img2net: Automated network-based analysis of imaged phenotypes

Automated analysis of imaged phenotypes enables fast and reproducible quantification of biologically relevant features. Despite recent developments, recordings of complex, networked structures, such as: leaf venation patterns, cytoskeletal structures, or traffic networks, remain challenging to analyze. Here we illustrate the applicability of img2net to automatedly analyze such structures by reconstructing the underlying network, computing relevant network properties, and statistically comparing networks of different types or under different conditions. The software can be readily used for analyzing image data of arbitrary 2D and 3D network-like structures. img2net is open-source software under the GPL and can be downloaded from http://mathbiol.mpimp-golm.mpg.de/img2net/, where supplementary information and data sets for testing are provided.Comment: Bioinformatics, 2014, btu50

On the effects of alternative optima in context-specific metabolic model predictions

Recent methodological developments have facilitated the integration of high-throughput data into genome-scale models to obtain context-specific metabolic reconstructions. A unique solution to this data integration problem often may not be guaranteed, leading to a multitude of context-specific predictions equally concordant with the integrated data. Yet, little attention has been paid to the alternative optima resulting from the integration of context-specific data. Here we present computational approaches to analyze alternative optima for different context-specific data integration instances. By using these approaches on metabolic reconstructions for the leaf of Arabidopsis thaliana and the human liver, we show that the analysis of alternative optima is key to adequately evaluating the specificity of the predictions in particular cellular contexts. While we provide several ways to reduce the ambiguity in the context-specific predictions, our findings indicate that the existence of alternative optimal solutions warrant caution in detailed context-specific analyses of metabolism

Graph-theoretic Approach To Modeling Propagation And Control Of Network Worms

In today\u27s network-dependent society, cyber attacks with network worms have become the predominant threat to confidentiality, integrity, and availability of network computing resources. Despite ongoing research efforts, there is still no comprehensive network-security solution aimed at controling large-scale worm propagation. The aim of this work is fivefold: (1) Developing an accurate combinatorial model of worm propagation that can facilitate the analysis of worm control strategies, (2) Building an accurate epidemiological model for the propagation of a worm employing local strategies, (3) Devising distributed architecture and algorithms for detection of worm scanning activities, (4) Designing effective control strategies against the worm, and (5) Simulation of the developed models and strategies on large, scale-free graphs representing real-world communication networks. The proposed pair-approximation model uses the information about the network structure--order, size, degree distribution, and transitivity. The empirical study of propagation on large scale-free graphs is in agreement with the theoretical analysis of the proposed pair-approximation model. We, then, describe a natural generalization of the classical cops-and-robbers game--a combinatorial model of worm propagation and control. With the help of this game on graphs, we show that the problem of containing the worm is NP-hard. Six novel near-optimal control strategies are devised: combination of static and dynamic immunization, reactive dynamic and invariant dynamic immunization, soft quarantining, predictive traffic-blocking, and contact-tracing. The analysis of the predictive dynamic traffic-blocking, employing only local information, shows that the worm can be contained so that 40\% of the network nodes are not affected. Finally, we develop the Detection via Distributed Blackholes architecture and algorithm which reflect the propagation strategy used by the worm and the salient properties of the network. Our distributed detection algorithm can detect the worm scanning activity when only 1.5% of the network has been affected by the propagation. The proposed models and algorithms are analyzed with an individual-based simulation of worm propagation on realistic scale-free topologies

Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations

<p>Abstract</p> <p>Background</p> <p>Flux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states.</p> <p>Results</p> <p>Here, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states.</p> <p>Conclusions</p> <p>Our methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.</p

The Choice between MapMan and Gene Ontology for Automated Gene Function Prediction in Plant Science

