PathCase-SB architecture and database design

<p>Abstract</p> <p>Background</p> <p>Integration of metabolic pathways resources and regulatory metabolic network models, and deploying new tools on the integrated platform can help perform more effective and more efficient systems biology research on understanding the regulation in metabolic networks. Therefore, the tasks of (a) integrating under a single database environment regulatory metabolic networks and existing models, and (b) building tools to help with modeling and analysis are desirable and intellectually challenging computational tasks.</p> <p>Description</p> <p>PathCase Systems Biology (PathCase-SB) is built and released. The PathCase-SB database provides data and API for multiple user interfaces and software tools. The current PathCase-SB system provides a database-enabled framework and web-based computational tools towards facilitating the development of kinetic models for biological systems. PathCase-SB aims to integrate data of selected biological data sources on the web (currently, BioModels database and KEGG), and to provide more powerful and/or new capabilities via the new web-based integrative framework. This paper describes architecture and database design issues encountered in PathCase-SB's design and implementation, and presents the current design of PathCase-SB's architecture and database.</p> <p>Conclusions</p> <p>PathCase-SB architecture and database provide a highly extensible and scalable environment with easy and fast (real-time) access to the data in the database. PathCase-SB itself is already being used by researchers across the world.</p

An online model composition tool for system biology models

Background: There are multiple representation formats for Systems Biology computational models, and the Systems Biology Markup Language (SBML) is one of the most widely used. SBML is used to capture, store, and distribute computational models by Systems Biology data sources (e.g., the BioModels Database) and researchers. Therefore, there is a need for all-in-one web-based solutions that support advance SBML functionalities such as uploading, editing, composing, visualizing, simulating, querying, and browsing computational models. Results: We present the design and implementation of the Model Composition Tool (Interface) within the PathCaseSB (PathCase Systems Biology) web portal. The tool helps users compose systems biology models to facilitate the complex process of merging systems biology models. We also present three tools that support the model composition tool, namely, (1) Model Simulation Interface that generates a visual plot of the simulation according to user’s input, (2) iModel Tool as a platform for users to upload their own models to compose, and (3) SimCom Tool that provides a side by side comparison of models being composed in the same pathway. Finally, we provide a web site that hosts BioModels Database models and a separate web site that hosts SBML Test Suite models. Conclusions: Model composition tool (and the other three tools) can be used with little or no knowledge of the SBML document structure. For this reason, students or anyone who wants to learn about systems biology will benefit from the described functionalities. SBML Test Suite models will be a nice starting point for beginners. And, for more advanced purposes, users will able to access and employ models of the BioModels Database as well

Généralisation de modèles métaboliques par connaissances

Genome-scale metabolic models describe the relationships between thousands of reactions and biochemical molecules, and are used to improve our understanding of organism’s metabolism. They found applications in pharmaceutical, chemical and bioremediation industries.The complexity of metabolic models hampers many tasks that are important during the process of model inference, such as model comparison, analysis, curation and refinement by human experts. The abundance of details in large-scale networks can mask errors and important organism-specific adaptations. It is therefore important to find the right levels of abstraction that are comfortable for human experts. These abstract levels should highlight the essential model structure and the divergences from it, such as alternative paths or missing reactions, while hiding inessential details.To address this issue, we defined a knowledge-based generalization that allows for production of higher-level abstract views of metabolic network models. We developed a theoretical method that groups similar metabolites and reactions based on the network structure and the knowledge extracted from metabolite ontologies, and then compresses the network based on this grouping. We implemented our method as a python library, that is available for download from metamogen.gforge.inria.fr.To validate our method we applied it to 1 286 metabolic models from the Path2Model project, and showed that it helps to detect organism-, and domain-specific adaptations, as well as to compare models.Based on discussions with users about their ways of navigation in metabolic networks, we defined a 3-level representation of metabolic networks: the full-model level, the generalized level, the compartment level. We combined our model generalization method with the zooming user interface (ZUI) paradigm and developed Mimoza, a user-centric tool for zoomable navigation and knowledgebased exploration of metabolic networks that produces this 3-level representation. Mimoza is available both as an on-line tool and for download atmimoza.bordeaux.inria.fr.Les réseaux métaboliques à l’échelle génomique décrivent les relations entre milliers de réactions et molécules biochimiques pour améliorer notre compréhension du métabolisme. Ils trouvent des applications dans les domaines chimiques, pharmaceutiques, et dans la biorestauration.La complexité de modèles métaboliques mets des obstacles á l’inférence des modèles, à la comparaison entre eux, ainsi que leur analyse, curation et amélioration par des experts humains. Parce que l’abondance des détailles dans les réseaux à grande échelle peut cacher des erreurs et des adaptations importantes de l’espèce qui est étudié, c’est important de trouver les correct niveaux d’abstraction qui sont confortables pour les experts humains : on doit mettre en évidence la structure essentiel du modèle ainsi que les divergences de celle-là (par exemple les chemins alternatives et les réactions manquantes), tout en masquant les détails non significatifs.Pour répondre a cette demande nous avons défini une généralisation des modèles métaboliques, fondée sur les connaissances, qui permet la création des vues abstraites de réseaux métaboliques. Nous avons développé une méthode théorétique qui regroupe les métabolites en classes d’équivalence et factorise les réactions reliant ces classes d’équivalence. Nous avons réalisé cette méthode comme une bibliothèque Python qui peut être téléchargée depuis metamogen.gforge.inria.fr.Pour valider l’intérêt de notre méthode, nous l’avons appliquée à 1 286 modèles métaboliques que nous avons extraits de la ressource Path2Model. Nous avons montré que notre méthode aide l’expert humain à relever de façon automatique les adaptations spécifiques de certains espèces et à comparer les modèles entre eux.Après en avoir discuté avec des utilisateurs, nous avons décidé de définir trois niveaux hiérarchiques de représentation de réseaux métaboliques : les compartiments, les modules et les réactions détaillées. Nous avons combiné notre méthode de généralisation et le paradigme des interfaces zoomables pour développer Mimoza, un système de navigation dans les réseaux métaboliques qui crée et visualise ces trois niveaux. Mimoza est accessible en ligne et pour le téléchargement depuis le site mimoza.bordeaux.inria.fr

