ABSTRACT
MOTIVATION: This article presents libRoadRunner 2.0, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using the systems biology markup language (SBML). RESULTS: libRoadRunner is a self-contained library, able to run either as a component inside other tools via its C++, C and Python APIs, or interactively through its Python or Julia interface. libRoadRunner uses a custom just-in-time (JIT) compiler built on the widely used LLVM JIT compiler framework. It compiles SBML-specified models directly into native machine code for a large variety of processors, making it fast enough to simulate extremely large models or repeated runs in reasonable timeframes. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and non-linear algebraic equations) as well as several SBML extensions such as hierarchical composition and probability distributions. It offers multiple deterministic and stochastic integrators, as well as tools for steady-state, sensitivity, stability and structural analyses. AVAILABILITY AND IMPLEMENTATION: libRoadRunner binary distributions for Windows, Mac OS and Linux, Julia and Python bindings, source code and documentation are all available at https://github.com/sys-bio/roadrunner, and Python bindings are also available via pip. The source code can be compiled for the supported systems as well as in principle any system supported by LLVM-13, such as ARM-based computers like the Raspberry Pi. The library is licensed under the Apache License Version 2.0.
Subject(s)
Programming Languages , Systems Biology , Models, Biological , Computer Simulation , Software , LanguageABSTRACT
Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.
Subject(s)
Computer Simulation , Software , Humans , Bioengineering , Models, Biological , Registries , Research PersonnelABSTRACT
Information processing in artificial neural networks is largely dependent on the nature of neuron models. While commonly used models are designed for linear integration of synaptic inputs, accumulating experimental evidence suggests that biological neurons are capable of nonlinear computations for many converging synaptic inputs via homo- and heterosynaptic mechanisms. This nonlinear neuronal computation may play an important role in complex information processing at the neural circuit level. Here we characterize the dynamics and coding properties of neuron models on synaptic transmissions delivered from two hidden states. The neuronal information processing is influenced by the cooperative and competitive interactions among synapses and the coherence of the hidden states. Furthermore, we demonstrate that neuronal information processing under two-input synaptic transmission can be mapped to linearly nonseparable XOR as well as basic AND/OR operations. In particular, the mixtures of linear and nonlinear neuron models outperform the fashion-MNIST test compared to the neural networks consisting of only one type. This study provides a computational framework for assessing information processing of neuron and synapse models that may be beneficial for the design of brain-inspired artificial intelligence algorithms and neuromorphic systems.
Subject(s)
Artificial Intelligence , Models, Neurological , Neurons/physiology , Synapses/physiology , Synaptic Transmission/physiologyABSTRACT
The considerable difficulty encountered in reproducing the results of published dynamical models limits validation, exploration and reuse of this increasingly large biomedical research resource. To address this problem, we have developed Tellurium Notebook, a software system for model authoring, simulation, and teaching that facilitates building reproducible dynamical models and reusing models by 1) providing a notebook environment which allows models, Python code, and narrative to be intermixed, 2) supporting the COMBINE archive format during model development for capturing model information in an exchangeable format and 3) enabling users to easily simulate and edit public COMBINE-compliant models from public repositories to facilitate studying model dynamics, variants and test cases. Tellurium Notebook, a Python-based Jupyter-like environment, is designed to seamlessly inter-operate with these community standards by automating conversion between COMBINE standards formulations and corresponding in-line, human-readable representations. Thus, Tellurium brings to systems biology the strategy used by other literate notebook systems such as Mathematica. These capabilities allow users to edit every aspect of the standards-compliant models and simulations, run the simulations in-line, and re-export to standard formats. We provide several use cases illustrating the advantages of our approach and how it allows development and reuse of models without requiring technical knowledge of standards. Adoption of Tellurium should accelerate model development, reproducibility and reuse.
