosine concentration is raised, and the uptake of GSH precursors by peripheral tissues is increased. Finally, we discuss how individual variation arises and its consequences for one-carbon and glutathione metabolism. http://www.tbiomed.com/content/5/1/8 Michael C Reed, Rachel L Thomas, Jovana Pavisic, S JILL James, Cornelia M Ulrich and H FREDERIK Nijhout Theoretical Biology and Medical Modelling 2008, 5:8 2008-04-28 doi:10.1186/1742-4682-5-8 Theoretical Biology and Medical Modelling 1742-4682 5 8 2008-04-28 The cancer incidence increases with age. This epidemiological pattern of cancer incidence can be attributed to molecular and cellular processes of individual subjects. Also, the incidence of cancer with ages can be controlled by genes. Here we present a dynamic statistical model for explaining the epidemiological pattern of cancer incidence based on individual genes that regulate cancer formation and progression. We incorporate the mathematical equations of age-specific cancer incidence into a framework for functional mapping aimed at identifying quantitative trait loci (QTLs) for dynamic changes of a complex trait. The mathematical parameters that specify differences in the curve of cancer incidence among QTL genotypes are estimated within the context of maximum likelihood. The model provides testable quantitative hypotheses about the initiation and duration of genetic expression for QTLs involved in cancer progression. Computer simulation was used to examine the statistical behavior of the model. The model can be used as a tool for explaining the epidemiological pattern of cancer incidence. http://www.tbiomed.com/content/5/1/7 Kiranmoy Das and Rongling Wu Theoretical Biology and Medical Modelling 2008, 5:7 2008-04-16 doi:10.1186/1742-4682-5-7 Theoretical Biology and Medical Modelling 1742-4682 5 7 2008-04-16 Background: Genomic imprinting, a phenomenon referring to nonequivalent expression of alleles depending on their parental origins, has been widely observed in nature. It has been shown recently that the epigenetic modification of an imprinted gene can be detected through a genetic mapping approach. Such an approach is developed based on traditional quantitative trait loci (QTL) mapping focusing on single trait analysis. Recent studies have shown that most imprinted genes in mammals play an important role in controlling embryonic growth and post-natal development. For a developmental character such as growth, current approach is less efficient in dissecting the dynamic genetic effect of imprinted genes during individual ontology. Results: Functional mapping has been emerging as a powerful framework for mapping quantitative trait loci underlying complex traits showing developmental characteristics. To understand the genetic architecture of dynamic imprinted traits, we propose a mapping strategy by integrating the functional mapping approach with genomic imprinting. We demonstrate the approach through mapping imprinted QTL controlling growth trajectories in an inbred F2 population. The statistical behavior of the approach is shown through simulation studies, in which the parameters can be estimated with reasonable precision under different simulation scenarios. The utility of the approach is illustrated through real data analysis in an F2 family derived from LG/J and SM/J mouse stains. Three maternally imprinted QTLs are identified as regulating the growth trajectory of mouse body weight. Conclusion: The functional iQTL mapping approach developed here provides a quantitative and testable framework for assessing the interplay between imprinted genes and a developmental process, and will have important implications for elucidating the genetic architecture of imprinted traits. http://www.tbiomed.com/content/5/1/6 Yuehua Cui, Shaoyu Li and Gengxin Li Theoretical Biology and Medical Modelling 2008, 5:6 2008-03-17 doi:10.1186/1742-4682-5-6 Theoretical Biology and Medical Modelling 1742-4682 5 6 2008-03-17 Background: The Phenomenological Universalities approach has been developed by P.P. Delsanto and collaborators during the past 2–3 years. It represents a new tool for the analysis of experimental datasets and cross-fertilization among different fields, from physics/engineering to medicine and social sciences. In fact, it allows similarities to be detected among datasets in totally different fields and acts upon them as a magnifying glass, enabling all the available information to be extracted in a simple way. In nonlinear problems it allows the nonscaling invariance to be retrieved by means of suitable redefined fractal-dimensioned variables. Results: The main goal of the present contribution is to extend the applicability of the new approach to the study of problems of growth with cyclicity, which are of particular relevance in the fields of biology and medicine. Conclusion: As an example of its implementation, the method is applied to the analysis of human growth curves. The excellent quality of the results (R2 = 0.988) demonstrates the usefulness and reliability of the approach. http://www.tbiomed.com/content/5/1/5 Pier Paolo Delsanto, Antonio