E-CELL: software environment for whole-cell simulation.
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MOTIVATION: Genome sequencing projects and further systematic functional analyses of complete gene sets are producing an unprecedented mass of molecular information for a wide range of model organisms. This provides us with a detailed account of the cell with which we may begin to build models for simulating intracellular molecular processes to predict the dynamic behavior of living cells. Previous work in biochemical and genetic simulation has isolated well-characterized pathways for detailed analysis, but methods for building integrative models of the cell that incorporate gene regulation, metabolism and signaling have not been established. We, therefore, were motivated to develop a software environment for building such integrative models based on gene sets, and running simulations to conduct experiments in silico. RESULTS: E-CELL, a modeling and simulation environment for biochemical and genetic processes, has been developed. The E-CELL system allows a user to define functions of proteins, protein-protein interactions, protein-DNA interactions, regulation of gene expression and other features of cellular metabolism, as a set of reaction rules. E-CELL simulates cell behavior by numerically integrating the differential equations described implicitly in these reaction rules. The user can observe, through a computer display, dynamic changes in concentrations of proteins, protein complexes and other chemical compounds in the cell. Using this software, we constructed a model of a hypothetical cell with only 127 genes sufficient for transcription, translation, energy production and phospholipid synthesis. Most of the genes are taken from Mycoplasma genitalium, the organism having the smallest known chromosome, whose complete 580 kb genome sequence was determined at TIGR in 1995. We discuss future applications of the E-CELL system with special respect to genome engineering. AVAILABILITY: The E-CELL software is available upon request. SUPPLEMENTARY INFORMATION: The complete list of rules of the developed cell model with kinetic parameters can be obtained via our web site at: http://e-cell.org/. (+info)
Titrating the effects of mitochondrial complex I impairment in the cell physiology.
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The mitochondrial oxidative phosphorylation system consists of five multimeric enzymes (complexes I-V). NADH dehydrogenase or complex I (CI) is affected in most of the mitochondrial diseases and in some neurodegenerative disorders. We have studied the physiological consequences of a partial CI inhibition at the cellular level. We used a genetic model (40% CI-inhibited human-ape xenomitochondrial cybrids) and a drug-induced model (0-100% CI-inhibited cells using different concentrations of rotenone). We observed a quantitative correlation between the level of CI impairment and cell respiration, cell growth, free radical production, lipid peroxidation, mitochondrial membrane potential, and apoptosis. We showed that cell death was quantitatively associated with free radical production rather than with a decrease in respiratory chain function. The results obtained with human xenomitochondrial cybrid cells were compatible with those observed in rotenone-induced 40% CI-inhibited cells. At high concentrations (5-6-fold higher than the concentration necessary for 100% CI inhibition), rotenone showed a second toxic effect at the level of microtubule assembly, which also led to apoptosis. The correlation found among all the parameters studied helped clarify the physiological consequences of partial CI inhibitions at the cellular level. (+info)
Time-resolved analysis and visualization of dynamic processes in living cells.
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Recent development of in vivo microscopy techniques, including green fluorescent proteins, has allowed the visualization of a wide range of dynamic processes in living cells. For quantitative and visual interpretation of such processes, new concepts for time-resolved image analysis and continuous time-space visualization are required. Here, we describe a versatile and fully automated approach consisting of four techniques, namely highly sensitive object detection, fuzzy logic-based dynamic object tracking, computer graphical visualization, and measurement in time-space. Systematic model simulations were performed to evaluate the reliability of the automated object detection and tracking method. To demonstrate potential applications, the method was applied to the analysis of secretory membrane traffic and the functional dynamics of nuclear compartments enriched in pre-mRNA splicing factors. (+info)
Hyaluronan and proteoglycans in ovarian follicles.
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Proteoglycans are macromolecules formed by a protein backbone to which one or more glycosaminoglycan side chains are co-valently attached. They can be secreted by the cells, retained at the cell surface, or stored in intracellular vacuoles. Hyaluronan is an extremely long glycosaminoglycan which, at variance with other glycosaminoglycans, is released into the extracellular matrix as a free polysaccharide not co-valently linked to a core protein. Both proteoglycans and hyaluronan influence many aspects of cell behaviour by multiple interactions with other molecules. They are involved in matrix formation, cell-cell and cell-matrix adhesion, cell proliferation and migration, and show co-receptor activity for growth factors. Both proteoglycan and hyaluranon synthesis change significantly during ovarian follicle development and atresia. This review describes the structure of these molecules and their possible function in ovarian physiology. (+info)
Modeling electroporation in a single cell. I. Effects Of field strength and rest potential.
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This study develops a model for a single cell electroporated by an external electric field and uses it to investigate the effects of shock strength and rest potential on the transmembrane potential V(m) and pore density N around the cell. As compared to the induced potential predicted by resistive-capacitive theory, the model of electroporation predicts a smaller magnitude of V(m) throughout the cell. Both V(m) and N are symmetric about the equator with the same value at both poles of the cell. Larger shocks do not increase the maximum magnitude of V(m) because more pores form to shunt the excess stimulus current across the membrane. In addition, the value of the rest potential does not affect V(m) around the cell because the electroporation current is several orders of magnitude larger than the ionic current that supports the rest potential. Once the field is removed, the shock-induced V(m) discharges within 2 micros, but the pores persist in the membrane for several seconds. Complete resealing to preshock conditions requires approximately 20 s. These results agree qualitatively and quantitatively with the experimental data reported by Kinosita and coworkers for unfertilized sea urchin eggs exposed to large electric fields. (+info)
Modeling electroporation in a single cell. II. Effects Of ionic concentrations.
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This study expands a previously developed model of a single cell electroporated by an external electric field by explicitly accounting for the ionic composition of the electroporation current. The previous model with non-specific electroporation current predicts that both the transmembrane potential V(m) and the pore density N are symmetric about the equator, with the same values at either end of the cell. The new, ion-specific case predicts that V(m) is symmetric and almost identical to the profile from the non-specific case, but N has a profound asymmetry with the pore density at the hyperpolarized end of the cell twice the value at the depolarized end. These modeling results agree with the experimentally observed preferential uptake of marker molecules at the hyperpolarized end of the cell as reported in the literature. This study also investigates the changes in intracellular ionic concentrations induced around an electroporated single cell. For all ion species, the concentrations near the membrane vary significantly, which may explain the electrical disturbances observed experimentally after large electric shocks are delivered to excitable cells and tissues. (+info)
The osmotic migration of cells in a solute gradient.
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The effect of a nonuniform solute concentration on the osmotic transport of water through the boundaries of a simple model cell is investigated. A system of two ordinary differential equations is derived for the motion of a single cell in the limit of a fast solute diffusion, and an analytic solution is obtained for one special case. A two-dimensional finite element model has been developed to simulate the more general case (finite diffusion rates, solute gradient induced by a solidification front). It is shown that the cell moves to regions of lower solute concentration due to the uneven flux of water through the cell boundaries. This mechanism has apparently not been discussed previously. The magnitude of this effect is small for red blood cells, the case in which all of the relevant parameters are known. We show, however, that it increases with cell size and membrane permeability, so this effect could be important for larger cells. The finite element model presented should also have other applications in the study of the response of cells to an osmotic stress and for the interaction of cells and solidification fronts. Such investigations are of major relevance for the optimization of cryopreservation processes. (+info)