Genomic Object Net: II. Modelling biopathways by hybrid functional Petri net with extension

This paper demonstrates how to create an HFPNe (hybrid functional Petri net with extension) model, using the lac operon gene regulatory mechanism and glycolytic pathway as an example. Using this example, readers can then model other biopathways of interest. Simulations of the HFPNe model were performed using the software package Genomic Object Net.     

Biopathways representation and simulation on hybrid functional Petri net

The following two matters should be resolved in order for biosimulation tools to be accepted by users in biology/medicine: (1) remove issues which are irrelevant to biological importance, and (2) allow users to represent biopathways intuitively and understand/manage easily the details of representation and simulation mechanism. From these criteria, we firstly define a novel notion of Petri net called Hybrid Functional Petri Net (HFPN). Then, we introduce a software tool, Genomic Object Net, for representing and simulating biopathways, which we have developed by employing the architecture of HFPN. In order to show the usefulness of Genomic Object Net for representing and simulating biopathways, we show two HFPN representations of gene regulation mechanisms of Drosophila melanogaster (fruit fly) circadian rhythm and apoptosis induced by Fas ligand. The simulation results of these biopathways are also correlated with biological observations. The software is available to academic users from http://www.GenomicObject.Net/.     

Online model checking approach based parameter estimation to a neuronal fate decision simulation model in Caenorhabditis elegans with hybrid functional Petri net with extension

Mathematical modeling and simulation studies are playing an increasingly important role in helping researchers elucidate how living organisms function in cells. In systems biology, researchers typically tune many parameters manually to achieve simulation results that are consistent with biological knowledge. This severely limits the size and complexity of simulation models built. In order to break this limitation, we propose a computational framework to automatically estimate kinetic parameters for a given network structure. We utilized an online (on-the-fly) model checking technique (which saves resources compared to the offline approach), with a quantitative modeling and simulation architecture named hybrid functional Petri net with extension (HFPNe). We demonstrate the applicability of this framework by the analysis of the underlying model for the neuronal cell fate decision model (ASE fate model) in Caenorhabditis elegans. First, we built a quantitative ASE fate model containing 3327 components emulating nine genetic conditions. Then, using our developed efficient online model checker, MIRACH 1.0, together with parameter estimation, we ran 20-million simulation runs, and were able to locate 57 parameter sets for 23 parameters in the model that are consistent with 45 biological rules extracted from published biological articles without much manual intervention. To evaluate the robustness of these 57 parameter sets, we run another 20 million simulation runs using different magnitudes of noise. Our simulation results concluded that among these models, one model is the most reasonable and robust simulation model owing to the high stability against these stochastic noises. Our simulation results provide interesting biological findings which could be used for future wet-lab experiments.     

Investigating the dynamic behavior of biochemical networks using model families

MOTIVATION: Supporting the evolutionary modeling process of dynamic biochemical networks based on sampled in vivo data requires more than just simulation. In the course of the modeling process, the modeler is typically concerned not only with a single model but also with sequences, alternatives and structural variants of models. Powerful automatic methods are then required to assist the modeler in the organization and the evaluation of alternative models. Moreover, the structure and peculiarities of the data require dedicated tool support. SUMMARY: To support all stages of an evolutionary modeling process, a new general formalism for the combinatorial specification of large model families is introduced. It allows for automatic navigation in the space of models and excludes biologically meaningless models on the basis of elementary flux mode analysis. An incremental usage of the measured data is supported by using splined data instead of state variables. With MMT2, a versatile tool has been developed as a computational engine intended to be built into a tool chain. Using automatic code generation, automatic differentiation for sensitivity analysis and grid computing technology, a high performance computing environment is achieved. MMT2 supplies XML model specification and several software interfaces. The performance of MMT2 is illustrated by several examples from ongoing research projects. AVAILABILITY: http://www.simtec.mb.uni-siegen.de/ CONTACT: wiechert@simtec.mb.uni-siegen.de.     

