MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'IET Systems Biology' source. Thu, 29 Dec 2011 07:07:25 +0100 http://www.medworm.com/index.php?rid=5482932&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6088372%26arnumber%3D6088375 Fatal neurodegenerative diseases such as bovine spongiform encephalopathy in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans are caused by prions. Prion is a protein encoded by a normal cellular gene. The cellular form of the prion, namely PrPC, is benign but can be converted into a disease-causing form (named scrapie), PrPSc, by a conformational change from α-helix to β-sheets. Prions replicate by this conformational change; that is, PrPSc interacts with PrPC producing a new molecule of PrPSc. This kind of replication is modelled in this contribution as an autocatalytic process. The kinetic model accounts for two of the three epidemiological manifestations: sporadic and infectious. By assuming irreversibility of the PrPSc replication and describing a first... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5482932 Tue, 01 Nov 2011 04:00:00 +0100 5482932 http://www.medworm.com/index.php?rid=5482931&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6088372%26arnumber%3D6088374 With the rising application of systems biology, sensitivity analysis methods have been widely applied to study the biological systems, including metabolic networks, signalling pathways and genetic circuits. Sensitivity analysis can provide valuable insights about how robust the biological responses are with respect to the changes of biological parameters and which model inputs are the key factors that affect the model outputs. In addition, sensitivity analysis is valuable for guiding experimental analysis, model reduction and parameter estimation. Local and global sensitivity analysis approaches are the two types of sensitivity analysis that are commonly applied in systems biology. Local sensitivity analysis is a classic method that studies the impact of small perturbations on the model ou... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5482931 Tue, 01 Nov 2011 04:00:00 +0100 5482931 http://www.medworm.com/index.php?rid=5482930&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6088372%26arnumber%3D6088373 This study presents a set of tools to aid in the analysis of systems within the MFK framework. A closed-form expression for the MFK Jacobian matrix is derived. This expression facilitates the computation of MFK equilibria and the characterisation of the dynamics of small deviations from the equilibria (i.e. local dynamics). Software developed in MATLAB to analyse systems within the MFK framework is also presented. The authors outline a homotopy continuation method that employs the Jacobian for bifurcation analysis, that is, to generate a locus of steady-state Jacobian eigenvalues corresponding to changing a chosen MFK parameter such as system volume or a rate constant. This method is applied to study the effect of small-volume stochasticity on local dynamics at equilibria in a pair of exam... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5482930 Tue, 01 Nov 2011 04:00:00 +0100 5482930 http://www.medworm.com/index.php?rid=5355235&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6055271%26arnumber%3D6055275 Based on the similarity between a reentrant wave in cardiac tissue and a vortex in fluid dynamics, the authors hypothesised that a new non-dimensional index, like the Reynolds number in fluid dynamics, may play a critical role in categorising reentrant wave dynamics. Therefore the goal of the present study is to devise a new index to characterise electric wave conduction in cardiac tissue and examined whether this index can be used as a biomarker for categorising the reentrant wave pattern in cardiac tissue. Similar to the procedure used to derive the Reynolds number in fluid dynamics, the authors used a non-dimensionalisation technique to obtain the new index. Its usefulness was verified using a two-dimensional simulation model of electrical wave propagation in cardiac tissue. The simulat... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5355235 Thu, 01 Sep 2011 04:00:00 +0100 5355235 http://www.medworm.com/index.php?rid=5355234&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6055271%26arnumber%3D6055274 Conclusions: This analysis enabled us to better understand the mechanisms regulating the FLR1 gene mancozeb response and confirmed the need of a new transcription factor for the full transcriptional activation of YAP1. The result is a computable model of the FLR1 gene response to mancozeb, permitting a quick and cost-effective test of hypotheses prior to experimental validation. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5355234 Thu, 01 Sep 2011 04:00:00 +0100 5355234 http://www.medworm.com/index.php?rid=5355233&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6055271%26arnumber%3D6055273 Experiments have recently shown that p53 expression can display oscillations in response to certain stress signals. In this work, mathematical modelling and bifurcation analysis are combined to investigate under which conditions the oscillation of p53 could propagate to its direct downstream transcription targets. The authors' analysis suggests that oscillations of p53 will propagate only to proteins with medium-fast mRNA and protein turnover rates. The authors retrieved data concerning the half-life of mRNA and protein for a number of p53-promoted genes and found that, according to their model, most of them are not able to inherit the oscillation of p53 because of their slow turnover rates. However, their analysis indicates that p53 oscillation may actually fine-tune the expression patter... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5355233 Thu, 01 Sep 2011 04:00:00 +0100 5355233 http://www.medworm.com/index.php?rid=5355232&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D6055271%26arnumber%3D6055272 Recent remarkable advances in computer performance have enabled us to estimate parameter values by the huge power of numerical computation, the so-called 'Brute force', resulting in the high-speed simultaneous estimation of a large number of parameter values. However, these advancements have not been fully utilised to improve the accuracy of parameter estimation. Here the authors review a novel method for parameter estimation using symbolic computation power, 'Bruno force', named after Bruno Buchberger, who found the Grobner base. In the method, the objective functions combining the symbolic computation techniques are formulated. First, the authors utilise a symbolic computation technique, differential elimination, which symbolically reduces an equivalent system of differential equations t... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5355232 Thu, 01 Sep 2011 04:00:00 +0100 5355232 http://www.medworm.com/index.php?rid=5191104&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5979218%26arnumber%3D5979223 The gene expression response of yeast to various types of stresses/perturbations shows a common functional and dynamical pattern for the vast majority of genes, characterised by a quick transient peak (affecting primarily short genes) followed by a return to the pre-stimulus level. Kinetically, this process of adaptation following the transient excursion can be modelled using a genome-wide autoregulatory mechanism by means of which yeast aims at maintaining a preferential concentration in its mRNA levels. The resulting feedback system explains well the different time constants observable in the transient response, while being in agreement with all the known experimental dynamical features. For example, it suggests that a very rapid transient can be induced also by a slowly varying concentr... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5191104 Thu, 30 Jun 2011 23:00:00 +0100 5191104 http://www.medworm.com/index.php?rid=5191103&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5979218%26arnumber%3D5979222 This study follows such a philosophy and completes a genome and metabolome combination. In a such integrated framework and as illustration, we applied a graph analysis that automatically investigates impacts of the gene adjacency to predict functional relationships between genes and reactions. Our approach, called SIPPER, creates a weighted graph, in which the weights rely on the given relationship between genes, and computes (alternative) chains of reactions catalysed by genes. This method, as a generalisation of methods already published, can be easily adapted to several biological assumptions, properties or measures. This paper evaluates SIPPER on Escherichia coli. We automatically extract subgraphs, called k-SIPs, and quantify their interest in both genomic and metabolic contexts by sh... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5191103 Thu, 30 Jun 2011 23:00:00 +0100 5191103 http://www.medworm.com/index.php?rid=5191102&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5979218%26arnumber%3D5979221 Linear I/O systems are a fundamental tool in systems theory, and have been used to design complex circuits and control systems in a variety of settings. Here we present a principled design method for implementing arbitrary linear I/O systems with biochemical reactions. This method relies on two levels of abstraction: first, an implementation of linear I/O systems using idealised chemical reactions, and second, an approximate implementation of the ideal chemical reactions with enzyme-free, entropy-driven DNA reactions. The ideal linear dynamics are shown to be closely approximated by the chemical reactions model and the DNA implementation. We illustrate the approach with integration, gain and summation as well as with the ubiquitous robust proportional-integral controller. (Source: IET Syst... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5191102 Thu, 30 Jun 2011 23:00:00 +0100 5191102 http://www.medworm.com/index.php?rid=5191101&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5979218%26arnumber%3D5979220 Biosynthesis of ethylene (ethene) is mainly performed by plants and some bacteria and fungi, via two distinct metabolic routes. Plants use two steps, starting with S-adenosylmethionine, while the ethylene-forming microbes perform an oxygen dependent reaction using 2-oxoglutarate and arginine. Introduction of these systems into Saccharomyces cerevisiae was studied in silico. The reactions were added to a metabolic network of yeast and flux over the two networks was optimised for maximal ethylene formation. The maximal ethylene yields obtained for the two systems were similar in the range of 7-8-mol ethylene/10-mol glucose. The microbial metabolic network was used for testing different strategies to increase the ethylene formation. It was suggested that supplementation of exogenous proline, ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5191101 Thu, 30 Jun 2011 23:00:00 +0100 5191101 http://www.medworm.com/index.php?rid=5191100&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5979218%26arnumber%3D5979219 Robustness, the ability of a system to function correctly in the presence of both internal and external uncertainty, has emerged as a key organising principle in many biological systems. Biological robustness has thus become a major focus of research in Systems Biology, particularly on the engineering-biology interface, since the concept of robustness was first rigorously defined in the context of engineering control systems. This review focuses on one particularly important aspect of robustness in Systems Biology, that is, the use of robustness analysis methods for the validation or invalidation of models of biological systems. With the explosive growth in quantitative modelling brought about by Systems Biology, the problem of validating, invalidating and discriminating between competing ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=5191100 Thu, 30 Jun 2011 23:00:00 +0100 5191100 http://www.medworm.com/index.php?rid=4944156&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876190 Acetyl-CoA carboxylase catalyses the first committed step in fatty acid synthesis in all organisms. The chemistry is accomplished in two half-reactions: activation of biotin via carboxylation by biotin carboxylase, followed by the carboxyltransferase-catalysed transfer of the carboxyl moiety from carboxybiotin to acetyl-CoA to generate malonyl-CoA. The Escherichia coli form of the carboxyltransferase subunit was recently found to regulate its own activity and expression by binding its own mRNA. By binding acetyl-CoA or the mRNA encoding its own subunits, carboxyltransferase is able to sense the metabolic state of the cell and attenuate its own translation and enzymatic activity using a negative feedback mechanism. Here, the network of these interactions is modelled mathematically with a se... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944156 Sat, 30 Apr 2011 23:00:00 +0100 4944156 http://www.medworm.com/index.php?rid=4944155&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876189 In this study, the author examines the effects of saturation and enzyme limitation in temporal and spatial signal transduction in a generic feedforward adaptive module. The feedforward module encompasses a range of temporal and spatial signal processing, and this study systematically examines the effect of enzyme limitation/saturating effects in each of the feedforward pathways, and their interplay. It is found that this saturation makes the adaptation inexact, and this effect is more pronounced for higher levels of input signals. Further, it has a very significant role in affecting the temporal dynamics of this module. In examining the role of saturation in the module response to static gradients, the author finds that in certain cases, saturation can completely alter the gradient respons... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944155 Sat, 30 Apr 2011 23:00:00 +0100 4944155 http://www.medworm.com/index.php?rid=4944154&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876188 This study starts with an introduction to graph theory and basic measures allowing to quantify structural properties of networks. Then, the authors present important network classes and gene networks as well as methods for their analysis. In the last part of this study, the authors review approaches that aim at analysing the functional organisation of gene networks and the use of networks in medicine. In addition to this, the authors advocate networks as a systematic approach to general problems in systems biology, because networks are capable of assuming multiple roles that are very beneficial connecting experimental data with a functional interpretation in biological terms. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944154 Sat, 30 Apr 2011 23:00:00 +0100 4944154 http://www.medworm.com/index.php?rid=4944153&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876187 In this study, the authors explored the utility of a descriptive and predictive bionetwork model for phospholipase C-coupled calcium signalling pathways, built with non-kinetic experimental information. Boolean models generated from these data yield oscillatory activity patterns for both the endoplasmic reticulum resident inositol-1,4,5-trisphosphate receptor (IP3R) and the plasma-membrane resident canonical transient receptor potential channel 3 (TRPC3). These results are specific as randomisation of the Boolean operators ablates oscillatory pattern formation. Furthermore, knock-out simulations of the IP3R, TRPC3 and multiple other proteins recapitulate experimentally derived results. The potential of this approach can be observed by its ability to predict previously undescribed cellular ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944153 Sat, 30 Apr 2011 23:00:00 +0100 4944153 http://www.medworm.com/index.php?rid=4944152&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876186 The control of stem cell properties during in vitro expansion is of paramount importance for their clinical use. According to Food and Drug Administration (FDA) guidelines, phenotypic heterogeneity is a critical aspect influencing therapeutic response. Even if the authors ability to reduce heterogeneity were limited, the sources from which it arises should be well understood for safe clinical applications. The aim of this work was to describe theoretically the intrinsic cell population heterogeneity that is present even when cells are cultured in a perfectly homogeneous environment. A bivariate population balance model is developed to account for the heterogeneity in the number of receptors and receptor-ligand complexes per cell, and is coupled with a ligand conservation equation. As a cas... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944152 Sat, 30 Apr 2011 23:00:00 +0100 4944152 http://www.medworm.com/index.php?rid=4944151&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5876184%26arnumber%3D5876185 Detailed kinetic models at the network reaction level are usually constructed using enzymatic mechanistic rate equations and the associated kinetic parameters. However, during the cellular life cycle thousands of different reactions occur, which makes it very difficult to build a detailed large-scale ldnetic model. In this work, we provide a critical overview of specific limitations found during the reconstruction of the central carbon metabolism dynamic model from E. coli (based on kinetic data available). In addition, we provide clues that will hopefully allow the systems biology community to more accurately construct metabolic dynamic models in the future. The difficulties faced during the construction of dynamic models are due not only to the lack of kinetic information but also to the... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4944151 Sat, 30 Apr 2011 23:00:00 +0100 4944151 http://www.medworm.com/index.php?rid=4621411&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5735002 Molecular fluctuations are known to affect dynamics of cellular systems in important ways. Studies aimed at understanding how molecular systems of certain regulatory architectures control noise therefore become essential. The interplay between feedback regulation and noise has been previously explored for cellular networks governed by a single negative feedback loop. However, similar issues within networks consisting of more complex regulatory structures remain elusive. The authors investigate how negative feedback loops manage noise within a biochemical cascade concurrently governed by multiple negative feedback loops, using the prokaryotic tryptophan (trp) operon system in Escherechia coli as the model system. To the authors knowledge, this is the first study of noise in the trp operon s... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621411 Tue, 01 Mar 2011 00:00:00 +0100 4621411 http://www.medworm.com/index.php?rid=4621410&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5735001 Despite myriads of possible gene expression profiles, cells tend to be found in a confined number of expression patterns. The dynamics of Boolean models of gene regulatory networks has proven to be a likely candidate for the description of such self-organisation phenomena. Because cells do not live in isolation, but they constantly shape their functions to adapt to signals from other cells, this raises the question of whether the cooperation among cells entails an expansion or a reduction of their possible steady states. Multi random Boolean networks are introduced here as a model for interaction among cells that might be suitable for the investigation of some generic properties regarding the influence of communication on the diversity of cell behaviours. In spite of its simplicity, the mo... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621410 Tue, 01 Mar 2011 00:00:00 +0100 4621410 http://www.medworm.com/index.php?rid=4621409&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5735000 Advances in systems biology are increasingly dependent upon the integration of various types of data and different methodologies to reconstruct how cells work at the systemic level. Thus, teams with a varied array of expertise and people with interdisciplinary training are needed. So far this training was thought to be more productive if aimed at the Masters or PhD level. At this level, multiple specialised and in-depth courses on the different subject matters of systems biology are taught to already well-prepared students. This approach is mostly based on the recognition that systems biology requires a wide background that is hard to find in undergraduate students. Nevertheless, and given the importance of the field, the authors argue that exposition of undergraduate students to the metho... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621409 Tue, 01 Mar 2011 00:00:00 +0100 4621409 http://www.medworm.com/index.php?rid=4621408&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5734999 Mathematical description of biological processes such as gene regulatory networks or signalling pathways by dynamic models utilising ordinary differential equations faces challenges if the model parameters like rate constants are estimated from incomplete and noisy experimental data. Typically, biological networks are only partially observed. Only a fraction of the modelled molecular species is measurable directly. This can result in structurally non-identifiable model parameters. Furthermore, practical non-identifiability can arise from limited amount and quality of experimental data. In the challenge of growing model complexity on one side, and experimental limitations on the other side, both types of non-identifiability arise frequently in systems biological applications often prohibiti... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621408 Tue, 01 Mar 2011 00:00:00 +0100 4621408 http://www.medworm.com/index.php?rid=4621407&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5734998 This note addresses the optimal control of non-linear metabolic networks by means of time-dependent enzyme synthesis rates. The authors consider networks with general topologies described by a control-affine dynamical system coupled with a linear model for enzyme synthesis and degradation. The problem formulation accounts for transitions between two metabolic equilibria, which typically arise in metabolic adaptations to environmental changes, and the minimisation of a quadratic functional that weights the cost/benefit relation between the transcriptional effort required for enzyme synthesis and the transition to the new phenotype. Using a linear time-variant approximation of the non-linear dynamics, the problem is recast as a sequence of linear-quadratic problems, the solution of which inv... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621407 Tue, 01 Mar 2011 00:00:00 +0100 4621407 http://www.medworm.com/index.php?rid=4621406&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5734997 Pathogenic bacteria employ a communication mechanism, known as quorum sensing (QS), to obtain information about their cell density and to synchronise their behaviour. Most bacteria species use QS signalling circuits to optimise the secretion of virulence factors that damage their host. Recently, QS has been recognised as a target for antimicrobial drugs that can control bacterial infections. Here the QS process is modelled as a state transition graph with transitions depending on the diffusion and local concentration of the QS molecules (autoinducers). Based on this model a simulation tool has been developed to simulate the QS process in both open and confined spaces. Using this simulation tool a number of numerical experiments has been carried out with various strategies of QS circuit reg... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621406 Tue, 01 Mar 2011 00:00:00 +0100 4621406 http://www.medworm.com/index.php?rid=4621405&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5734996 In conclusion, network-assisted regression, combined AMI3 and ODE model, was a more precisely to infer the topological structure and the regulatory dynamics of transcriptional network from microarray data. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621405 Tue, 01 Mar 2011 00:00:00 +0100 4621405 http://www.medworm.com/index.php?rid=4621404&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5734994%26arnumber%3D5734995 This study takes a modular systems approach to systematically understand the interaction of adaptive modules and threshold modules (both monostable and bistable). The authors employ representative modules of adaptive and threshold elements and use these to examine and analyse various aspects of their interaction including the order of interconnection, the role of relative time scales, the difference between monostable and bistable thresholds in this context and how threshold modules may act as a switch induced by transient signals. Numerical simulations, bifurcation analysis and analytical work are employed to address these questions. Overall, the author' analysis is a first step towards a detailed systems engineering understanding of the different kinds of interactions between these ubiqu... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4621404 Tue, 01 Mar 2011 00:00:00 +0100 4621404 http://www.medworm.com/index.php?rid=4393540&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701745 Systems biology is uniquely situated at the interface of computing, mathematics, engineering and the biological sciences. This positioning creates unique challenges and opportunities over other interdisciplinary studies when developing academic curricula. Integrative systems biology attempts to span the field from observation to innovation, and thus requires successful students to gain skills from mining to manipulation. The authors outline examples of graduate program structures, as well as curricular aspects and assessment metrics that can be customised around the environmental niche of the academic institution towards the formalisation of effective educational opportunities in systems biology. Some of this material was presented at the 2009 Foundations of Systems Biology in Engineering ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393540 Sat, 01 Jan 2011 00:00:00 +0100 4393540 http://www.medworm.com/index.php?rid=4393539&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701744 Michaelis??Menten kinetics are commonly used to represent enzyme-catalysed reactions in biochemical models. The Michaelis??Menten approximation has been thoroughly studied in the context of traditional differential equation models. The presence of small concentrations in biochemical systems, however, encourages the conversion to a discrete stochastic representation. It is shown that the Michaelis??Menten approximation is applicable in discrete stochastic models and that the validity conditions are the same as in the deterministic regime. The authors then compare the Michaelis??Menten approximation to a procedure called the slow-scale stochastic simulation algorithm (ssSSA). The theory underlying the ssSSA implies a formula that seems in some cases to be different from the well-known Michae... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393539 Sat, 01 Jan 2011 00:00:00 +0100 4393539 http://www.medworm.com/index.php?rid=4393538&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701743 Classical sensitivity analysis is routinely used to identify points of fragility or robustness in biochemical networks. However, intracellular systems often contain components that number in the thousands to tens or less and consequently motivate a stochastic treatment. Although methodologies exist to quantify sensitivities in stochastic models, they differ substantially from those used in deterministic regimes. Therefore it is not possible to tell whether observed differences in sensitivity measured in deterministic and stochastic elaborations of the same network are the result of methodology or model form. The authors introduce here a distribution-based methodology to measure sensitivity that is equally applicable in both regimes, and demonstrate its use and applicability on a sophistica... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393538 Sat, 01 Jan 2011 00:00:00 +0100 4393538 http://www.medworm.com/index.php?rid=4393537&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701742 Circadian clocks are regulated at the post-translational level by a variety of processes among which protein phosphorylation plays a prominent, although complex, role. Thus, the phosphorylation of different sites on the clock protein PER by casein kinase I (CKI) can lead to opposite effects on the stability of the protein and on the period of circadian oscillations. Here the authors extend a computational model previously proposed for the mammalian circadian clock by incorporating two distinct phosphorylations of PER by CKI. On the basis of experimental observations the authors consider that phosphorylation at one site (denoted here PER-P1) enhances the rate of degradation of the protein and decreases the period, while phosphorylation at another site (PER-P2) stabilises the protein, enhanc... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393537 Sat, 01 Jan 2011 00:00:00 +0100 4393537 http://www.medworm.com/index.php?rid=4393536&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701741 A detailed intracellular (IC) model describing the pharmacokinetics (PK) of gemcitabine (2',2'-difluoro-2'- deoxycytidine, dFdC) was developed and linked to a systemic plasma dFdC PK model. Based on in vivo PK, pharmacodynamic (PD) effect predictions were made using a simplified cell-cycle model (CCM). A reduced-order compartmental model describing the IC metabolism of dFdC was fit to in vitro data taken from the literature to estimate the kinetic parameters of gemcitabine triphosphate (dFdCTP) generation and elimination in leukaemia cells. For comparison with in vivo patient data, the proposed detailed IC model, coupled with the systemic PK model and the CCM PD model, was simulated; Monte Carlo randomisation of the parameter vector was used to simulate interpatient variability. This compa... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393536 Sat, 01 Jan 2011 00:00:00 +0100 4393536 http://www.medworm.com/index.php?rid=4393535&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701740 The authors propose a novel minimum oscillator whereby a protein with multiple phosphorylation sites directly embedded in a negative feedback loop can exhibit oscillation. They demonstrate that if the fully phosphorylated substrate inhibits the first phosphorylation step in a cooperative manner, multisite substrates can exhibit oscillatory behaviour at the presence of a kinase and phosphatase. With a fixed number of sites, the non-linearity of the negative feedback and the substrate/ enzyme ratio must be above certain threshold values to generate undamped oscillation. There is an inverse relationship between the number of phosphorylation sites and the minimum non-linearity of the negative feedback required for oscillation; that is, the ultrasensitivity and time delay rooted in multisite ph... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393535 Sat, 01 Jan 2011 00:00:00 +0100 4393535 http://www.medworm.com/index.php?rid=4393534&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701739 Steatosis, i.e., the accumulation of fat in hepatocytes, plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD). It has been shown that STAT3 activation is involved in a decrease of lipid accumulation while C/EBPβ is correlated with an increase of fat content and steatosis. It is known that STAT3 and C/EBPβ are activated by IL-6 and that IL-6 signalling is also affected by IL-10, even though the exact mechanism is unclear. This paper develops a model for IL-6 and IL-10 signal transduction and then investigates the effect that stimulation with these cytokines has on the transcription factor dynamics. In an initial step, some parameters of a previously developed IL-6 signalling model are re-estimated based upon newly developed experimental dat... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393534 Sat, 01 Jan 2011 00:00:00 +0100 4393534 http://www.medworm.com/index.php?rid=4393533&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701738 In this study, the authors constructed an ensemble of mathematical models describing the integration of growth factor signals with translation initiation. Using these models, the authors estimated critical structural features of the translation architecture. Sensitivity and robustness analysis with and without growth factors suggested that a balance between competing regulatory programmes governed translation initiation. Proteins such as Akt and mTor promoted initiation by integrating growth factor signals with the assembly of the 80S initiation complex. However, negative regulators such as PTEN and 4EBP1 restrained initiation in the absence of stimulation. Other proteins such as eIF4E were also found to be structurally critical as deletion of amplification of these components resulted in ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393533 Sat, 01 Jan 2011 00:00:00 +0100 4393533 http://www.medworm.com/index.php?rid=4393532&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5701736%26arnumber%3D5701737 This special issue contains 8 selected papers from the Third International Conference on Foundations of Systems Biology in Engineering (FOSBE 2009), which took place August 9??12, 2009 at the Inverness Hotel and Conference Center in Englewood, Colorado. The primary objectives of FOSBE 2009 were to provide an in-depth review and critical assessment of the current state-of-the-art, to discuss current and future needs of research, education and training, and to identify new directions, opportunities and challenges in systems biology. An important aim of FOSBE 2009 was to bring together and foster interactions among worldrenowned experts from academia, industry and government. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4393532 Sat, 01 Jan 2011 00:00:00 +0100 4393532 http://www.medworm.com/index.php?rid=4166969&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638198 The authors propose a theoretical formalism, molecular finite automata (MFA), to describe individual proteins as rule-based computing machines. The MFA formalism provides a framework for modelling individual protein behaviours and systems-level dynamics via construction of programmable and executable machines. Models specified within this formalism explicitly represent the context-sensitive dynamics of individual proteins driven by external inputs and represent protein¿protein interactions as synchronised machine reconfigurations. Both deterministic and stochastic simulations can be applied to quantitatively compute the dynamics of MFA models. They apply the MFA formalism to model and simulate a simple example of a signaltransduction system that involves an MAP kinase cascade and a scaffo... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166969 Mon, 01 Nov 2010 00:00:00 +0100 4166969 http://www.medworm.com/index.php?rid=4166968&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638197 In this study, the authors present an on-the-fly variant of uniformisation, where they improve the original algorithm at the cost of a small approximation error. By means of several examples, the authors show that their approach is particularly well-suited for biochemical reaction networks. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166968 Mon, 01 Nov 2010 00:00:00 +0100 4166968 http://www.medworm.com/index.php?rid=4166967&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638196 A critical task in systems biology is the identification of genes that interact to control cellular processes by transcriptional activation of a set of target genes. Many methods have been developed that use statistical correlations in high-throughput data sets to infer such interactions. However, cellular pathways are highly cooperative, often requiring the joint effect of many molecules. Few methods have been proposed to explicitly identify such higher-order interactions, partially due to the fact that the notion of multivariate statistical dependence itself remains imprecisely defined. The authors define the concept of dependence among multiple variables using maximum entropy techniques and introduce computational tests for their identification. Synthetic network results reveal that thi... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166967 Mon, 01 Nov 2010 00:00:00 +0100 4166967 http://www.medworm.com/index.php?rid=4166966&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638195 The combination of microfluidic cell trapping devices with ion mobility-mass spectrometry offers the potential for elucidating in real time the dynamic responses of small populations of cells to paracrine signals, changes in metabolite levels and delivery of drugs and toxins. Preliminary experiments examining peptides in methanol and recording the interactions of yeast and Jurkat cells with their superfusate have identified instrumental set-up and control parameters and online desalting procedures. Numerous initial experiments demonstrate and validate this new instrumental platform. Future outlooks and potential applications are addressed, specifically how this instrumentation may be used for fully automated systems biology studies of the significantly interdependent, dynamic internal work... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166966 Mon, 01 Nov 2010 00:00:00 +0100 4166966 http://www.medworm.com/index.php?rid=4166965&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638194 The authors generalise the concept of the geometric phase in stochastic kinetics to a non-cyclic evolution. Its application is demonstrated on kinetics of the Michaelis¿Menten reaction. It is shown that the non-periodic geometric phase is responsible for the correction to the Michaelis ¿Menten law when parameters, such as a substrate concentration, are changing with time. The authors apply these ideas to a model of chemical reactions in a bacterial culture of a growing size, where the geometric correction qualitatively changes the outcome of the reaction kinetics. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166965 Mon, 01 Nov 2010 00:00:00 +0100 4166965 http://www.medworm.com/index.php?rid=4166964&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638193 The dynamical properties of distal and proximal gene regulatory elements are crucial to their functionality in gene regulatory networks. However, the multiplicity of regulatory interactions at control elements makes their theoretical and experimental characterisation difficult. Here a thermodynamic framework to describe gene regulation by distant enhancers via a chromatin mechanism is developed. In this mechanism transcription factors (TFs) modulate gene expression via shifts in the equilibrium between chromatin states. The designs of AND, OR, XOR and NAND two-input transcriptional gates for the chromatin mechanism are proposed and compared to similar gates based on the direct physical interactions of TFs with the transcriptional machinery. An algorithm is developed to estimate the thermod... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166964 Mon, 01 Nov 2010 00:00:00 +0100 4166964 http://www.medworm.com/index.php?rid=4166963&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638192 Regulatory networks in cells may comprise a variety of types of molecular interactions. The most basic are pairwise interactions, in which one species controls the behaviour of another (e.g. a transcription factor activates or represses a gene). Higher-order interactions, while more subtle, may be important for determining the function of networks. Here, the authors systematically expand a simple master equation model for a gene to derive an approach for robustly assessing the cooperativity (effective copy number) with which a transcription factor acts. The essential idea is that moments of a joint distribution of protein copy numbers determine the Hill coefficient of a cis-regulatory input function without non-linear fitting. The authors show that this method prescribes a definition of co... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166963 Mon, 01 Nov 2010 00:00:00 +0100 4166963 http://www.medworm.com/index.php?rid=4166962&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638191 Certain short polycations, such as trans-activating transcriptional activator and oligoarginine, rapidly pass through the plasma membranes of mammalian cells by a mechanism called transduction, as well as by endocytosis and macropinocytosis. These cell-penetrating peptides can carry with them cargos of 30 amino acids, more than the nominal limit of 500 Da and enough to be therapeutic. An analysis of the electrostatics of a charge outside the cell membrane and some recent experiments suggest that transduction may proceed by molecular electroporation. Ways to target diseased cells, rather than all cells, are discussed. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166962 Mon, 01 Nov 2010 00:00:00 +0100 4166962 http://www.medworm.com/index.php?rid=4166961&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638190 This article explores the possibility of identifying the model parameters from different types of statistical information, such as mean expression levels, Lacl-λcl protein distributions and LacI-lcI multivariate distributions. It is determined that although the toggle model parameters cannot be uniquely identified from measurements that track just the LacI variability, the parameters could be identified from measurements of the cell-to-cell variability in both regulatory proteins. Based upon the simulated data and the computational investigations of this study, experiments are proposed that could enable this identification. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166961 Mon, 01 Nov 2010 00:00:00 +0100 4166961 http://www.medworm.com/index.php?rid=4166960&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638189 In conclusion, the analysis of the proposed model shows that, for the fixed substrate interaction rates, spatial distribution of the surface receptors together with the motility of intracellular kinases control cell signalling and sensitivity to extracellular signals. The increase of the cell sensitivity can be achieved by (i) localisation of receptors in a small subdomain of the cell membrane, (ii) lowering the motility of receptor-interacting kinase, (iii) increasing the motility of down-stream kinases which distribute the signal over the whole cell. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166960 Mon, 01 Nov 2010 00:00:00 +0100 4166960 http://www.medworm.com/index.php?rid=4166959&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638188 Many receptor systems initiate cell signalling through ligand-induced receptor aggregation. For bivalent ligands binding to mono- or bivalent receptors, a plot of the equilibrium concentration of receptors in aggregates against the log of the free ligand concentration, the cross-linking curve, is symmetric and bell shaped. However, steady state cellular responses initiated through receptor cross-linking may have a different dependence on ligand concentration than the aggregated receptors that initiate and maintain these responses. The authors illustrate by considering the activation of the protein kinase Syk that rapidly occurs after high affinity receptors for IgE, Fce RI, are aggregated on the surface of mast cells and basophils. Using a mathematical model of Syk activation the authors i... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166959 Mon, 01 Nov 2010 00:00:00 +0100 4166959 http://www.medworm.com/index.php?rid=4166958&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5638186%26arnumber%3D5638187 The q-bio Conference hasmarked its third anniversary (in fact, as we are writing this, the fourth installment of the conference has concluded, the discussion of which is for the next Special Issue). It is fair to say that, in the three years since the inaugural event, the conference has established itself as a prominent meeting on the landscape of international systems biology gatherings. The conference fills an important gap in the field through its emphasis on quantitative, predictive modelling, high precision, physics-style experimentation, and theoretical quest for general principles of biological design. This year we began to see the students and postdocs of those who had presented at the earlier q-bio events, providing a glimpse of the impact of the conference on the community. The n... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=4166958 Mon, 01 Nov 2010 00:00:00 +0100 4166958 http://www.medworm.com/index.php?rid=3972355&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5567072%26arnumber%3D5567075 Mathematical models, as instruments for understanding the workings of nature, are a traditional tool of physics, but they also play an ever increasing role in biology ¿ in the description of fundamental processes as well as that of complex systems. In this review, the authors discuss two examples of the application of group theoretical methods, which constitute the mathematical discipline for a quantitative description of the idea of symmetry, to genetics. The first one appears, in the form of a pseudo-orthogonal (Lorentz like) symmetry, in the stochastic modelling of what may be regarded as the simplest possible example of a genetic network and, hopefully, a building block for more complicated ones: a single self-interacting or externally regulated gene with only two possible states: `on... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3972355 Tue, 31 Aug 2010 23:00:00 +0100 3972355 http://www.medworm.com/index.php?rid=3972354&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5567072%26arnumber%3D5567074 The problem of reverse engineering in the topology of functional interaction networks from time-course experimental data has received considerable attention in literature, due to the potential applications in the most diverse fields, comprising engineering, biology, economics and social sciences. The present work introduces a novel technique, CORE-Net, which addresses this problem focusing on the case of biological interaction networks. The method is based on the representation of the network in the form of a dynamical system and on an iterative convex optimisation procedure. A first advantage of the proposed approach is that it allows to exploit qualitative prior knowledge about the network interactions, of the same kind as typically available from biological literature and databases. A s... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3972354 Tue, 31 Aug 2010 23:00:00 +0100 3972354 http://www.medworm.com/index.php?rid=3972353&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5567072%26arnumber%3D5567073 Epigenetics is the study of regulatory mechanisms that are not accompanied by the action of genetic elements. Recently, a system-wide extension of epigenetics has been driven by the rapid evolution of genomics technology. This means not simply profiling multiple genes together as gene expression microarrays, but also factoring in the crosstalk among various epigenetic components and extending our focus to relatively uncharted genomic areas, including intergenic and intragenic regions. Although this exciting extension provides many interesting research topics as described in this review, the future expansion of epigenomics to cover multiple samples will offer an even more profound opportunity for systems biology research. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3972353 Tue, 31 Aug 2010 23:00:00 +0100 3972353 http://www.medworm.com/index.php?rid=3801815&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5511173%26arnumber%3D5511176 The purpose of this study is to compare the inferability of various synthetic as well as real biological regulatory networks. In order to assess differences we apply local network-based measures. That means, instead of applying global measures, we investigate and assess an inference algorithm locally, on the level of individual edges and subnetworks. We demonstrate the behaviour of our local network-based measures with respect to different regulatory networks by conducting large-scale simulations. As inference algorithm we use exemplarily ARACNE. The results from our exploratory analysis allow us not only to gain new insights into the strength and weakness of an inference algorithm with respect to characteristics of different regulatory networks, but also to obtain information that could b... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3801815 Wed, 30 Jun 2010 23:00:00 +0100 3801815 http://www.medworm.com/index.php?rid=3801814&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5511173%26arnumber%3D5511175 The dynamics induced by the existence of different timescales in a system is explored, in the context of a model composed of activation and signalling modules regulated by a slowly evolving process, such as some particular protein¿protein interactions or genetic-like dynamics. It is shown that slowly varying regulation patterns can induce rapid changes in the steady states of the (fast varying) signal transduction pathway, and lead to sustained oscillations. These results are illustrated by a reduced model of the Cdc2-cyclin B cell cycle oscillator. Using available experimental data, parameters of the model are estimated and found to agree with the requirements for a mechanism for oscillatory behaviour arising from coupling fast and slow processes. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3801814 Wed, 30 Jun 2010 23:00:00 +0100 3801814 http://www.medworm.com/index.php?rid=3801813&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5511173%26arnumber%3D5511174 The sparse grid-based experiment design algorithm sequentially selects an experimental design point to discriminate between hypotheses for given experimental conditions. Sparse grids efficiently screen the global uncertain parameter space to identify acceptable parameter subspaces. Clustering the located acceptable parameter vectors by the similarity of the simulated model trajectories characterises the data-compatible model dynamics. The experiment design algorithm capitalises on the diversity of the experimentally distinguishable system output dynamics to select the design point that best discerns between competing model-structure and parameter-encoded hypotheses. As opposed to designing the experiments to explicitly reduce uncertainty in the model parameters, this approach selects desig... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3801813 Wed, 30 Jun 2010 23:00:00 +0100 3801813 http://www.medworm.com/index.php?rid=3602936&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470322 In this contribution, the authors consider multi-criteria optimisation problems arising from the field of systems biology when both continuous and integer decision variables are involved. Mathematically, they are formulated as mixed-integer non-linear programming problems. The authors present a novel solution strategy based on a global optimisation approach for dealing with this class of problems. Its usefulness and capabilities are illustrated with two metabolic engineering case studies. For these problems, the authors show how the set of optimal solutions (the so-called Pareto front) is successfully and efficiently obtained, providing further insight into the systems under consideration regarding their optimal manipulation. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602936 Fri, 30 Apr 2010 23:00:00 +0100 3602936 http://www.medworm.com/index.php?rid=3602935&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470321 The authors use ideas from graph theory in order to determine how distant is a given biological network from being monotone. On the signed graph representing the system, the minimal number of sign inconsistencies (i.e. the distance to monotonicity) is shown to be equal to the minimal number of fundamental cycles having a negative sign. Suitable operations aiming at computing such a number are also proposed and shown to outperform all algorithms that are so far existing for this task. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602935 Fri, 30 Apr 2010 23:00:00 +0100 3602935 http://www.medworm.com/index.php?rid=3602934&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470320 It is of vital importance to find genetic variants that underlie human complex diseases and locate genes that are responsible for these diseases. Since proteins are typically composed of several structural domains, it is reasonable to assume that harmful genetic variants may alter structures of protein domains, affect functions of proteins and eventually cause disorders. With this understanding, the authors explore the possibility of recovering associations between protein domains and complex diseases. The authors define associations between protein domains and disease families on the basis of associations between non-synonymous single nucleotide polymorphisms (nsSNPs) and complex diseases, similarities between diseases, and relations between proteins and domains. Based on a domain¿domain... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602934 Fri, 30 Apr 2010 23:00:00 +0100 3602934 http://www.medworm.com/index.php?rid=3602933&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470319 Modelling stochastic processes inside the cell is difficult due to the size and complexity of the processes being investigated. As a result, new approaches are needed to address the problems of model reduction, parameter estimation, model comparison and model invalidation. Here, the authors propose addressing these problems by using Wasserstein pseudometrics to quantify the differences between processes. The method the authors propose is applicable to any bounded continuous-time stochastic process and pseudometrics between processes are defined only in terms of the available outputs. Algorithms for approximating Wasserstein pseudometrics are developed from experimental or simulation data and demonstrate how to optimise parameter values to minimise the pseudometrics. The approach is illustr... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602933 Fri, 30 Apr 2010 23:00:00 +0100 3602933 http://www.medworm.com/index.php?rid=3602932&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470318 The author explores the application of graph colouring to biological networks, specifically protein¿ protein interaction (PPI) networks. First, the author finds that given similar conditions (i.e. graph size, degree distribution and clustering), fewer colours are needed to colour disassortative than assortative networks. Fewer colours create fewer independent sets which in turn imply higher concurrency potential for a network. Since PPI networks tend to be disassortative, the author suggests that in addition to functional specificity and stability proposed previously by Maslov and Sneppen (Science, 296, 2002), the disassortative nature of PPI networks may promote the ability of cells to perform multiple, crucial and functionally diverse tasks concurrently. Second, because graph colouring ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602932 Fri, 30 Apr 2010 23:00:00 +0100 3602932 http://www.medworm.com/index.php?rid=3602931&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5470316%26arnumber%3D5470317 Cyclic dominance of species is a potential mechanism for maintaining biodiversity. The author investigates the generalised scenario when the cyclic dominance of three or more interacting species is described by a non-symmetric matrix game that has multiple Nash equilibria. Modified Lotka¿Volterra equations are proposed to incorporate the effects of swarming, and the condition for biodiversity is derived. The species are modelled using replicator equations, where each member of the species is assigned a fitness value. The authors show, for the first time, that the `swarming effect¿ has an important role to play in the maintenance of biodiversity. The authors have also discovered the existence of a critical value of the swarming parameter for a given mobility, above which there is a high p... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3602931 Fri, 30 Apr 2010 23:00:00 +0100 3602931 http://www.medworm.com/index.php?rid=3377700&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430864 Continuous and Boolean models for the Drosophila segment polarity network have shown that the system is able to maintain the wild-type pattern when subjected to sustained changes in the interaction parameters and initial conditions. Embryo development is likely to occur under fluctuating environmental conditions. Here, a well-established Boolean model is used to explore the ability of the segment polarity network to resist transient changes. Paths along which alternate unviable states are reached, and hence critical nodes whose state changes lead the system away from the wild-type state, are identified. It is found that the system appears to be more sensitive to changes that involve activation of normally inactive nodes. Through a simulation of the heat shock response, it is shown how a lo... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377700 Mon, 01 Mar 2010 00:00:00 +0100 3377700 http://www.medworm.com/index.php?rid=3377699&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430863 In this study, the authors investigated how the glycolytic flux was regulated in time upon nitrogen starvation of cells with different growth histories. We have compared cells grown in glucose-limited chemostat cultures under respiratory conditions (low dilution rate of 0.1/h) to cells grown under respirofermentative conditions (high dilution rate of 0.35/h). The fermentative capacity was lower in cells grown under respiratory conditions than in cells grown under respirofermentative conditions, yet more resilient to prolonged nitrogen starvation. The time profiles revealed that the fermentative capacity even increased in cells grown under respiratory conditions during the first hours of nitrogen starvation. In cells grown under respirofermentative conditions the fermentative capacity decre... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377699 Mon, 01 Mar 2010 00:00:00 +0100 3377699 http://www.medworm.com/index.php?rid=3377698&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430862 With the increased availability of DNA microarray time-series data, it is possible to discover dynamic gene regulatory networks (GRNs). S-system is a promising model to capture the rich dynamics of GRNs. However, owing to the complexity of the inference problem and limited number of available data comparing to the number of unknown kinetic parameters, S-system can only be applied to a very small GRN with few parameters. This significantly limits its applications. A unified approach to infer GRNs using the S-system model is proposed. In order to discover the structure of large-scale GRNs, a simplified S-system model is proposed that enables fast parameter estimation to determine the major gene interactions. If a detailed S-system model is desirable for a subset of genes, a two-step method i... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377698 Mon, 01 Mar 2010 00:00:00 +0100 3377698 http://www.medworm.com/index.php?rid=3377697&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430861 Gene expression is regulated by transcription factor activity, which can be extremely difficult to measure directly. Previous work has established a method to extract the `hidden¿ transcription factor activity profile from microarray data and use it to effectively identify genes that are targets of a single transcription factor. However, most genes are regulated by two or more transcription factors, and so may not be recognised by this method. Here, the authors present a model-based analysis technique which is able to extract two separate `hidden¿ transcription factor profiles using microarray data from wild-type and gene knock-down samples. The algorithm can predict targets of each of the transcription factors as well as the amount of cooperative regulation of genes which occurs because... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377697 Mon, 01 Mar 2010 00:00:00 +0100 3377697 http://www.medworm.com/index.php?rid=3377696&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430860 One of the most challenging tasks in systems biology is parameter identification from experimental data. In particular, if the available data are noisy, the resulting parameter uncertainty can be huge and should be quantified. In this work, a set-based approach for parameter identification in discrete time models of biochemical reaction networks from time series data is developed. The basic idea is to determine an outer approximation to the set of parameters for which trajectories are consistent with the available data. In order to approximate the set of consistent parameters (SCP) a feasibility problem is derived. This feasibility problem is used to verify that complete parameter sets cannot contain consistent parameters. This method is very appealing because instead of checking a finite ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377696 Mon, 01 Mar 2010 00:00:00 +0100 3377696 http://www.medworm.com/index.php?rid=3377695&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430859 This study addresses this issue as it introduces a procedure that computes quantitative transcription factor profiles from fluorescent microscopy data collected from green fluorescent protein (GFP) reporter cells. This technique forms a generalisation of a method that has recently been introduced for monitoring NF-kB profiles. The contribution made in this work is that the assumption that the transcription factor profile exhibits damped oscillations is relaxed, as transcription factors, other than the previously investigated NF-kB, may exhibit different profiles. This is achieved by investigating a variety of potential profiles and solving the inverse problem for the model describing transcription, translation and activation of GFP for each one. The transcription factor profile that result... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377695 Mon, 01 Mar 2010 00:00:00 +0100 3377695 http://www.medworm.com/index.php?rid=3377694&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5430857%26arnumber%3D5430858 Aberrant gene functions usually contribute to the pathology or diseases. Avoiding undesirable cellular phenotypes as many as possible is a major purpose of external control for gene regulatory networks. An interesting question is how to control a gene network subjected to the condition that the genes reach some undesirable states with minimal probability during a cell cycle. In this paper, we make use of the theory of the first passage model for discrete-time Markov decision processes to determine the optimal control for a gene intervention model. Specifically, we first use a control model for a probabilistic Boolean network to model interactions among genes and then solve an optimal control problem for maximising the probability of the first arrival time to desirable gene states. In order... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3377694 Mon, 01 Mar 2010 00:00:00 +0100 3377694 http://www.medworm.com/index.php?rid=3110652&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356261 The deep understanding of the biochemical and biophysical basis of visual transduction, makes it ideal for systems-level analysis. A sensitivity analysis is presented for a self-consistent set of parameters involved in mouse phototransduction. The organising framework is a spatio-temporal mathematical model, which includes the geometry of the rod outer segment (ROS), the layered array of the discs, the incisures, the biochemistry of the activation/deactivation cascade and the biophysics of the diffusion of the second messengers in the cytoplasm and the closing of the cyclic guanosine monophosphate (cGMP) gated cationic channels. These modules include essentially all the relevant geometrical, biochemical and biophysical parameters. The parameters are selected from within experimental ranges... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3110652 Tue, 22 Dec 2009 15:53:42 +0100 3110652 http://www.medworm.com/index.php?rid=3099925&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356267 Attempts to account for the variations in photosystem II (PSII) under general conditions result in non-linear and cumbersome models that are difficult to validate and render few insights about the system kinetics. In this research, the authors experimentally show that under certain conditions, linear-system techniques could be applied to advantage for probing some basic kinetic characteristics of the plastoquinones (PQs). The PQ redox states of the reaction centres were represented in a conditionally linear model structure with delayed fluorescence (DF) as a measurable output. DF data were acquired for different plant samples and conditions. After least-squares parameter optimisation, not only could the model closely describe the measured DF, but more significantly, the estimated parameter... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099925 Fri, 18 Dec 2009 15:54:19 +0100 3099925 http://www.medworm.com/index.php?rid=3099924&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356266 In this study, we have focused on the noise in natural regulatory networks to understand the relationship between the characteristics of the noise and the structures of regulatory interactions. We targeted the expressions of genes related to amino acid biosynthesis (AAB) because of their well known regulatory structures. By measuring the noise of AAB genes in isogeneic Escherichia coli cells using flow cytometry, we found the noise amplitude in AAB genes to depend on the structure of the regulatory network. We categorised the regulatory networks with feedback regulation into two cases. In one case, the gene expression is negatively regulated by the final products of the AAB pathway known as feedback repression, whereas in another case, the gene expression is negatively regulated as a resul... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099924 Fri, 18 Dec 2009 15:54:19 +0100 3099924 http://www.medworm.com/index.php?rid=3099923&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356265 The authors have applied the dynamic sensitivity and control analyses to study the GLUT4 metabolic insulin signalling pathways, based on the models developed by Sedaghat et al. They have calculated the timedependent sensitivities of the concentration of the membrane GLUT4 with respect to all reaction parameters (reaction rate constants and initial concentrations of the effectors). These time-dependent sensitivities provide dynamic information about pathways, in particular, the separate roles of the negative and positive feedbacks in the network. In addition, the integrated sensitivities of the membrane GLUT4 have been used to rank the potential drug targets according to the accumulated influence of each reaction rate or initial concentration on the membrane GLUT4. The results are consisten... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099923 Fri, 18 Dec 2009 15:54:19 +0100 3099923 http://www.medworm.com/index.php?rid=3099922&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356264 Bone remodelling in adult skeleton is a process of maintaining bone mass through combined activities of bone forming osteoblasts and bone resorbing osteoclasts. Focusing on a molecular pathway mediated by osteoprotegerin, the authors derived a mathematical formulation for molecular interactions and cellular behaviours. The authors also treated this remodelling process as a homeostatic regulator in a framework of linear quadratic problems. A primary question was: does a solution of a matrix Riccati equation provide a guideline for therapeutic interventions for prevention of bone loss? In order to elucidate the systems dynamics, the authors analysed the perturbed set of equations around a stable equilibrium state together with the original equations. The results demonstrate that a homeostati... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099922 Fri, 18 Dec 2009 15:54:19 +0100 3099922 http://www.medworm.com/index.php?rid=3099921&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356263 This note studies feedforward circuits as models for perfect adaptation to step signals in biological systems. A global convergence theorem is proved in a general framework, which includes examples from the literature as particular cases. A notable aspect of these circuits is that they do not adapt to pulse signals, because they display a memory phenomenon. Estimates are given of the magnitude of this effect. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099921 Fri, 18 Dec 2009 15:54:19 +0100 3099921 http://www.medworm.com/index.php?rid=3099920&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356262 Evolutionary graphs (EGs) were initially introduced in 2005 and give an outlet for the evolutionary dynamic determined by the population structures, the fitness of the mutants and the number of the individuals. Bi-level EGs with different fitness are discussed. The corresponding fixation probability is given, especially when the lower level and the upper level are all isothermal. The optimisation fixation probabilities are also built if the lower and the upper graphs are all isothermal structures and the number of the total individuals is finite. At last, some applications to the system biology are involved. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099920 Fri, 18 Dec 2009 15:54:19 +0100 3099920 http://www.medworm.com/index.php?rid=3099919&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5356259%26arnumber%3D5356260 Stem cells have the capability to self-renew and maintain their undifferentiated state or to differentiate into one or more specialised cell types. Stem cell expansion and manipulation ex vivo is a promising approach for engineering cell replacement therapies, and endogenous stem cells represent potential drugable targets for tissue repair. Before we can harness stem cells' therapeutic potential, we must first understand the intracellular mechanisms controlling their fate choices. These mechanisms involve complex signal transduction and gene regulation networks that feature, for example, intricate feed-forward loops, feedback loops and cross-talk between multiple signalling pathways. Systems biology applies computational and experimental approaches to investigate the emergent behaviour of ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3099919 Fri, 18 Dec 2009 15:54:19 +0100 3099919 http://www.medworm.com/index.php?rid=3059217&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344683 Many approaches to discovering significant pathways in gene expression profiles have been developed to facilitate biological interpretation and hypothesis generation. In this work, the authors propose a pathway identification scheme integrating the activity of pathway member genes with that of target genes of transcription factors (TFs) in the same pathway by the weighted Z-method. The authors evaluated the integrative scoring scheme in gene expression profiles of essential thrombocythemia patients with JAK2V617F mutation status, primary breast tumour samples with the status of metastasis occurrence, two independent lung cancer expression profiles with their prognosis, and found that our approach identified cancer-typespecific pathways better than gene set enrichment analysis (GSEA) and Ti... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059217 Sun, 01 Nov 2009 00:00:00 +0100 3059217 http://www.medworm.com/index.php?rid=3059216&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344682 In this study, the problem of detecting drug targets was addressed, which finds a set of enzymes whose inhibition stops the production of a given set of target compounds and meanwhile minimally eliminates non-target compounds in the context of metabolic networks. The model aims to make the side effects of drugs as small as possible and thus has practical significance of potential pharmaceutical applications. Specifically, by exploiting special features of metabolic systems, a novel approach was proposed to exactly formulate this drug target detection problem as an integer linear programming model, which ensures that optimal solutions can be found efficiently without any heuristic manipulations. To verify the effectiveness of our approach, computational experiments on both Escherichia coli ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059216 Sun, 01 Nov 2009 00:00:00 +0100 3059216 http://www.medworm.com/index.php?rid=3059215&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344681 Parameter estimation is the main bottleneck of metabolic pathway modelling. It may be addressed from the bottom up, using information on metabolites, enzymes and modulators, or from the top down, using metabolic time series data, which have become more prevalent in recent years. The authors propose here that it is useful to combine the two strategies and to complement time-series analysis with kinetic information. In particular, the authors investigate how the recent method of dynamic flux estimation (DFE) may be supplemented with other types of estimation. Using the glycolytic pathway in Lactococcus lactis as an illustration example, the authors demonstrate some strategies of such supplementation. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059215 Sun, 01 Nov 2009 00:00:00 +0100 3059215 http://www.medworm.com/index.php?rid=3059214&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344680 Discovering biomarkers using mass spectrometry (MS) and microarray expression profiles is a promising strategy in molecular diagnosis. Here, the authors proposed a new pipeline for biomarker discovery that integrates disease information for proteins and genes, expression profiles in both genomic and proteomic levels, and protein¿protein interactions (PPIs) to discover high confidence network biomarkers. Using this pipeline, a total of 474 molecules (genes and proteins) related to prostate cancer were identified and a prostate-cancer-related network (PCRN) was derived from the integrative information. Thus, a set of candidate network biomarkers were identified from multiple expression profiles composed by eight microarray datasets and one proteomics dataset. The network biomarkers with PPI... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059214 Sun, 01 Nov 2009 00:00:00 +0100 3059214 http://www.medworm.com/index.php?rid=3059213&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344679 In this study, the authors integrate transcriptional and post-transcriptional regulation into four different kinds of microRNAmediated motifs and investigate the mechanism of microRNAs regulation from the viewpoints of dynamics. Theoretical analysis and numerical simulations show that all the four motifs exhibit strong robustness to external and stochastic perturbations. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059213 Sun, 01 Nov 2009 00:00:00 +0100 3059213 http://www.medworm.com/index.php?rid=3059212&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344678 In this study, the authors monitored the expression of rat genes measured with multiple phase-resetting stimuli, and developed a technique to extract the candidate genes for the changes in circadian rhythm by the stimuli, from microarray data. First, the spectra for the time series of gene expression were estimated by fast Fourier transform, and then two fitting methods, the random period fitting method and the conditional curve fitting method, using the estimated periods as the initial values, were applied to the control and the stimulated expression data to estimate the periods and the phases. Finally, by comparing the two sets of periods and phases, the period change and the phase shift by stimuli were estimated to extract the candidate genes related to the master clock, by mapping the ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059212 Sun, 01 Nov 2009 00:00:00 +0100 3059212 http://www.medworm.com/index.php?rid=3059211&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344677 The identification of genes and pathways involved in biological processes is a central problem in systems biology. Recent microarray technologies and other high-throughput experiments provide information which sheds light on this problem. In this article, the authors propose a new computational method to detect active pathways, or identify differentially expressed pathways via integration of gene expression and interactomic data in a sophisticated and efficient manner. Specifically, by using signal-to-noise ratio to measure the differentially expressed level of networks, this problem is formulated as a mixed integer linear programming problem (MILP). The results on yeast and human data demonstrate that the proposed method is more accurate and robust than existing approaches. (Source: IET S... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059211 Sun, 01 Nov 2009 00:00:00 +0100 3059211 http://www.medworm.com/index.php?rid=3059210&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344676 In this study, the authors study attractors in probabilistic Boolean networks (PBNs). They study the expected number of singleton attractors in a PBN and show that it is (2 - (1=2)/sup L-1)/sup n/, where n is the number of nodes in a PBN and L is the number of Boolean functions assigned to each node. In the case of L = 2, this number is simplified into 1.5/sup n/. It is an interesting result because it is known that the expected number of singleton attractors in a Boolean network (BN) is 1. Then, we present algorithms for identifying singleton and small attractors and perform both theoretical and computational analyses on their average case time complexities. For example, the average case time complexities for identifying singleton attractors of a PBN with L = 2 and L = 3 are O(1.601/sup n... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059210 Sun, 01 Nov 2009 00:00:00 +0100 3059210 http://www.medworm.com/index.php?rid=3059209&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344675 In this study, the authors propose efficient algorithms for constructing a PBN when its transition probability matrix is given. The complexities of the algorithms are also analysed. This is an interesting inverse problem in network inference using steady-state data. The problem is important as most microarray data sets are assumed to be obtained from sampling the steady-state. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059209 Sun, 01 Nov 2009 00:00:00 +0100 3059209 http://www.medworm.com/index.php?rid=3059208&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344674 A cis-regulatory module often processes multiple regulatory inputs provided by transcription factors that bind to DNA and regulate the expression of the gene in a combinatorial logic manner. Here the authors analyse dynamic cross correlations between the regulator concentrations and the output of the gene using stochastic modelling, and show their characteristics for different logic operations. The authors find that the dynamic cross-correlation curve with respect to the correlation time near the peak close to the point of the zero correlation time is upwards convex in the case of AND logic whereas downwards convex in the case of OR logic, where intrinsic and extrinsic noise plays a distinct role. This result implies that the cross-correlation function is a useful and robust index for dist... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059208 Sun, 01 Nov 2009 00:00:00 +0100 3059208 http://www.medworm.com/index.php?rid=3059207&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5344672%26arnumber%3D5344673 One of the major challenges for post-genomic biology is to understand how genes, proteins and small molecules interact to form cellular systems. It has been recognised that a complicated living organism cannot be fully understood by merely analysing individual components, and that interactions of those components or networks are ultimately responsible for an organism¿s form and functions. Instead of analysing individual components or aspects of the organism, systems biology is the study of an organism, viewed as a dynamical and interacting network of biomolecules which give rise to a complicated life. With increasingly accumulated data from high-throughput technologies, molecular networks and their dynamics have been studied extensively from various aspects of living organisms. Many mathe... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=3059207 Sun, 01 Nov 2009 00:00:00 +0100 3059207 http://www.medworm.com/index.php?rid=2889894&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243219 In this study, the authors address this problem by solving the chemical master equations for various enzymatic reactions. A perturbation theory analogous to that used in quantum mechanics allows the determination of the first (langnrang) and the second (sigma2) cumulants of the distribution of created product molecules as a function of the substrate concentration and the kinetic rates of the intermediate processes. The mean product flux V = dlangnrang / dt (or dasiadosedasiaresponsedasia curve) and the Fano factor F = sigma2/langnrang are both realistically measurable quantities, and whereas the mean flux can often appear the same for different reaction types, the Fano factor can be quite different. This suggests both qualitative and quantitative ways to discriminate between different reac... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889894 Mon, 31 Aug 2009 23:00:00 +0100 2889894 http://www.medworm.com/index.php?rid=2889893&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243218 Fungal-plant root associations involve nutrient exchanges, between the partners and the soil, particularly phosphate, that benefit both organisms. Discrete dynamical system (DDS) models are reconstructed to capture gene regulation in the arbuscular mycorrhizae Glomus versiforme-Medicago trunculata root symbiosis. Previously published time-course gene expression data derived from various days post-inoculation were clustered to identify genes co-regulated in mycorrhizal roots. Uncolonised roots grown with high phosphate provide a key nutritional control condition. First-order linear DDS models were created using a data-driven method to fit to the observed gene expression data. The result of the modelling constitutes active gene interactions in the regulatory network of the plant root at 8, 1... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889893 Mon, 31 Aug 2009 23:00:00 +0100 2889893 http://www.medworm.com/index.php?rid=2889892&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243217 Cellular networks inferred from condition-specific microarray data can capture the functional rewiring of cells in response to different environmental conditions. Unfortunately, many algorithms for inferring cellular networks do not scale to whole-genome data with thousands of variables. We propose a novel approach for scalable learning of large networks: cluster and infer networks (CIN). CIN learns network structures in two steps: (a) partition variables into smaller clusters, and (b) learn networks per cluster. We optionally revisit the cluster assignment of variables with poor neighbourhoods. Results on networks with known topologies suggest that CIN has substantial speed benefits, without substantial performance loss. We applied our approach to microarray compendia of glucose-starved y... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889892 Mon, 31 Aug 2009 23:00:00 +0100 2889892 http://www.medworm.com/index.php?rid=2889891&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243216 Analysis of gene expression data sets reveals that the variation in expression is concentrated to significantly fewer dasiacharacteristic modesdasia or dasiaeigengenesdasia than the number of both recorded assays and measured genes. Previous works have stressed the importance of these characteristic modes, but neglected the equally important weak modes. Herein a generic system property dasia interampatteness dasia is defined that explains the previous feature, and assigns equal weight to the characteristic and weak modes. An interampatte network is characterised by strong INTERactions enabling simultaneous AMPlification and ATTEnuation of different signals. It is postulated that biochemical networks are interampatte, based on published experimental data and theoretical considerations. Exis... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889891 Mon, 31 Aug 2009 23:00:00 +0100 2889891 http://www.medworm.com/index.php?rid=2889890&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243215 The authors introduce a quantitative measure of the capacity of a small biological network to evolve. The measure is applied to a stochastic description of the experimental setup of Guet et al. (Science 2002, 296, pp. 1466), treating chemical inducers as functional inputs to biochemical networks and the expression of a reporter gene as the functional output. The authors take an information-theoretic approach, allowing the system to set parameters that optimise signal processing ability, thus enumerating each network's highest-fidelity functions. All networks studied are highly evolvable by the measure, meaning that change in function has little dependence on change in parameters. Moreover, each network's functions are connected by paths in the parameter space along which information is not... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889890 Mon, 31 Aug 2009 23:00:00 +0100 2889890 http://www.medworm.com/index.php?rid=2889889&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243214 Auto-regulatory negative feedback loops, where the protein expressed from a gene inhibits its own expression are common gene network motifs within cells. We investigate when will introducing a negative feedback mechanism be beneficial in terms of increasing a fitness function that is given by the probability of maintaining protein numbers above a critical threshold. Our results show the existence of a trade-off as introducing feedback decreases the average number of protein molecules driving this number closer to the critical threshold (which decreases fitness) but also reduces stochastic fluctuations around the mean (which increases fitness). We provide analytical conditions under which a negative feedback mechanism can evolve, that is, introducing feedback will increase the above fitness... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889889 Mon, 31 Aug 2009 23:00:00 +0100 2889889 http://www.medworm.com/index.php?rid=2889888&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243213 Nuclear factors p53 and NF-kappaB control many physiological processes including cell cycle arrest, DNA repair, apoptosis, death, innate and adaptive immune responses, and inflammation. There are numerous pathways linking these systems and there is a bulk of evidence for cooperation as well as for antagonisms between p53 and NF-kappaB. In this theoretical study, the authors use earlier models of p53 and NF-kappaB systems and construct a crosstalk model of p53-NF-kappaB network in order to explore the consequences of the two-way coupling, in which NF-kappaB upregulates the transcription of p53, whereas in turn p53 attenuates transcription of NF-kappaB inhibitors IkappaBalpha and A20. We consider a number of protocols in which cells are stimulated by tumour necrosis factor-alpha (TNFalpha) (... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889888 Mon, 31 Aug 2009 23:00:00 +0100 2889888 http://www.medworm.com/index.php?rid=2889887&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243212 A number of regulatory networks have the potential to generate sustained oscillations of irregular amplitude, but well conserved period. Single-cell experiments revealed that in p53 and nuclear factor (NF)-kappaB systems the oscillation period is homogenous in cell populations, insensitive to the strength of the stimulation, and is not influenced by the overexpression of p53 or NF-kappaB transcription factors. We propose a novel computational method of validation of molecular pathways models, based on the analysis of sensitivity of the oscillation period to the particular gene(s) copy number and the level of stimulation. Using this method, the authors demonstrate that existing p53 models, in which oscillations are borne at a saddle-node-on-invariant-circle or subcritical Hopf bifurcations ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889887 Mon, 31 Aug 2009 23:00:00 +0100 2889887 http://www.medworm.com/index.php?rid=2889886&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243211 Following phosphorylation, nuclear translocation of the mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, is critical for both gene expression and DNA replication induced by growth factors. ERK nuclear translocation has therefore been studied extensively, but many details remain unresolved, including whether or not ERK dimerisation is required for translocation. Here, we simulate ERK nuclear translocation with a compartmental computational model that includes systematic sensitivity analysis. The governing ordinary differential equations are solved with the backward differentiation formula and decoupled direct methods. To better understand the regulation of ERK nuclear translocation, we use this model in conjunction with a previously published model of the ERK pathway that does not ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889886 Mon, 31 Aug 2009 23:00:00 +0100 2889886 http://www.medworm.com/index.php?rid=2889885&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243210 Online databases store thousands of molecular interactions and pathways, and numerous modelling software tools provide users with an interface to create and simulate mathematical models of such interactions. However, the two most widespread used standards for storing pathway data (biological pathway exchange; BioPAX) and for exchanging mathematical models of pathways (systems biology markup language; SBML) are structurally and semantically different. Conversion between formats (making data present in one format available in another format) based on simple one-to-one mappings may lead to loss or distortion of data, is difficult to automate, and often impractical and/or erroneous. This seriously limits the integration of knowledge data and models. In this paper we introduce an approach for s... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889885 Mon, 31 Aug 2009 23:00:00 +0100 2889885 http://www.medworm.com/index.php?rid=2889884&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243209 Regulation of protein-protein interactions because of their spatial organisation in cells often shapes cell signalling responses to external stimuli, yet most current cell signalling models do not include spatial segregation of proteins beyond coarse control volumes like the cytosol or nucleus. A significant hindrance to spatial modelling of cell signalling is a lack of data describing the spatial organisation of proteins in cells. One signalling system in which spatial organisation is critical is integrin signalling, where protein interactions are restricted to small, micron-sized protein complexes that form on clusters of transmembrane integrin proteins. Using confocal microscopy and image analysis to quantify the size, shape and location of integrin clusters, the authors observed that c... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889884 Mon, 31 Aug 2009 23:00:00 +0100 2889884 http://www.medworm.com/index.php?rid=2889883&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243208 Cell-penetrating peptides (CPPs) such as HIV's trans-activating transcriptional activator (TAT) and polyarginine rapidly pass through the plasma membranes of mammalian cells by an unknown mechanism called transduction. They may be medically useful when fused to well-chosen chains of fewer than about 35 amino acids. The author offers a simple model of transduction in which phosphatidylserines and CPPs effectively form two plates of a capacitor with a voltage sufficient to cause the formation of transient pores (electroporation). The model is consistent with experimental data on the transduction of oligoarginine into mouse C2C12 myoblasts and makes three testable predictions. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889883 Mon, 31 Aug 2009 23:00:00 +0100 2889883 http://www.medworm.com/index.php?rid=2889882&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5243186%26arnumber%3D5243207 This special issue consists of 12 original papers that elaborate on work presented at The Second q-bio Conference on Cellular Information Processing, which was held on the campus of St. John¿s College in Santa Fe, New Mexico, USA, 6-9 August 2008. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2889882 Mon, 31 Aug 2009 23:00:00 +0100 2889882 http://www.medworm.com/index.php?rid=2644575&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174556 Uncertainty is an intrinsic phenomenon in control of gene regulatory networks (GRNs). The presence of uncertainty is related to impreciseness of GRN models due to: (1) Errors caused by imperfection of measurement devices and (2) Models¿ inability to fully capture a complex structure of the GRN. Consequently, there is a discrepancy between actual behaviour of the GRN and what is predicted by its mathematical model. This can result in false control signals, which can drive a cell to an undesirable state. To address the problem of control under uncertainties, a risk-sensitive control paradigm is proposed. Robustness is accomplished by minimisation of the mean exponential cost as opposed to, for instance, minimisation of the mean square cost by riskneutral controllers. The authors derive an o... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644575 Tue, 30 Jun 2009 23:00:00 +0100 2644575 http://www.medworm.com/index.php?rid=2644574&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174555 In this study the authors propose a novel approach to identify local communities based on iterative agglomeration and local optimisation. The proposed solution has two significant improvements: (i) in each iteration, agglomeration strengthens the local community measure by selecting the best possible set of vertices, and (ii) the proposed vertex and community rank criterion are suitable for the dynamic networks where the interactions among vertices may change over time. In order to evaluate the proposed algorithm, extensive experiments and benchmarking on computer generated networks as well as real-world social and biological networks have been conducted. The experiment results reflect that the proposed algorithm can identify local communities, irrespective of the source vertex position, w... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644574 Tue, 30 Jun 2009 23:00:00 +0100 2644574 http://www.medworm.com/index.php?rid=2644573&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174554 The activation of caspases is a central mechanism in apoptosis. To gain further insights into complex processes like this, mathematical modelling using ordinary differential equations (ODEs) can be a very powerful research tool. Unfortunately, the lack of measurement data is a common problem in building such kinetic models, because it practically constrains the identifiability of the model parameters. An existing mathematical model of caspase activation during apoptosis was used in order to design future experimental setups that will help to maximise the obtained information. For this purpose, artificial measurement data are generated in silico to simulate potential experiments, and the model is fitted to this data. The model is also analysed using observability gramian and sensitivity ana... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644573 Tue, 30 Jun 2009 23:00:00 +0100 2644573 http://www.medworm.com/index.php?rid=2644572&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174553 The multi-element probabilistic collocation method (ME-PCM) as a tool for sensitivity analysis of differential equation models as applied to cellular signalling networks is formulated. This method utilises a simple, efficient sampling algorithm to quantify local sensitivities throughout the parameter space. The application of the ME-PCM to a previously published ordinary differential equation model of the apoptosis signalling network is presented. The authors verify agreement with the previously identified regions of sensitivity and then go on to analyse this region in greater detail with the ME-PCM. The authors demonstrate the generality of the ME-PCM by studying sensitivity of the system using a variety of biologically relevant markers in the system such as variation in one (or many) che... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644572 Tue, 30 Jun 2009 23:00:00 +0100 2644572 http://www.medworm.com/index.php?rid=2644571&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174552 In this study, a new mathematical model is built to characterise the p53-Mdm2 interaction based on the recent biological findings, as well as a few reasonable hypotheses and approximations. The dynamics of ATM (Ataxia Telangiectasia Mutated) is introduced to the model so as to connect DNA damage signal with the core regulation. The simulation results are in good accord with the experimental observations in the literature. More importantly, through bifurcation analysis on the model, a new threshold mechanism is predicted with respect to the dose of ionising radiation (IR). Furthermore, a novel frequency shifting phenomenon is also observed through Fourier frequency analysis on the simulation data. Finally, based on the predicted dominant frequency, an optimised experimental scheme is propos... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644571 Tue, 30 Jun 2009 23:00:00 +0100 2644571 http://www.medworm.com/index.php?rid=2644570&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D5174550%26arnumber%3D5174551 Recently, important insights into static network topology for biological systems have been obtained, but still global dynamical network properties determining stability and system responsiveness have not been accessible for analysis. Herein, we explore a genome-wide gene-to-gene regulatory network based on expression data from the cell cycle in Saccharomyces cerevisae (budding yeast). We recover static properties like hubs (genes having several out-going connections), network motifs and modules, which have previously been derived from multiple data sources such as whole-genome expression measurements, literature mining, protein¿protein and transcription factor binding data. Further, our analysis uncovers some novel dynamical design principles; hubs are both repressed and repressors, and t... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2644570 Tue, 30 Jun 2009 23:00:00 +0100 2644570 http://www.medworm.com/index.php?rid=2426926&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957267 Composed of linear difference equations, a discrete dynamical system (DDS) model was designed to reconstruct transcriptional regulations in gene regulatory networks (GRNs) for ethanologenic yeast Saccharomyces cerevisiae in response to 5-hydroxymethylfurfural (HMF), a bioethanol conversion inhibitor. The modelling aims at identification of a system of linear difference equations to represent temporal interactions among significantly expressed genes. Power stability is imposed on a system model under the normal condition in the absence of the inhibitor. Non-uniform sampling, typical in a time-course experimental design, is addressed by a log-time domain interpolation. A statistically significant DDS model of the yeast GRN derived from time-course gene expression measurements by exposure to ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426926 Thu, 21 May 2009 04:00:00 +0100 2426926 http://www.medworm.com/index.php?rid=2426925&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957266 The coefficient of determination (CoD) has been used to infer Boolean networks (BNs) from steady-state data, in particular, to estimate the constituent BNs for a probabilistic BN. The advantage of the CoD method over design methods that emphasise graph topology or attractor structure is that the CoD produces a network based on strong predictive relationships between target genes and their predictor (parent) genes. The disadvantage is that spurious attractor cycles appear in the inferred network, so that there is poor inference relative to the attractor structure, that is, relative to the steady-state behaviour of the network. Given steady-state data, there should not be a significant amount of steady-state probability mass in the inferred network lying outside the mass of the data distribu... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426925 Thu, 21 May 2009 04:00:00 +0100 2426925 http://www.medworm.com/index.php?rid=2426924&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957265 The aim here was to explore the potential of pharmacokinetic (PK)/pharmacodynamic (PD) and physiopathological parameters in explaining the primary effects of an anti-cancer treatment that targets cells in a specific cell cycle phase. The authors applied a theoretical multi-scale disease model of tumour growth that integrates cancer processes at the cellular and tissue scales. The mathematical model at the cell level relies on a dynamic description of cell cycle regulation while the model at the tissue level is based on fluid mechanics considerations. Simulations show that the number of target cells oscillates as the tumour grows after a first cycle of chemotherapy. Both treatment effect and tumour growth processes drive these oscillations. Nonetheless, results indicate that parameters rela... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426924 Thu, 21 May 2009 04:00:00 +0100 2426924 http://www.medworm.com/index.php?rid=2426923&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957264 Steady-state and dynamic flux balance analysis (DFBA) was used to investigate the effects of metabolic model complexity and parameters on ethanol production predictions for wild-type and engineered Saccharomyces cerevisiae. Three metabolic network models ranging from a single compartment representation of metabolism to a genome-scale reconstruction with seven compartments and detailed charge balancing were studied. Steady-state analysis showed that the models generated similar wild-type predictions for the biomass and ethanol yields, but for ten engineered strains the seven compartment model produced smaller ethanol yield enhancements. Simplification of the seven compartment model to two intracellular compartments produced increased ethanol yields, suggesting that reaction localisation had... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426923 Thu, 21 May 2009 04:00:00 +0100 2426923 http://www.medworm.com/index.php?rid=2426922&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957263 Gene regulatory networks capture interactions between genes and other cell substances, resulting in various models for the fundamental biological process of transcription and translation. The expression levels of the genes are typically measured as mRNA concentration in micro-array experiments. In a so-called genetic perturbation experiment, small perturbations are applied to equilibrium states and the resulting changes in expression activity are measured. One of the most important problems in systems biology is to use these data to identify the interaction pattern between genes in a regulatory network, especially in a large scale network. The authors develop a novel algorithm for identifying the smallest genetic network that explains genetic perturbation experimental data. By construction... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426922 Thu, 21 May 2009 04:00:00 +0100 2426922 http://www.medworm.com/index.php?rid=2426921&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957262 Modelling and analysis of biochemical systems such as sugar cataract development (SCD) are critical because they can provide new insights into systems, which cannot be easily tested with experiments; however, they are challenging problems due to the highly coupled chemical reactions that are involved. The authors present a stochastic hybrid system (SHS) framework for modelling biochemical systems and demonstrate the approach for the SCD process. A novel feature of the framework is that it allows modelling the effect of drug treatment on the system dynamics. The authors validate the three sugar cataract models by comparing trajectories computed by two simulation algorithms. Further, the authors present a probabilistic verification method for computing the probability of sugar cataract forma... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426921 Thu, 21 May 2009 04:00:00 +0100 2426921 http://www.medworm.com/index.php?rid=2426920&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4957260%26arnumber%3D4957261 The following report selects and summarises some of the conclusions and recommendations generated throughout a series of workshops and discussions that have lead to the publication of the Science Policy Briefing (SPB) Nr. 35, published by the European Science Foundation. (Large parts of the present text are directly based on the ESF SPB. Detailed recommendations with regard to specific application areas are not given here but can be found in the SPB. Issues related to mathematical modelling, including training and the need for an infrastructure supporting modelling are discussed in greater detail in the present text.) The numerous reports and publications about the advances within the rapidly growing field of systems biology have led to a plethora of alternative definitions for key concept... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2426920 Thu, 21 May 2009 04:00:00 +0100 2426920 http://www.medworm.com/index.php?rid=2295281&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4801436%26arnumber%3D4801441 Complex regulatory dynamics is ubiquitous in molecular networks composed of genes and proteins. Recent progress in computational biology and its application to molecular data generate a growing number of complex networks. Yet, it has been difficult to understand the governing principles of these networks beyond graphical analysis or extensive numerical simulations. Here the authors exploit several simplifying biological circumstances which thereby enable to directly detect the underlying dynamical regularities driving periodic oscillations in a dynamical nonlinear computational model of a protein¿protein network. System analysis is performed using the cell cycle, a mathematically well-described complex regulatory circuit driven by external signals. By introducing an explicit time delay an... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2295281 Sat, 28 Mar 2009 04:00:00 +0100 2295281 http://www.medworm.com/index.php?rid=2295280&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4801436%26arnumber%3D4801440 In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered as the master circadian pacemaker. Each cell in the SCN contains an autonomous molecular clock, and the SCN is composed of multiple single-cell circadian oscillators. The fundamental question is how the individual cellular oscillators, expressing a wide range of periods, interact and assemble to create an integrated pacemaker that can govern behavioural and physiological rhythmicity and be reset by environmental light. The key is that the heterogeneous network formed by the cellular clocks within the SCN must synchronise to maintain timekeeping activity. To study the synchronisation mechanisms and the circadian rhythm generation, we propose a model based on the structural and functional heterogeneity of the SCN... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2295280 Sat, 28 Mar 2009 04:00:00 +0100 2295280 http://www.medworm.com/index.php?rid=2295278&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4801436%26arnumber%3D4801439 It is well known that the control/intervention of some genes in a genetic regulatory network is useful for avoiding undesirable states associated with some diseases like cancer. For this purpose, both optimal finitehorizon control and infinite-horizon control policies have been proposed. Boolean networks (BNs) and its extension probabilistic Boolean networks (PBNs) as useful and effective tools for modelling gene regulatory systems have received much attention in the biophysics community. The control problem for these models has been studied widely. The optimal control problem in a PBN can be formulated as a probabilistic dynamic programming problem. In the previous studies, the optimal control problems did not take into account the hard constraints, i.e. to include an upper bound for the ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2295278 Sat, 28 Mar 2009 04:00:00 +0100 2295278 http://www.medworm.com/index.php?rid=2295276&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4801436%26arnumber%3D4801438 Researchers use constructs from the field of electrical engineering for the modelling and analysis of biological systems, but few exploit parallels between electrical and biological circuits for simulation purposes. The authors discuss the development of BioXyce, a circuit-based biological simulation platform that uses XyceTM, a large-scale electrical circuit simulator, as its simulation engine. BioXyce is capable of simulating whole-cell and multicellular systems. Simulation results for the central metabolism in Escherichia coli K12 and cellular differentiation in Drosophila sp. are presented. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2295276 Sat, 28 Mar 2009 04:00:00 +0100 2295276 http://www.medworm.com/index.php?rid=2295270&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4801436%26arnumber%3D4801437 The authors discuss the role of the Raf kinase inhibitory protein (RKIP) as a modulator of oscillations in NFγkB signalling. A mathematical model of the NFγkB signalling pathway was derived and the Lyapunov¿Andronov theory was used to analyse dynamical properties of the system. The analytical results were complemented by predictive numerical simulations. Our results suggest that the nature of oscillations, emerging under sustained stimulation of the system, depends on the interplay between the IkB kinase (IKK) stimulation and the inhibitory action of RKIP. The authors found a mathematical relation that defines isoclines in IKK and RKIP levels for which the properties of oscillations are conserved and changes in the stimulation can be compensated by modulating RKIP inhibiti... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2295270 Sat, 28 Mar 2009 04:00:00 +0100 2295270 http://www.medworm.com/index.php?rid=2138698&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4762245%26arnumber%3D4762250 Although stochastic population models have proved to be a powerful tool in the study of process generating mechanisms across a wide range of disciplines, all too often the associated mathematical development involves nonlinear mathematics, which immediately raises difficult and challenging analytic problems that need to be solved if useful progress is to be made. One approximation that is often employed to estimate the moments of a stochastic process is moment closure. This approximation essentially truncates the moment equations of the stochastic process. A general expression for the marginal- and joint-moment equations for a large class of stochastic population models is presented. The generalisation of the moment equations allows this approximation to be applied easily to a wide range o... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2138698 Wed, 28 Jan 2009 05:00:00 +0100 2138698 http://www.medworm.com/index.php?rid=2138697&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4762245%26arnumber%3D4762249 An algorithm for automatic order reduction of models defined by large systems of differential equations is presented. The algorithm was developed with systems biology models in mind and the motivation behind it is to develop mechanistic pharmacokinetic/pharmacodynamic models from already available systems biology models. The approach used for model reduction is proper lumping of the system¿s states and is based on a search through the possible combinations of lumps. To avoid combinatorial explosion, a heuristic, greedy search strategy is employed and comparison with the full exhaustive search provides evidence that it performs well. The method takes advantage of an apparent property of this kind of systems that lumps remain consistent over different levels of order reduction. Advantages o... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2138697 Wed, 28 Jan 2009 05:00:00 +0100 2138697 http://www.medworm.com/index.php?rid=2138696&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4762245%26arnumber%3D4762248 Quantitative modelling and analysis of biochemical networks is challenging because of the inherent complexities and nonlinearities of the system and the limited availability of parameter values. Even if a mathematical model of the network can be developed, the lack of large-scale good-quality data makes accurate estimation of a large number of parameters impossible. Hence, coarse-grained models (CGMs) consisting of essential biochemical mechanisms are more suitable for computational analysis and for studying important systemic functions. The central question in constructing a CGM is which mechanisms should be deemed ?essential? and which can be ignored. Also, how should parameter values be defined when data are sparse? A mixed-integer nonlinear-programming (MINLP) based optimisation approa... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2138696 Wed, 28 Jan 2009 05:00:00 +0100 2138696 http://www.medworm.com/index.php?rid=2138695&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4762245%26arnumber%3D4762247 Using mathematical models for a quantitative description of dynamical systems requires the identification of uncertain parameters by minimising the difference between simulation and measurement. Owing to the measurement noise also, the estimated parameters possess an uncertainty expressed by their variances. To obtain highly predictive models, very precise parameters are needed. The optimal experimental design (OED) as a numerical optimisation method is used to reduce the parameter uncertainty by minimising the parameter variances iteratively. A frequently applied method to define a cost function for OED is based on the inverse of the Fisher information matrix. The application of this traditional method has at least two shortcomings for models that are nonlinear in their parameters: (i) it... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2138695 Wed, 28 Jan 2009 05:00:00 +0100 2138695 http://www.medworm.com/index.php?rid=2138694&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4762245%26arnumber%3D4762246 Dynamic modelling of biochemical reaction networks has to cope with the inherent uncertainty about biological processes, concerning not only data and parameters but also kinetics and structure. These different types of uncertainty are nested within each other: uncertain network structures contain uncertain reaction kinetics, which in turn are governed by uncertain parameters. Here, the authors review some issues arising from such uncertainties and sketch methods, solutions and future directions to deal with them. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=2138694 Wed, 28 Jan 2009 05:00:00 +0100 2138694 http://www.medworm.com/index.php?rid=1976681&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4677816%26arnumber%3D4677821 Genetical systems biology or systems genetics treats the genome as the central reference point for all omics variations and is an emerging new branch of systems biology. Quantitative genetic principles were developed for high-throughput genomic, transcriptomic and metabolomic data observed in large populations. New statistical genetic models were developed for expression quantitative trait loci (eQTL), namely, marker regression eQTL mapping and marker-expression co-factor mapping. Evaluations of power to detect eQTL showed that sample size requirements are higher for detecting trans-acting genes than cis-acting genes. Power is higher for eQTL with high heritability than for eQTL with low heritability. These results will be valuable for systems genetic investigations. Gonadotrophin releasin... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1976681 Fri, 21 Nov 2008 05:00:00 +0100 1976681 http://www.medworm.com/index.php?rid=1976680&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4677816%26arnumber%3D4677820 The physical sites of calcium entry and exit in the skeletal muscle cell are distinct and highly organised in space. It was investigated whether the highly structured spatial organisation of sites of Ca2 release, uptake and action in skeletal muscle cells substantially impacts the dynamics of cytosolic Ca2 handling and thereby the physiology of the cell. Hereto, the spatiotemporal dynamics of the free calcium distribution in a fast-twitch (FT) muscle sarcomere was studied using a reaction¿diffusion computational model for two genotypes with known anatomical differences. A computational model of a murine FT muscle sarcomere is developed, de novo including a closed calcium mass balance to simulate spatiotemporal high stimulation frequency calcium dynamics at 358°C. Literature data o... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1976680 Fri, 21 Nov 2008 05:00:00 +0100 1976680 http://www.medworm.com/index.php?rid=1976679&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4677816%26arnumber%3D4677819 Cells adapt to changes in environmental conditions through the concerted action of signalling, gene expression and metabolic subsystems. The authors will discuss a theoretical framework addressing such integrated systems. This 'hierarchical analysis' was first developed as an extension to a metabolic control analysis. It builds on the phenomenon that often the communication between signalling, gene expression and metabolic subsystems is almost exclusively via regulatory interactions and not via mass flow interactions. This allows for the treatment of the said subsystems as 'levels' in a hierarchical view of the organisation of the molecular reaction network of cells. Such a hierarchical approach has as a major advantage that levels can be analysed conceptually in isolation of each other (f... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1976679 Fri, 21 Nov 2008 05:00:00 +0100 1976679 http://www.medworm.com/index.php?rid=1976678&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4677816%26arnumber%3D4677818 One of the main aims of system biology is to understand the structure and dynamics of genomic systems. A computational approach, facilitated by new technologies for high-throughput quantitative experimental data, is put forward to investigate the regulatory system of dynamic interaction among genes in Kaposi¿s sarcoma-associated herpesvirus network after induction of lytic replication. A reconstruction of transcription factor activity and gene-regulatory kinetics using data from a time-course microarray experiment is proposed. The computational approach uses nonlinear differential equations. In particular, the quantitative Michaelis¿Menten model of generegulatory kinetics is extended to allow for post-transcriptional modifications and synergic interactions between target genes and the Rt... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1976678 Fri, 21 Nov 2008 05:00:00 +0100 1976678 http://www.medworm.com/index.php?rid=1976677&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4677816%26arnumber%3D4677817 System-oriented biological research (Systems Biology) is a vibrant field which aims to establish the higher-order principles behind complex multi-cellular processes. This classic theme of the Life Sciences was recently reinforced with a new armamentarium of high-throughput molecular tools. These omics approaches ('omes', greek for 'complete') allow us to now study biological behaviour in unprecedented width and detail. Consequently, Systems Biology is seen to bear the potential for major discoveries in the Life Sciences. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1976677 Fri, 21 Nov 2008 05:00:00 +0100 1976677 http://www.medworm.com/index.php?rid=1906658&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648918 The advent of thousands of annotated genomes, detailed metabolic reconstructions and databases within the flourishing field of systems biology necessitates the development of functionally complete computer models of whole cells and cellular systems. Such models would realistically describe fundamental properties of living systems such as growth, division and chromosome replication. This will inevitably bridge bioinformatic technologies with ongoing mathematical modelling efforts and would allow for in silico prediction of important dynamic physiological events. To demonstrate a potential for the anticipated merger of bioinformatic genome-wide data with a whole-cell computer model, the authors present here an updated version of a dynamic model of Escherichia coli, including a module that co... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906658 Thu, 25 Sep 2008 04:00:00 +0100 1906658 http://www.medworm.com/index.php?rid=1906657&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648917 Assembly of quantitative models of large complex networks brings about several challenges. One of them is the combinatorial complexity, where relatively few signalling molecules can combine to form thousands or millions of distinct chemical species. A receptor that has several separate phosphorylation sites can exist in hundreds of different states, many of which must be accounted for individually when simulating the time course of signalling. When assembly of protein complexes is being included, the number of distinct molecular species can easily increase by a few orders of magnitude. Validation, visualisation and understanding the network can become intractable. Another challenge appears when the modeller needs to recast or grow a model. Keeping track of changes and adding new elements p... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906657 Thu, 25 Sep 2008 04:00:00 +0100 1906657 http://www.medworm.com/index.php?rid=1906656&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648916 The Virtual Cell (VCell; http://vcell.org/) is a problem solving environment, built on a central database, for analysis, modelling and simulation of cell biological processes. VCell integrates a growing range of molecular mechanisms, including reaction kinetics, diffusion, flow, membrane transport, lateral membrane diffusion and electrophysiology, and can associate these with geometries derived from experimental microscope images. It has been developed and deployed as a web-based, distributed, client?server system, with more than a thousand world-wide users. VCell provides a separation of layers (core technologies and abstractions) representing biological models, physical mechanisms, geometry, mathematical models and numerical methods. This separation clarifies the impact of modelling deci... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906656 Thu, 25 Sep 2008 04:00:00 +0100 1906656 http://www.medworm.com/index.php?rid=1906655&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648915 The coupling of membrane-bound receptors to transcriptional regulators and other effector functions is mediated by multi-domain proteins that form complex assemblies. The modularity of protein interactions lends itself to a rule-based description, in which species and reactions are generated by rules that encode the necessary context for an interaction to occur, but also can produce a combinatorial explosion in the number of chemical species that make up the signalling network. The authors have shown previously that exact network reduction can be achieved using hierarchical control relationships between sites/domains on proteins to dissect multidomain proteins into sets of non-interacting sites, allowing the replacement of each `full¿ (progenitor) protein with a set of derived auxiliary (... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906655 Thu, 25 Sep 2008 04:00:00 +0100 1906655 http://www.medworm.com/index.php?rid=1906654&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648914 Morton-Firth and Bray¿s stochastic simulator (StochSim) and Gillespie¿s stochastic simulation algorithm (SSA) are two important methods for stochastic modelling and simulation of biochemical systems. They have been widely applied to different biological problems. A key question is discussed here: Are these two methods equivalent? These two methods are compared using fundamental probability analysis. The analysis clearly shows that, when the time step in the StochSim is chosen very small, the StochSim can be viewed as a first-order approximation to the SSA. The analysis also explains why the SSA is usually much more efficient than the StochSim for biochemical systems. However, when multistate species present in a system, the StochSim clearly shows its advantage. The Complexity analysis is... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906654 Thu, 25 Sep 2008 04:00:00 +0100 1906654 http://www.medworm.com/index.php?rid=1906653&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648913 This article also presents two systems-theory based FSP model reduction approaches that are particularly useful in such studies. The benefits of these approaches are illustrated in the analysis of the stochastic switching behaviour of Gardner¿s genetic toggle switch. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906653 Thu, 25 Sep 2008 04:00:00 +0100 1906653 http://www.medworm.com/index.php?rid=1906652&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648912 It is shown that biological networks with serial regulation (each node regulated by at most one other node) are constrained to direct functionality, in which the sign of the effect of an environmental input on a target species depends only on the direct path from the input to the target, even when there is a feedback loop allowing for multiple interaction pathways. Using a stochastic model for a set of small transcriptional regulatory networks that have been studied experimentally, it is further found that all networks can achieve all functions permitted by this constraint under reasonable settings of biochemical parameters. This underscores the functional versatility of the networks. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906652 Thu, 25 Sep 2008 04:00:00 +0100 1906652 http://www.medworm.com/index.php?rid=1906651&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648911 Biological information processing as implemented by regulatory and signalling networks in living cells requires sufficient specificity of molecular interaction to distinguish signals from one another, but much of regulation and signalling involves somewhat fuzzy and promiscuous recognition of molecular sequences and structures, which can leave systems vulnerable to crosstalk. A simple model of biomolecular interactions that reveals both a sharp onset of crosstalk and a fragmentation of the neutral network of viable solutions is examined as more proteins compete for regions of sequence space, revealing intrinsic limits to reliable signalling in the face of promiscuity. These results suggest connections to both phase transitions in constraint satisfaction problems and coding theory bounds on... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906651 Thu, 25 Sep 2008 04:00:00 +0100 1906651 http://www.medworm.com/index.php?rid=1906650&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648910 The authors have developed a mathematical model of regulation of expression of the Escherichia coli lac operon, and have investigated bistability in its steady-state induction behaviour in the absence of external glucose. Numerical analysis of equations describing regulation by artificial inducers revealed two natural bistability parameters that can be used to control the range of inducer concentrations over which the model exhibits bistability. By tuning these bistability parameters, the authors found a family of biophysically reasonable systems that are consistent with an experimentally determined bistable region for induction by thio-methylgalactoside (TMG) (in Ozbudak et al. Nature, 2004, 427; p. 737). To model regulation by lactose, the authors developed similar equations in which all... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906650 Thu, 25 Sep 2008 04:00:00 +0100 1906650 http://www.medworm.com/index.php?rid=1906649&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648909 Recent research has highlighted several examples wherein bacterial cell fate is determined by precise subcellular localisation of proteins. A prominent example is the polar localisation and oscillation of the Min proteins which is necessary for accurate cell division in Escherichia coli. Several computational models have been proposed which reproduce the oscillatory behaviour and observed phenotypes. However, these models use varying assumptions to do so leading to different mechanisms for precise polar localisation of MinD zones. To gain further insight, the authors extend a simplified model which focused on some key processes to explain the observed length scale for MinD zone formation. Using analytical approaches and numerical simulations, the authors explore cellular MinD distributions... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906649 Thu, 25 Sep 2008 04:00:00 +0100 1906649 http://www.medworm.com/index.php?rid=1906648&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648908 In this report, the authors apply a system theoretical analysis approach to derive the time-dependent input¿ output relationships of the functional module for the human epidermal growth factor receptor (HER) mediated Erk and Akt signalling pathways. Using a library of cell lines expressing endogenous levels of epidermal growth factor receptor (EGFR) and varying levels of HER2, the authors show that a transfer function-based representation can be successfully applied to quantitatively characterise information transfer in this system. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906648 Thu, 25 Sep 2008 04:00:00 +0100 1906648 http://www.medworm.com/index.php?rid=1906647&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648907 ErbB overexpression is linked to carcinogenesis. It is hypothesised that this is due to increased receptor density and receptor clustering, leading to increased receptor dimerisation and activation. Herein, spatial stochastic simulations have been performed to shed light receptor dimerisation processes. First, ligandindependent homodimerisation, is considered, based upon constitutive oligomerisation estimates (14%) in A431 cells that overexpress epidermal growth factor receptor (EGFR). When autocrine stimulation is blocked, ligand-independent EGFR activation is demonstrated by persistent, low levels of phosphorylation. The possibility that ligand-independent signalling is due to the fluctuation of EGFR conformation is considered. The agent-based model predicts the frequency (expressed as a... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906647 Thu, 25 Sep 2008 04:00:00 +0100 1906647 http://www.medworm.com/index.php?rid=1906646&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648906 The assembly of macromolecular structures consisting of proteins and DNA lies at the core of many fundamental cellular processes, such as transcription, recombination and replication. A common theme to all these processes is DNA looping, which provides the backbone for the required long-range interactions on DNA and results in further complexity that is exceptionally difficult to tackle with traditional quantitative approaches. Here, recent advances in mathematical and computational methods to study the assembly of protein¿protein/DNA complexes with loops and their effects in the cellular behaviour through gene regulation are reviewed. The interplay between multisite DNA looping and DNA bending regulatory proteins, such as the catabolite activator protein (CAP), and on its physiological c... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906646 Thu, 25 Sep 2008 04:00:00 +0100 1906646 http://www.medworm.com/index.php?rid=1906645&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648905 Biological processes are inherently noisy, as highlighted in recent measurements of stochasticity in gene expression. Here, the authors show that such phenotypic noise is essential to the adaptation of organisms to a variety of environments and also to the evolution of robustness against mutations. First, the authors show that for any growing cell showing stochastic gene expression, the adaptive cellular state is inevitably selected by noise, without the use of a specific signal transduction network. In general, changes in any protein concentration in a cell are products of its synthesis minus dilution and degradation, both of which are proportional to the rate of cell growth. In an adaptive state, both the synthesis and dilution terms of proteins are large, and so the adaptive state is le... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906645 Thu, 25 Sep 2008 04:00:00 +0100 1906645 http://www.medworm.com/index.php?rid=1906644&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648904 One goal of systems biology is to understand how genome-encoded parts interact to produce quantitative phenotypes. The Alpha Project is a medium-scale, interdisciplinary systems biology effort that aims to achieve this goal by understanding fundamental quantitative behaviours of a prototypic signal transduction pathway, the yeast pheromone response system from Saccharomyces cerevisiae. The Alpha Project distinguishes itself from many other systems biology projects by studying a tightly bounded and well-characterised system that is easily modified by genetic means, and by focusing on deep understanding of a discrete number of important and accessible quantitative behaviours. During the project, the authors have developed tools to measure the appropriate data and develop models at appropriat... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906644 Thu, 25 Sep 2008 04:00:00 +0100 1906644 http://www.medworm.com/index.php?rid=1906643&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648903 Abstraction of intracellular biomolecular interactions into networks is useful for data integration and graph analysis. Network analysis tools facilitate predictions of novel functions for proteins, prediction of functional interactions and identification of intracellular modules. These efforts are linked with drug and phenotype data to accelerate drug-target and biomarker discovery. This review highlights the currently available varieties of mammalian biomolecular networks, and surveys methods and tools to construct, compare, integrate, visualise and analyse such networks. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906643 Thu, 25 Sep 2008 04:00:00 +0100 1906643 http://www.medworm.com/index.php?rid=1906642&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4648901%26arnumber%3D4648902 This special issue consists of 12 original papers and 4 reviews that elaborate on work presented at the First q-bio Conference on Cellular Information Processing [1], which was held on the campus of St. John¿s College in Santa Fe, New Mexico, USA, 8-11 August 2007. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1906642 Thu, 25 Sep 2008 04:00:00 +0100 1906642 http://www.medworm.com/index.php?rid=1603599&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4537507%26arnumber%3D4537511 Axon guidance by graded diffusible ligands plays an important role in the developing nervous system. Concentration gradients induce an asymmetric localisation of molecules in the axon tip, the growth cone, and the consequent internal polarised signalling pathway leads to rearrangement of the growth cone cytoskeleton and, ultimately, to motility. Here the authors provide a mathematical description of the growth cone transduction chain as a series of functional boxes characterised by input/output relations. The model relies on the assumption that the characteristic time of independent concentration measures by growth cone receptors, the characteristic time of growth cone internal reorganisation preceding motion and the characteristic time needed for a discernible axon turning belong to separ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1603599 Sat, 10 May 2008 04:00:00 +0100 1603599 http://www.medworm.com/index.php?rid=1603598&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4537507%26arnumber%3D4537510 The performance of the lin-log method for modelling the glycolytic pathway in Lactococcus lactis using in vivo time-series data is investigated. The network structure of this pathway has been studied in previous reports and the authors concentrate here on the challenge of fitting the lin-log model parameters to experimental data. To calibrate the estimation methods, the performance of the lin-log method on a simpler model of a small gene regulatory system was first investigated, which has become a benchmark in the field. Two families of optimisation algorithms were employed. One computes the objective function by solving a system of ordinary differential equations (odes), whereas the other discretises the odes and incorporates them as nonlinear equality constraints in the optimisation prob... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1603598 Sat, 10 May 2008 04:00:00 +0100 1603598 http://www.medworm.com/index.php?rid=1603597&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4537507%26arnumber%3D4537509 The authors propose piecewise deterministic Markov processes as an alternative approach to model gene regulatory networks. A hybrid simulation algorithm is presented and discussed, and several standard regulatory modules are analysed by numerical means. It is shown that despite of the partial simplification of the mesoscopic nature of regulatory networks such processes are suitable to reveal the intrinsic noise effects because of the low copy numbers of genes. (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1603597 Sat, 10 May 2008 04:00:00 +0100 1603597 http://www.medworm.com/index.php?rid=1603596&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4537507%26arnumber%3D4537508 Networks that contain only sign-consistent loops, such as positive feedforward and feedback loops, function as monotone systems. simulated using differential equations, monotone systems display well-ordered behaviour that excludes the possibility for chaotic dynamics. Perturbations of such systems have unambiguous global effects and a predictability characteristic that confers robustness and adaptability. The authors assess whether the topology of biological regulatory networks is similar to the topology of monotone systems. for this, three intracellular regulatory networks are analysed where links are specified for the directionality and the effects of interactions. These networks were assembled from functional studies in the experimental literature. It is found that the three biological ... IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1603596 Sat, 10 May 2008 04:00:00 +0100 1603596 http://www.medworm.com/index.php?rid=1567536&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4483538%26arnumber%3D4483543 (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1567536 Mon, 03 Mar 2008 05:00:00 +0100 1567536 http://www.medworm.com/index.php?rid=1567535&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4483538%26arnumber%3D4483542 (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1567535 Mon, 03 Mar 2008 05:00:00 +0100 1567535 http://www.medworm.com/index.php?rid=1567534&cid=s_37231_62_f&fid=37231&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Fisnumber%3D4483538%26arnumber%3D4483541 (Source: IET Systems Biology) IET Systems Biology journals http://www.medworm.com/rss/comments.php?id=1567534 Mon, 03 Mar 2008 05:00:00 +0100 1567534