Subject(s)
Systems Biology/methods , Computer Simulation , Humans , Models, Biological , Reproducibility of Results , Software , Systems Biology/instrumentationABSTRACT
Living systems continually respond to signals from the surrounding environment. Survival requires that their responses adapt quickly and robustly to the changes in the environment. One particularly challenging example is olfactory navigation in turbulent plumes, where animals experience highly intermittent odor signals while odor concentration varies over many length- and timescales. Here, we show theoretically that Drosophila olfactory receptor neurons (ORNs) can exploit proximity to a bifurcation point of their firing dynamics to reliably extract information about the timing and intensity of fluctuations in the odor signal, which have been shown to be critical for odor-guided navigation. Close to the bifurcation, the system is intrinsically invariant to signal variance, and information about the timing, duration, and intensity of odor fluctuations is transferred efficiently. Importantly, we find that proximity to the bifurcation is maintained by mean adaptation alone and therefore does not require any additional feedback mechanism or fine-tuning. Using a biophysical model with calcium-based feedback, we demonstrate that this mechanism can explain the measured adaptation characteristics of Drosophila ORNs.
ABSTRACT
Living systems continually respond to signals from the surrounding environment. Survival requires that their responses adapt quickly and robustly to the changes in the environment. One particularly challenging example is olfactory navigation in turbulent plumes, where animals experience highly intermittent odor signals while odor concentration varies over many length- and timescales. Here, we show theoretically that Drosophila olfactory receptor neurons (ORNs) can exploit proximity to a bifurcation point of their firing dynamics to reliably extract information about the timing and intensity of fluctuations in the odor signal, which have been shown to be critical for odor-guided navigation. Close to the bifurcation, the system is intrinsically invariant to signal variance, and information about the timing, duration, and intensity of odor fluctuations is transferred efficiently. Importantly, we find that proximity to the bifurcation is maintained by mean adaptation alone and therefore does not require any additional feedback mechanism or fine-tuning. Using a biophysical model with calcium-based feedback, we demonstrate that this mechanism can explain the measured adaptation characteristics of Drosophila ORNs.
ABSTRACT
Recognizing that diverse morphologies of neurons are reminiscent of structures of branched polymers, we put forward a principled and systematic way of classifying neurons that employs the ideas of polymer physics. In particular, we use 3D coordinates of individual neurons, which are accessible in recent neuron reconstruction datasets from electron microscope images. We numerically calculate the form factor, F(q), a Fourier transform of the distance distribution of particles comprising an object of interest, which is routinely measured in scattering experiments to quantitatively characterize the structure of materials. For a polymer-like object consisting of n monomers spanning over a length scale of r, F(q) scales with the wavenumber [Formula: see text] as [Formula: see text] at an intermediate range of q, where [Formula: see text] is the fractal dimension or the inverse scaling exponent ([Formula: see text]) characterizing the geometrical feature ([Formula: see text]) of the object. F(q) can be used to describe a neuron morphology in terms of its size ([Formula: see text]) and the extent of branching quantified by [Formula: see text]. By defining the distance between F(q)s as a measure of similarity between two neuronal morphologies, we tackle the neuron classification problem. In comparison with other existing classification methods for neuronal morphologies, our F(q)-based classification rests solely on 3D coordinates of neurons with no prior knowledge of morphological features. When applied to publicly available neuron datasets from three different organisms, our method not only complements other methods but also offers a physical picture of how the dendritic and axonal branches of an individual neuron fill the space of dense neural networks inside the brain.
Subject(s)
Neurons , Polymers , Neurons/physiology , Axons , Neural Networks, Computer , BrainABSTRACT
This work presents a general chemical reaction network theory for olfactory sensing processes that employ G-protein-coupled receptors as olfactory receptors (ORs). The theory can be applied to general mixtures of odorants and an arbitrary number of ORs. Reactions of ORs with G-proteins, in both the presence and absence of odorants, are explicitly considered. A unique feature of the theory is the definition of an odor activity vector consisting of strengths of odorant-induced signals from ORs relative to those due to background G-protein activity in the absence of odorants. It is demonstrated that each component of the odor activity defined this way reduces to a Michaelis-Menten form capable of accounting for cooperation or competition effects between different odorants. The main features of the theory are illustrated for a two-odorant mixture. Known and potential mixture effects, such as suppression, shadowing, inhibition, and synergy, are quantitatively described. Effects of relative values of rate constants, basal activity, and G-protein concentration are also demonstrated.