S Gliozzi and Caterina Guiot Theoretical Biology and Medical Modelling 2008, 5:5 2008-02-29 doi:10.1186/1742-4682-5-5 Theoretical Biology and Medical Modelling 1742-4682 5 5 2008-02-29 SaSAT (Sampling and Sensitivity Analysis Tools) is a user-friendly software package for applying uncertainty and sensitivity analyses to mathematical and computational models of arbitrary complexity and context. The toolbox is built in Matlab®, a numerical mathematical software package, and utilises algorithms contained in the Matlab® Statistics Toolbox. However, Matlab® is not required to use SaSAT as the software package is provided as an executable file with all the necessary supplementary files. The SaSAT package is also designed to work seamlessly with Microsoft Excel but no functionality is forfeited if that software is not available. A comprehensive suite of tools is provided to enable the following tasks to be easily performed: efficient and equitable sampling of parameter space by various methodologies; calculation of correlation coefficients; regression analysis; factor prioritisation; and graphical output of results, including response surfaces, tornado plots, and scatterplots. Use of SaSAT is exemplified by application to a simple epidemic model. To our knowledge, a number of the methods available in SaSAT for performing sensitivity analyses have not previously been used in epidemiological modelling and their usefulness in this context is demonstrated. http://www.tbiomed.com/content/5/1/4 Alexander Hoare, David G Regan and David P Wilson Theoretical Biology and Medical Modelling 2008, 5:4 2008-02-27 doi:10.1186/1742-4682-5-4 Theoretical Biology and Medical Modelling 1742-4682 5 4 2008-02-27 Background: This study attempted to replicate Luminex experimental results for large numbers of beads per classifier using multiplexed assays and routine instrument use conditions. Conclusion: Using larger numbers of microspheres per classifier highlights a fundamental stochastic distribution of bead counts issue complicated by other factors. The more classifiers and the higher the count required per classifier there are, the more apparent the distribution of counts per classifier will be, and the more microspheres are required. Additional problems have been identified. Alternate methods of improving precision and reliability are recommended such as intraplexing and multi-well sample replicates to improve precision and confidence. http://www.tbiomed.com/content/5/1/3 Brian P Hanley Theoretical Biology and Medical Modelling 2008, 5:3 2008-01-28 doi:10.1186/1742-4682-5-3 Theoretical Biology and Medical Modelling 1742-4682 5 3 2008-01-28 Background: In hemodialysis patients, the most common cause of vascular access failure is neointimal hyperplasia of vascular smooth muscle cells at the venous anastomosis of arteriovenous fistulas and grafts. The release of growth factors due to surgical injury, oxidative stress and turbulent flow has been suggested as a possible mechanism for neointimal hyperplasia. Results: In this work, we construct a mathematical model which analyzes the role that growth factors might play in the stenosis at the venous anastomosis. The model consists of a system of partial differential equations describing the influence of oxidative stress and turbulent flow on growth factors, the interaction among growth factors, smooth muscle cells, and extracellular matrix, and the subsequent effect on the stenosis at the venous anastomosis, which, in turn, affects the level of oxidative stress and degree of turbulent flow. Computer simulations suggest that our model can be used to predict access stenosis as a function of the initial concentration of the growth factors inside the intimal-luminal space. Conclusion: The proposed model describes the formation of venous neointimal hyperplasia, based on pathogenic mechanisms. The results suggest that interventions aimed at specific growth factors may be successful in prolonging the life of the vascular access, while reducing the costs of vascular access maintenance. The model may also provide indication of when invasive access surveillance to repair stenosis should be undertaken. http://www.tbiomed.com/content/5/1/2 Paula Budu-Grajdeanu, Richard C Schugart, Avner Friedman, Christopher Valentine, Anil K Agarwal and Brad H Rovin Theoretical Biology and Medical Modelling 2008, 5:2 2008-01-23 doi:10.1186/1742-4682-5-2 Theoretical Biology and Medical Modelling 1742-4682 5 2 2008-01-23 Genetic and environmental agents that disrupt organogenesis are numerous and well described. Less well established, however, is the role of delay in the developmental processes that yield functionally immature tissues at birth. Evidence is mounting that organs do not continue to develop postnatally in the context of these organogenesis insults, condemning the patient to utilize under-developed tissues for adult processes. These poorly differentiated organs may appear histologically normal at birth but with age may deteriorate revealing progressive or adult-onset pathology. The genetic and molecular underpinning of the proposed paradigm reveals