36,064 research outputs found
Developing Predictive Molecular Maps of Human Disease through Community-based Modeling
The failure of biology to identify the molecular causes of disease has led to disappointment in the rate of development of new medicines. By combining the power of community-based modeling with broad access to large datasets on a platform that promotes reproducible analyses we can work towards more predictive molecular maps that can deliver better therapeutics
Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor
Background
The transition from exponential to stationary phase in Streptomyces coelicolor is accompanied by a major metabolic switch and results in a strong activation of secondary metabolism. Here we have explored the underlying reorganization of the metabolome by combining computational predictions based on constraint-based modeling and detailed transcriptomics time course observations.
Results
We reconstructed the stoichiometric matrix of S. coelicolor, including the major antibiotic biosynthesis pathways, and performed flux balance analysis to predict flux changes that occur when the cell switches from biomass to antibiotic production. We defined the model input based on observed fermenter culture data and used a dynamically varying objective function to represent the metabolic switch. The predicted fluxes of many genes show highly significant correlation to the time series of the corresponding gene expression data. Individual mispredictions identify novel links between antibiotic production and primary metabolism.
Conclusion
Our results show the usefulness of constraint-based modeling for providing a detailed interpretation of time course gene expression data
Current advances in systems and integrative biology
Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result. This latter approach foregoes assumptions which predict how a biological system should react to an altered microenvironment within a cellular context, across a tissue or impacting on distant organs. Additionally, re-use of existing data by systematic data mining and re-stratification, one of the cornerstones of integrative systems biology, is also gaining attention. While tremendous efforts using a systems methodology have already yielded excellent results, it is apparent that a lack of suitable analytic tools and purpose-built databases poses a major bottleneck in applying a systematic workflow. This review addresses the current approaches used in systems analysis and obstacles often encountered in large-scale data analysis and integration which tend to go unnoticed, but have a direct impact on the final outcome of a systems approach. Its wide applicability, ranging from basic research, disease descriptors, pharmacological studies, to personalized medicine, makes this emerging approach well suited to address biological and medical questions where conventional methods are not ideal
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Archiving and disseminating integrative structure models.
Limitations in the applicability, accuracy, and precision of individual structure characterization methods can sometimes be overcome via an integrative modeling approach that relies on information from all available sources, including all available experimental data and prior models. The open-source Integrative Modeling Platform (IMP) is one piece of software that implements all computational aspects of integrative modeling. To maximize the impact of integrative structures, the coordinates should be made publicly available, as is already the case for structures based on X-ray crystallography, NMR spectroscopy, and electron microscopy. Moreover, the associated experimental data and modeling protocols should also be archived, such that the original results can easily be reproduced. Finally, it is essential that the integrative structures are validated as part of their publication and deposition. A number of research groups have already developed software to implement integrative modeling and have generated a number of structures, prompting the formation of an Integrative/Hybrid Methods Task Force. Following the recommendations of this task force, the existing PDBx/mmCIF data representation used for atomic PDB structures has been extended to address the requirements for archiving integrative structural models. This IHM-dictionary adds a flexible model representation, including coarse graining, models in multiple states and/or related by time or other order, and multiple input experimental information sources. A prototype archiving system called PDB-Dev ( https://pdb-dev.wwpdb.org ) has also been created to archive integrative structural models, together with a Python library to facilitate handling of integrative models in PDBx/mmCIF format
Theoretical model for the formation of caveolae and similar membrane invaginations
We study a physical model for the formation of bud-like invaginations on fluid lipid membranes under tension, and apply this model to caveolae formation. We demonstrate that budding can be driven by membrane-bound proteins, provided that they exert asymmetric forces on the membrane that give rise to bending moments. In particular, caveolae formation does not necessarily require forces to be applied by the cytoskeleton. Our theoretical model is able to explain several features observed experimentally in caveolae, where proteins in the caveolin family are known to play a crucial role in the formation of caveolae buds. These include 1), the formation of caveolae buds with sizes in the 100-nm range and 2), that certain N- and C-termini deletion mutants result in vesicles that are an order-of-magnitude larger. Finally, we discuss the possible origin of the morphological striations that are observed on the surfaces of the caveolae
Integrative biological simulation praxis: Considerations from physics, philosophy, and data/model curation practices
Integrative biological simulations have a varied and controversial history in
the biological sciences. From computational models of organelles, cells, and
simple organisms, to physiological models of tissues, organ systems, and
ecosystems, a diverse array of biological systems have been the target of
large-scale computational modeling efforts. Nonetheless, these research agendas
have yet to prove decisively their value among the broader community of
theoretical and experimental biologists. In this commentary, we examine a range
of philosophical and practical issues relevant to understanding the potential
of integrative simulations. We discuss the role of theory and modeling in
different areas of physics and suggest that certain sub-disciplines of physics
provide useful cultural analogies for imagining the future role of simulations
in biological research. We examine philosophical issues related to modeling
which consistently arise in discussions about integrative simulations and
suggest a pragmatic viewpoint that balances a belief in philosophy with the
recognition of the relative infancy of our state of philosophical
understanding. Finally, we discuss community workflow and publication practices
to allow research to be readily discoverable and amenable to incorporation into
simulations. We argue that there are aligned incentives in widespread adoption
of practices which will both advance the needs of integrative simulation
efforts as well as other contemporary trends in the biological sciences,
ranging from open science and data sharing to improving reproducibility.Comment: 10 page
Cardiac cell modelling: Observations from the heart of the cardiac physiome project
In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field
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