Subject(s)
Olfactory Receptor Neurons , Receptors, Odorant , Odorants , Olfactory Receptor Neurons/physiology , Smell/physiology , Receptors, G-Protein-CoupledABSTRACT
The projection neurons (PNs), reconstructed from electron microscope (EM) images of the Drosophila olfactory system, offer a detailed view of neuronal anatomy, providing glimpses into information flow in the brain. About 150 uPNs constituting 58 glomeruli in the antennal lobe (AL) are bundled together in the axonal extension, routing the olfactory signal received at AL to mushroom body (MB) calyx and lateral horn (LH). Here we quantify the neuronal organization in terms of the inter-PN distances and examine its relationship with the odor types sensed by Drosophila. The homotypic uPNs that constitute glomeruli are tightly bundled and stereotyped in position throughout the neuropils, even though the glomerular PN organization in AL is no longer sustained in the higher brain center. Instead, odor-type dependent clusters consisting of multiple homotypes innervate the MB calyx and LH. Pheromone-encoding and hygro/thermo-sensing homotypes are spatially segregated in MB calyx, whereas two distinct clusters of food-related homotypes are found in LH in addition to the segregation of pheromone-encoding and hygro/thermo-sensing homotypes. We find that there are statistically significant associations between the spatial organization among a group of homotypic uPNs and certain stereotyped olfactory responses. Additionally, the signals from some of the tightly bundled homotypes converge to a specific group of lateral horn neurons (LHNs), which indicates that homotype (or odor type) specific integration of signals occurs at the synaptic interface between PNs and LHNs. Our findings suggest that before neural computation in the inner brain, some of the olfactory information are already encoded in the spatial organization of uPNs, illuminating that a certain degree of labeled-line strategy is at work in the Drosophila olfactory system.
Subject(s)
Drosophila , Olfactory Receptor Neurons , Animals , Smell/physiology , Mushroom Bodies/physiology , Odorants , Neurons/physiology , Pheromones , Olfactory Pathways/physiology , Olfactory Receptor Neurons/physiologyABSTRACT
BACKGROUND: Neurons have specialized structures that facilitate information transfer using electrical and chemical signals. Within the perspective of neural computation, the neuronal structure is an important prerequisite for the versatile computational capabilities of neurons resulting from the integration of diverse synaptic input patterns, complex interactions among the passive and active dendritic local currents, and the interplay between dendrite and soma to generate action potential output. For this, characterization of the relationship between the structure and neuronal spike dynamics could provide essential information about the cellular-level mechanism supporting neural computations. RESULTS: This work describes simulations and an information-theoretic analysis to investigate how specific neuronal structure affects neural dynamics and information processing. Correlation analysis on the Allen Cell Types Database reveals biologically relevant structural features that determine neural dynamics-eight highly correlated structural features are selected as the primary set for characterizing neuronal structures. These features are used to characterize biophysically realistic multi-compartment mathematical models for primary neurons in the direct and indirect hippocampal pathways consisting of the pyramidal cells of Cornu Ammonis 1 (CA1) and CA3 and the granule cell in the dentate gyrus (DG). Simulations reveal that the dynamics of these neurons vary depending on their specialized structures and are highly sensitive to structural modifications. Information-theoretic analysis confirms that structural factors are critical for versatile neural information processing at a single-cell and a neural circuit level; not only basic AND/OR but also linearly non-separable XOR functions can be explained within the information-theoretic framework. CONCLUSIONS: Providing quantitative information on the relationship between the structure and the dynamics/information flow of neurons, this work would help us understand the design and coding principles of biological neurons and may be beneficial for designing biologically plausible neuron models for artificial intelligence (AI) systems.