Sensitivity of the gradient oscillatory number to flow input waveform shapes

The sensitivity of the gradient oscillatory number (GON), which is a potential hemodynamic indicator for cerebral aneurysm initiation, to flow input waveform shapes was examined by performing computational fluid dynamics (CFD) simulations of an anatomical model of a human internal carotid artery under three different waveform shape conditions. The local absolute variation (standard deviation) and relative variation (coefficient of variation) of the GON calculations for three waveform shapes were computed to quantify the variation in GON due to waveform shape changes. For all waveform shapes, an elevated GON was evident at a known aneurysm site, albeit occurring at additional sites. No significant differences were observed among the qualitative GON distributions derived using the three different waveform shapes. These results suggest that the GON is largely insensitive to the variability in flow input waveform shapes. The quantitative analysis revealed that GON displays an improved relative variation over a relatively high GON range. We therefore conclude that it is reasonable to use assumed flow input waveform shapes as a substitute for individual real waveform shapes for the detection of possible GON elevations of individual clinical cases in large-scale studies, where the higher values of GON are of primary interest.     

Modeling and analysis of biopathways dynamics

Cellular processes are governed and coordinated by a multitude of biopathways. A pathway can be viewed as a complex network of biochemical reactions. The dynamics of this network largely determines the functioning of the pathway. Hence the modeling and analysis of biochemical networks dynamics is an important problem and is an active area of research. Here we review quantitative models of biochemical networks based on ordinary differential equations (ODEs). We mainly focus on the parameter estimation and sensitivity analysis problems and survey the current methods for tackling them. In this context we also highlight a recently developed probabilistic approximation technique using which these two problems can be considerably simplified.     

simBio: a Java package for the development of detailed cell models

Quantitative dynamic computer models, which integrate a variety of molecular functions into a cell model, provide a powerful tool to create and test working hypotheses. We have developed a new modeling tool, the simBio package (freely available from http://www.sim-bio.org/), which can be used for constructing cell models, such as cardiac cells (the Kyoto model from Matsuoka et al., 2003, 2004a, b, the LRd model from Faber and Rudy, 2000, and the Noble 98 model from Noble et al., 1998), epithelial cells (Strieter et al., 1990) and pancreatic β cells (Magnus and Keizer, 1998). The simBio package is written in Java, uses XML and can solve ordinary differential equations. In an attempt to mimic biological functional structures, a cell model is, in simBio, composed of independent functional modules called Reactors, such as ion channels and the sarcoplasmic reticulum, and dynamic variables called Nodes, such as ion concentrations. The interactions between Reactors and Nodes are described by the graph theory and the resulting graph represents a blueprint of an intricate cellular system. Reactors are prepared in a hierarchical order, in analogy to the biological classification. Each Reactor can be composed or improved independently, and can easily be reused for different models. This way of building models, through the combination of various modules, is enabled through the use of object-oriented programming concepts. Thus, simBio is a straightforward system for the creation of a variety of cell models on a common database of functional modules.     

Bifurcation analysis of continuous biochemical reactor models

The validity of a biochemical reactor model often is evaluated by comparing transient responses to experimental data. Dynamic simulation can be a rather inefficient and ineffective tool for analyzing bioreactor models that exhibit complex nonlinear behavior. Bifurcation analysis is a powerful tool for obtaining a more efficient and complete characterization of the model behavior. To illustrate the power of bifurcation analysis, the steady-state and transient behavior of three continuous bioreactor models consisting of a small number of ordinary differential equations are investigated. Several important features, as well as potential limitations, that are difficult to ascertain via dynamic simulation are disclosed through the bifurcation analysis. The results motivate the use of dynamic simulation and bifurcation analysis as complementary tools for analyzing the nonlinear behavior of bioreactor models.     

An efficient grid layout algorithm for biological networks utilizing various biological attributes

Background  

Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity.     