the need for a comprehensive systems biology approach to evaluate the role of maternal-fetal environment on organogenesis.You may delay, but time will notBenjamin FranklinUSA Founding Father http://www.tbiomed.com/content/5/1/1 J Craig Cohen and Janet E Larson Theoretical Biology and Medical Modelling 2008, 5:1 2008-01-08 doi:10.1186/1742-4682-5-1 Theoretical Biology and Medical Modelling 1742-4682 5 1 2008-01-08 Background: The epidermal growth factor receptor (EGFR) is frequently overexpressed in many cancers, including non-small cell lung cancer (NSCLC). In silico modeling is considered to be an increasingly promising tool to add useful insights into the dynamics of the EGFR signal transduction pathway. However, most of the previous modeling work focused on the molecular or the cellular level only, neglecting the crucial feedback between these scales as well as the interaction with the heterogeneous biochemical microenvironment. Results: We developed a multiscale model for investigating expansion dynamics of NSCLC within a two-dimensional in silico microenvironment. At the molecular level, a specific EGFR-ERK intracellular signal transduction pathway was implemented. Dynamical alterations of these molecules were used to trigger phenotypic changes at the cellular level. Examining the relationship between extrinsic ligand concentrations, intrinsic molecular profiles and microscopic patterns, the results confirmed that increasing the amount of available growth factor leads to a spatially more aggressive cancer system. Moreover, for the cell closest to nutrient abundance, a phase-transition emerges where a minimal increase in extrinsic ligand abolishes the proliferative phenotype altogether. Conclusion: Our in silico results indicate that in NSCLC, in the presence of a strong extrinsic chemotactic stimulus (and depending on the cell's location) downstream EGFR-ERK signaling may be processed more efficiently, thereby yielding a migration-dominant cell phenotype and overall, an accelerated spatio-temporal expansion rate. http://www.tbiomed.com/content/4/1/50 Zhihui Wang, Le Zhang, Jonathan Sagotsky and Thomas S Deisboeck Theoretical Biology and Medical Modelling 2007, 4:50 2007-12-21 doi:10.1186/1742-4682-4-50 Theoretical Biology and Medical Modelling 1742-4682 4 50 2007-12-21 Background: The desire to better understand the immuno-biology of infectious diseases as a broader ecological system has motivated the explicit representation of epidemiological processes as a function of immune system dynamics. While several recent and innovative contributions have explored unified models across cellular and organismal domains, and appear well-suited to describing particular aspects of intracellular pathogen infections, these existing immuno-epidemiological models lack representation of certain cellular components and immunological processes needed to adequately characterize the dynamics of some important epidemiological contexts. Here, we complement existing models by presenting an alternate framework of anti-viral immune responses within individual hosts and infection spread across a simple network-based population. Results: Our compartmental formulation parsimoniously demonstrates a correlation between immune responsiveness, network connectivity, and the natural history of infection in a population. It suggests that an increased disparity between people's ability to respond to an infection, while maintaining an average immune responsiveness rate, may worsen the overall impact of an outbreak within a population. Additionally, varying an individual's network connectivity affects the rate with which the population-wide viral load accumulates, but has little impact on the asymptotic limit in which it approaches. Whilst the clearance of a pathogen in a population will lower viral loads in the short-term, the longer the time until re-infection, the more severe an outbreak is likely to be. Given the eventual likelihood of reinfection, the resulting long-run viral burden after elimination of an infection is negligible compared to the situation in which infection is persistent. Conclusion: Future infectious disease research would benefit by striving to not only continue to understand the properties of an invading microbe, or the body's response to infections, but how these properties, jointly, affect the propagation of an infection throughout a population. These initial results offer a refinement to current immuno-epidemiological modelling methodology, and reinforce how coupling principles of immunology with epidemiology can provide insight into a multi-scaled description of an ecological system. Overall, we anticipate these results to as a further step towards articulating an integrated, more refined epidemiological theory of the reciprocal influences between host-pathogen interactions, epidemiological mixing, and disease spread. http://www.tbiomed.com/content/4/1/49 David M Vickers and Nathaniel D Osgood Theoretical Biology and Medical Modelling 2007, 4:49 2007-12-20 doi:10.1186/1742-4682-4-49 Theoretical Biology and Medical Modelling 1742-4682 4 49 2007-12-20