Subject(s)
Artificial Intelligence , Pyramidal Cells , CA1 Region, Hippocampal , Hippocampus , Models, Neurological , Neurons/physiologyABSTRACT
Background: Ever since the seminal work by McCulloch and Pitts, the theory of neural computation and its philosophical foundation known as 'computationalism' have been central to brain-inspired artificial intelligence (AI) technologies. The present study describes neural dynamics and neural coding approaches to understand the mechanisms of neural computation. The primary focus is to characterize the multiscale nature of logic computations in the brain, which might occur at a single neuron level, between neighboring neurons via synaptic transmission, and at the neural circuit level. Results: For this, we begin the analysis with simple neuron models to account for basic Boolean logic operations at a single neuron level and then move on to the phenomenological neuron models to explain the neural computation from the viewpoints of neural dynamics and neural coding. The roles of synaptic transmission in neural computation are investigated using biologically realistic multi-compartment neuron models: two representative computational entities, CA1 pyramidal neuron in the hippocampus and Purkinje fiber in the cerebellum, are analyzed in the information-theoretic framework. We then construct two-dimensional mutual information maps, which demonstrate that the synaptic transmission can process not only basic AND/OR Boolean logic operations but also the linearly non-separable XOR function. Finally, we provide an overview of the evolutionary algorithm and discuss its benefits in automated neural circuit design for logic operations. Conclusions: This study provides a comprehensive perspective on the multiscale logic operations in the brain from both neural dynamics and neural coding viewpoints. It should thus be beneficial for understanding computational principles of the brain and may help design biologically plausible neuron models for AI devices.
Subject(s)
Artificial Intelligence , Neurons , Logic , Pyramidal Cells , Synaptic TransmissionABSTRACT
Biomedical simulations are widely used to understand disease, engineer cells, and model cellular processes. In this article, we explore how to improve the quality of biomedical simulations by developing simulation models using tools and practices employed in software engineering. We refer to this direction as model engineering. Not all techniques used by software engineers are directly applicable to model engineering, and so some adaptations are required. That said, we believe that simulation models can benefit from software engineering practices for requirements, design, and construction as well as from software engineering tools for version control, error checking, and testing. Here we survey current efforts to improve simulation quality and discuss promising research directions for model engineering.
Subject(s)
Biomedical Research/trends , Computer Simulation , Software DesignABSTRACT
This paper presents pySBOL, a software library for computer-aided design of synthetic biological systems in the Python scripting language. This library provides an easy-to-use, object-oriented, application programming interface (API) with low barrier of entry for synthetic biology application developers. The pySBOL library enables reuse of genetic parts and designs through standardized data exchange with biological parts repositories and software tools that communicate using the Synthetic Biology Open Language (SBOL). In addition, pySBOL supports data management of design-build-test-learn workflows for individual laboratories as well as large, distributed teams of synthetic biologists. PySBOL also lets users add custom data to SBOL files to support the specific data requirements of their research. This extensibility helps users integrate software tool chains and develop workflows for new applications. These features and others make the pySBOL library a valuable tool for supporting engineering practices in synthetic biology. Documentation and installation instructions can be found at pysbol2.readthedocs.io .
Subject(s)
Automation/methods , Synthetic Biology/methods , Documentation/methods , Programming Languages , Reference Standards , Software , WorkflowABSTRACT
Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems is to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.3.0 of SBOL, which builds upon version 2.2.0 published in last year's JIB Standards in Systems Biology special issue. In particular, SBOL 2.3.0 includes means of succinctly representing sequence modifications, such as insertion, deletion, and replacement, an extension to support organization and attachment of experimental data derived from designs, and an extension for describing numerical parameters of design elements. The new version also includes specifying types of synthetic biology activities, unambiguous locations for sequences with multiple encodings, refinement of a number of validation rules, improved figures and examples, and clarification on a number of issues related to the use of external ontology terms.