Since the introduction of the Gene Ontology (GO), the analysis of high-throughput data has become tightly coupled with the use of ontologies to establish associations between knowledge and data in an automated fashion. Ontologies provide a systematic description of knowledge by a controlled vocabulary of defined structure in which ontological concepts are connected by pre-defined relationships. In plant science, MapMan and GO offer two alternatives for ontology-driven analyses. Unlike GO, initially developed to characterize microbial systems, MapMan was specifically designed to cover plant-specific pathways and processes. While the dependencies between concepts in MapMan are modeled as a tree, in GO these are captured in a directed acyclic graph. Therefore, the difference in ontologies may cause discrepancies in data reduction, visualization, and hypothesis generation. Here provide the first systematic comparative analysis of GO and MapMan for the case of the model plant species Arabidopsis thaliana (Arabidopsis) with respect to their structural properties and difference in distributions of information content. In addition, we investigate the effect of the two ontologies on the specificity and sensitivity of automated gene function prediction via the coupling of co-expression networks and the guilt-by-association principle. Automated gene function prediction is particularly needed for the model plant Arabidopsis in which only half of genes have been functionally annotated based on sequence similarity to known genes. The results highlight the need for structured representation of species-specific biological knowledge, and warrants caution in the design principles employed in future ontologies

Assessing the significance of knockout cascades in metabolic networks

Complex networks have been shown to be robust against random structural perturbations, but vulnerable against targeted attacks. Robustness analysis usually simulates the removal of individual or sets of nodes, followed by the assessment of the inflicted damage. For complex metabolic networks, it has been suggested that evolutionary pressure may favor robustness against reaction removal. However, the removal of a reaction and its impact on the network may as well be interpreted as selective regulation of pathway activities, suggesting a tradeoff between the efficiency of regulation and vulnerability. Here, we employ a cascading failure algorithm to simulate the removal of single and pairs of reactions from the metabolic networks of two organisms, and estimate the significance of the results using two different null models: degree preserving and mass-balanced randomization. Our analysis suggests that evolutionary pressure promotes larger cascades of non-viable reactions, and thus favors the ability of efficient metabolic regulation at the expense of robustness

A simulation-free constrained regression approach for flux estimation in isotopically nonstationary metabolic flux analysis with applications in microalgae

IntroductionFlux phenotypes from different organisms and growth conditions allow better understanding of differential metabolic networks functions. Fluxes of metabolic reactions represent the integrated outcome of transcription, translation, and post-translational modifications, and directly affect growth and fitness. However, fluxes of intracellular metabolic reactions cannot be directly measured, but are estimated via metabolic flux analysis (MFA) that integrates data on isotope labeling patterns of metabolites with metabolic models. While the application of metabolomics technologies in photosynthetic organisms have resulted in unprecedented data from 13CO2-labeling experiments, the bottleneck in flux estimation remains the application of isotopically nonstationary MFA (INST-MFA). INST-MFA entails fitting a (large) system of coupled ordinary differential equations, with metabolite pools and reaction fluxes as parameters. Here, we focus on the Calvin-Benson cycle (CBC) as a key pathway for carbon fixation in photosynthesizing organisms and ask if approaches other than classical INST-MFA can provide reliable estimation of fluxes for reactions comprising this pathway.MethodsFirst, we show that flux estimation with the labeling patterns of all CBC intermediates can be formulated as a single constrained regression problem, avoiding the need for repeated simulation of time-resolved labeling patterns.ResultsWe then compare the flux estimates of the simulation-free constrained regression approach with those obtained from the classical INST-MFA based on labeling patterns of metabolites from the microalgae Chlamydomonas reinhardtii, Chlorella sorokiniana and Chlorella ohadii under different growth conditions.DiscussionOur findings indicate that, in data-rich scenarios, simulation-free regression-based approaches provide a suitable alternative for flux estimation from classical INST-MFA since we observe a high qualitative agreement (rs=0.89) to predictions obtained from INCA, a state-of-the-art tool for INST-MFA

Mass-balanced randomization of metabolic networks

Motivation: Network-centered studies in systems biology attempt to integrate the topological properties of biological networks with experimental data in order to make predictions and posit hypotheses. For any topology-based prediction, it is necessary to first assess the significance of the analyzed property in a biologically meaningful context. Therefore, devising network null models, carefully tailored to the topological and biochemical constraints imposed on the network, remains an important computational problem