A flexible online metadata editing and management system

Our team developed a metadata editing and management system employing state of the art XML technologies initially aimed at the environmental sciences but with the potential to be useful across multiple domains. We chose a modular and distributed design for scalability, flexibility, options for customizations, and the possibility to add more functionality at a later stage. The system consists of a desktop design tool that generates code for the actual online editor, a native XML database, and an online user access management application. A Java Swing application that reads an XML schema, the design tool provides the designer with options to combine input fields into online forms with user-friendly tags and determine the flow of input forms. Based on design decisions, the tool generates XForm code for the online metadata editor which is based on the Orbeon XForms engine. The design tool fulfills two requirements: First data entry forms based on a schema are customized at design time and second the tool can generate data entry applications for any valid XML schema without relying on custom information in the schema. A configuration file in the design tool saves custom information generated at design time. Future developments will add functionality to the design tool to integrate help text, tool tips, project specific keyword lists, and thesaurus services.Cascading style sheets customize the look-and-feel of the finished editor. The editor produces XML files in compliance with the original schema, however, a user may save the input into a native XML database at any time independent of validity. The system uses the open source XML database eXist for storage and uses a MySQL relational database and a simple Java Server Faces user interface for file and access management. We chose three levels to distribute administrative responsibilities and handle the common situation of an information manager entering the bulk of the metadata but leave specifics to the actual data provider.     

Inhibition of vascular endothelial growth factor receptor tyrosine kinases impairs adipose tissue development in mouse models of obesity

We have studied the effect of PTK787 (Vatalanib), an inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, on adipose tissue development. Oral administration of PTK787 for 4 weeks (2 mg/g high fat diet, HFD) to C57Bl/6 mice resulted in a significant reduction in total body weight and of subcutaneous (SC) and gonadal (GON) adipose tissue mass, as compared to control animals fed HFD only (all p<0.0005). In the GON adipose tissue adipocytes were hypertrophic after PTK787 treatment. Blood vessel size and density were not significantly affected by PTK787 treatment. Expression of Flk-1 (VEGFR-2) mRNA was significantly reduced in SC and GON adipose tissues of PTK787 treated mice. De novo fat pad formation following injection of preadipocytes in NUDE mice was significantly (p<0.005) impaired by PTK787 administration (2 mg/g HFD for 4 weeks), without associated effect on blood vessel size or density. Thus, in nutritionally induced murine obesity models, oral administration of the VEGFR tyrosine kinases inhibitor PTK787 resulted in reduced adipose tissue development.     

Adenovirus polypeptide IX revealed as capsid cement by difference images from electron microscopy and crystallography.

Particles of adenovirus type 2 (ad2), when disassembled, consistently yield groups-of-nine (GON) hexons, which are the major virion shell component. The location of a minor component (6%) of the GON has been determined using a novel combination of electron microscopy and X-ray crystallography. The Brookhaven Scanning Transmission Electron Microscope (STEM) was used to estimate the distribution of protein in the GON to a resolution of 15-18 A. The relative hexon positions then were determined to within 1 A using a model of the hexon derived from the X-ray crystal structure to search the STEM image. The difference image between the STEM image and a model hexon group reveals individual monomers of polypeptide IX extending along the hexon--hexon interfaces. The distribution confirms our earlier proposal that four trimers of polypeptide IX are embedded in the large cavities in the upper surface of the GON to cement hexons into a highly-stable assembly.     