Subject(s)
Models, Biological , Synthetic Biology , Systems Biology , Humans , Programming LanguagesABSTRACT
The topology of a reaction network can have a significant influence on the network's dynamical properties. Such influences can include constraints on network flows and concentration changes or more insidiously result in the emergence of feedback loops. These effects are due entirely to mass constraints imposed by the network configuration and are important considerations before any dynamical analysis is made. Most established simulation software tools usually carry out some kind of structural analysis of a network before any attempt is made at dynamic simulation. In this paper, we describe a portable software library, libStructural, that can carry out a variety of popular structural analyses that includes conservation analysis, flux dependency analysis and enumerating elementary modes. The library employs robust algorithms that allow it to be used on large networks with more than a two thousand nodes. The library accepts either a raw or fully labeled stoichiometry matrix or models written in SBML format. The software is written in standard C/C++ and comes with extensive on-line documentation and a test suite. The software is available for Windows, Mac OS X, and can be compiled easily on any Linux operating system. A language binding for Python is also available through the pip package manager making it simple to install on any standard Python distribution. The bulk of the source code is licensed under the open source BSD license with other parts using as either the MIT license or more simply public domain. All source is available on GitHub (https://github.com/sys-bio/Libstructural).
Subject(s)
Cell Physiological Phenomena , Computer Simulation , Neural Networks, Computer , Software , Systems Biology , Algorithms , Humans , Programming Languages , Structure-Activity RelationshipABSTRACT
Here we present Tellurium, a Python-based environment for model building, simulation, and analysis that facilitates reproducibility of models in systems and synthetic biology. Tellurium is a modular, cross-platform, and open-source simulation environment composed of multiple libraries, plugins, and specialized modules and methods. Tellurium is a self-contained modeling platform which comes with a fully configured Python distribution. Two interfaces are provided, one based on the Spyder IDE which has an accessible user interface akin to MATLAB and a second based on the Jupyter Notebook, which is a format that contains live code, equations, visualizations, and narrative text. Tellurium uses libRoadRunner as the default SBML simulation engine which supports deterministic simulations, stochastic simulations, and steady-state analyses. Tellurium also includes Antimony, a human-readable model definition language which can be converted to and from SBML. Other standard Python scientific libraries such as NumPy, SciPy, and matplotlib are included by default. Additionally, we include several user-friendly plugins and advanced modules for a wide-variety of applications, ranging from complex algorithms for bifurcation analysis to multidimensional parameter scanning. By combining multiple libraries, plugins, and modules into a single package, Tellurium provides a unified but extensible solution for biological modeling and analysis for both novices and experts. AVAILABILITY: tellurium.analogmachine.org.
Subject(s)
Models, Biological , Synthetic Biology , Systems Biology , Tellurium/chemistry , Reproducibility of ResultsABSTRACT
Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year's JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model.
Subject(s)
Models, Biological , Programming Languages , Software , Synthetic Biology/standards , Animals , Guidelines as Topic , Humans , Signal TransductionABSTRACT
Here we describe Tellurium, a Python based platform for supporting the development of reproducible models in systems biology. The tool exploits a number of available standards, including SBML, SED-ML and COMBINE archives to achieve its goal.
ABSTRACT
MOTIVATION: Model simulation exchange has been standardized with the Simulation Experiment Description Markup Language (SED-ML), but specialized software is needed to generate simulations in this format. Text-based languages allow researchers to create and modify experimental protocols quickly and easily, and export them to a common machine-readable format. RESULTS: phraSED-ML language allows modelers to use simple text commands to encode various elements of SED-ML (models, tasks, simulations, and results) in a format easy to read and modify. The library can translate this script to SED-ML for use in other softwares. AVAILABILITY: phraSED-ML language specification, libphrasedml library, and source code are available under BSD license from http://phrasedml.sourceforge.net/ .
Subject(s)
Models, Theoretical , Programming Languages , Systems Biology/methods , Computer Simulation , Extracellular Signal-Regulated MAP Kinases/metabolism , Software , Stochastic ProcessesABSTRACT
Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The Synthetic Biology Open Language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.1 of SBOL that builds upon version 2.0 published in last year’s JIB special issue. In particular, SBOL 2.1 includes improved rules for what constitutes a valid SBOL document, new role fields to simplify the expression of sequence features and how components are used in context, and new best practices descriptions to improve the exchange of basic sequence topology information and the description of genetic design provenance, as well as miscellaneous other minor improvements.