Complexity, Emergent Systems and Complex Biological Systems:\ud Complex Systems Theory and Biodynamics. [Edited book by I.C. Baianu, with listed contributors (2011)]

An overview is presented of System dynamics, the study of the behaviour of complex systems, Dynamical system in mathematics Dynamic programming in computer science and control theory, Complex systems biology, Neurodynamics and Psychodynamics.\u

Tools and Algorithms for the Construction and Analysis of Systems

This open access two-volume set constitutes the proceedings of the 27th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2021, which was held during March 27 – April 1, 2021, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2021. The conference was planned to take place in Luxembourg and changed to an online format due to the COVID-19 pandemic. The total of 41 full papers presented in the proceedings was carefully reviewed and selected from 141 submissions. The volume also contains 7 tool papers; 6 Tool Demo papers, 9 SV-Comp Competition Papers. The papers are organized in topical sections as follows: Part I: Game Theory; SMT Verification; Probabilities; Timed Systems; Neural Networks; Analysis of Network Communication. Part II: Verification Techniques (not SMT); Case Studies; Proof Generation/Validation; Tool Papers; Tool Demo Papers; SV-Comp Tool Competition Papers

Filling in gaps of Drosophila melanogaster urate degradation metabolic pathway using metabolomics approaches: towards the core metabolome of the fruit fly

The primary goal of systems biology is to integrate complex omics data, and data obtained from traditional experimental studies in order to provide a holistic understanding of organismal function. One way of achieving this aim is to generate genome-scale metabolic models (GEMs), which contain information on all metabolites, enzyme-coding genes, and biochemical reactions in a biological system. Drosophila melanogaster GEM has not been reconstructed to date. Constraint-free genome-wide metabolic model of the fruit fly has been reconstructed in our lab, identifying gaps, where no enzyme was identified and metabolites were either only produced or consume. The main focus of the work presented in this thesis was to develop a pipeline for efficient gap filling using metabolomics approaches combined with standard reverse genetics methods, using 5-hydroxyisourate hydrolase (5-HIUH) as an example. 5-HIUH plays a role in urate degradation pathway. Inability to degrade urate can lead to inborn errors of metabolism (IEMs) in humans, including hyperuricemia. Based on sequence analysis Drosophila CG30016 gene was hypothesised to encode 5- HIUH. CG30016 knockout flies were examined to identify Malpighian tubules phenotype, and shortened lifespan might reflect kidney disorders in hyperuricemia in humans. Moreover, LC-MS analysis of mutant tubules revealed that CG30016 is involved in purine metabolism, and specifically urate degradation pathway. However, the exact role of the gene has not been identified, and the complete method for gap filling has not been developed. Nevertheless, thanks to the work presented here, we are a step closer towards the development of a gap-filling pipeline in Drosophila melanogaster GEM. Importantly, the areas that require further optimisation were identified and are the focus of future research. Moreover, LC-MS analysis confirmed that tubules rather than the whole fly were more suitable for metabolomics analysis of purine metabolism. Previously, Dow/Davies lab has generated the most complete tissue-specific transcriptomic atlas for Drosophila – FlyAtlas.org, which provides data on gene expression across multiple tissues of adult fly and larva. FlyAtlas revealed that transcripts of many genes are enriched in specific Drosophila tissues, and that it is possible to deduce the functions of individual tissues within the fly. Based on FlyAtlas data, it has become clear that the fly (like other metazoan species) must be considered as a set of tissues, each 2 with its own distinct transcriptional and functional profile. Moreover, it revealed that for about 30% of the genome, reverse genetic methods (i.e. mutation in an unknown gene followed by observation of phenotype) are only useful if specific tissues are investigated. Based on the FlyAtlas findings, we aimed to build a primary tissue-specific metabolome of the fruit fly, in order to establish whether different Drosophila tissues have different metabolomes and if they correspond to tissue-specific transcriptome of the fruit fly (FlyAtlas.org). Different fly tissues have been dissected and their metabolome elucidated using LC-MS. The results confirmed that tissue metabolomes differ significantly from each other and from the whole fly, and that some of these differences can be correlated to the tissue function. The results illustrate the need to study individual tissues as well as the whole organism. It is clear that some metabolites that play an important role in a given tissue might not be detected in the whole fly sample because their abundance is much lower in comparison to other metabolites present in all tissues, which prevent the detection of the tissue-specific compound