XEMBL: distributing EMBL data in XML format

Data in the EMBL Nucleotide Sequence Database is traditionally available in a flat file format that has a number of known shortcomings. With XML rapidly emerging as a standard data exchange format that can address some problems of flat file formats by defining data structure and syntax, there is now a demand to distribute EMBL data in an XML format. XEMBL is a service tool that employs CORBA servers to access EMBL data, and distributes the data in XML format via a number of mechanisms. AVAILABILITY: Use of the XEMBL service is free of charge at http://www.ebi.ac.uk/xembl/, and can be accessed via web forms, CGI, and a SOAP-enabled service. SUPPLEMENTARY INFORMATION: Information on the EMBL Nucleotide Sequence Database is available at http://www.ebi.ac.uk/embl/. The EMBL Object Model is available at http://corba.ebi.ac.uk/models/. Information on the EMBL CORBA servers is at http://corba.ebi.ac.uk/     

Stromelysin-2 (MMP-10) deficiency does not affect adipose tissue formation in a mouse model of nutritionally induced obesity

Adipose tissue development is associated with angiogenesis, adipogenesis and extracellular matrix degradation. The class of matrix metalloproteinases contributes to these processes, but little information is available on the role of individual proteinases. We report that stromelysin-2 (MMP-10) deficiency has no significant effect on total body weight or on subcutaneous (SC) or gonadal (GON) adipose tissue mass of mice kept on a high fat diet for 15 weeks. The adipocyte size and density in SC and GON adipose tissues were also comparable in MMP-10 deficient and wild-type control mice. Similarly, blood vessel size and density in obese SC and GON adipose tissues was not affected by MMP-10 deficiency.Metabolic parameters and blood cell composition were similar for both genotypes. Stromelysin-1 (MMP-3) expression was significantly reduced in adipose tissues of the deficient mice as compared to the wild-type controls.These data indicate that MMP-10 does not significantly contribute to adipose tissue development and associated angiogenesis in a mouse model of nutritionally induced obesity.     

Software Review of Analytica 1.2

Analytica is an easy-to-learn, easy-to-use modeling tool that allows modelers to represent what they know through influence diagrams. These diagrams show which model quantities are derived from which others and indicate by shape and color the roles that different nodes play in the model, e.g., decision variables, chance variables, outcome variables, deterministic functions, or abstractions of sub-models. A wide variety of built-in probability distributions allow uncertainties about input values to be painlessly specified and propagated through the model via a fast, professional Monte-Carlo simulation engine. Resulting uncertainties and sensitivities about any quantity in the model can be viewed with admirable ease and flexibility by selecting among probability density, cumulative distribution, confidence band, sensitivity analysis, and other displays. Analytica features clever hierarchical model management and navigation features that serious model-builders will appreciate and that novice modelers will learn from as they are led to develop well-structured, well-documented models. Simple continuous (compartmental-flow) and Markov chain dynamic simulation models can be built by paying some detailed attention to arrays and indices, although Analytica does not support true discrete-event simulation. Within its chosen domain—uncertainty propagation through influence diagram models—Analytica is by far the easiest and best tool that we have seen.     

A novel and versatile computational tool to model translation

MOTIVATION: Much is now known about the mechanistic details of gene translation. There are also rapid advances in high-throughput technologies to determine quantitative aspects of the system. As a consequence-realistic and system-wide simulation models of translation are now feasible. Such models are also needed as devices to integrate a large volume of highly fragmented data known about translation. Software: In this application note, we present a novel, highly efficient software tool to model translation. The tool represents the main aspects of translation. Features include a representation of exhaustible tRNA pools, ribosome-ribosome interactions and differential initiation rates for different mRNA species. The tool is written in Java, and is hence portable and can be parameterized for any organism. AVAILABILITY: The model can be obtained from the authors or directly downloaded from the authors' home-page (http://goo.gl/JUWvI).     

StarDOM: From STAR format to XML

StarDOM is a software package for the representation of STAR files as document object models and the conversion of STAR files into XML. This allows interactive navigation by using the Document Object Model representation of the data as well as easy access by XML query languages. As an example application, the entire BioMagResBank has been transformed into XML format. Using an XML query language, statistical queries on the collected NMR data sets can be constructed with very little effort. The BioMagResBank/XML data and the software can be obtained at http://www.nmr.embl-heidelberg.de/nmr/StarDOM/