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Plant cell walls are versatile materials that can adopt a wide range of mechanical properties through controlled deposition of cellulose fibrils. Wall integrity requires a sufficiently homogeneous fibril distribution to cope effectively with wall stresses. Additionally, specific conditions, such as the negative pressure in water transporting xylem vessels, may require more complex wall patterns, e.g., bands in protoxylem. The orientation and patterning of cellulose fibrils are guided by dynamic cortical microtubules. New microtubules are predominantly nucleated from parent microtubules causing positive feedback on local microtubule density with the potential to yield highly inhomogeneous patterns. Inhomogeneity indeed appears in all current cortical array simulations that include microtubule-based nucleation, suggesting that plant cells must possess an as-yet unknown balancing mechanism to prevent it. Here, in a combined simulation and experimental approach, we show that a limited local recruitment of nucleation complexes to microtubules can counter the positive feedback, whereas local tubulin depletion cannot. We observe that nucleation complexes preferentially appear at the plasma membrane near microtubules. By incorporating our experimental findings in stochastic simulations, we find that the spatial behavior of nucleation complexes delicately balances the positive feedback, such that differences in local microtubule dynamics-as in developing protoxylem-can quickly turn a homogeneous array into a banded one. Our results provide insight into how the plant cytoskeleton has evolved to meet diverse mechanical requirements and greatly increase the predictive power of computational cell biology studies.
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Biologia Computacional , MicrotúbulosRESUMO
In plant vascular tissue development, different cell wall patterns are formed, offering different mechanical properties optimised for different growth stages. Critical in these patterning processes are Rho of Plants (ROP) proteins, a class of evolutionarily conserved small GTPase proteins responsible for local membrane domain formation in many organisms. While te spotted metaxylem pattern can easily be understood as a result of a Turing-style reaction-diffusion mechanism, it remains an open question how the consistent orientation of evenly spaced bands and spirals as found in protoxylem is achieved. We hypothesise that this orientation results from an interaction between ROPs and an array of transversely oriented cortical microtubules that acts as a directional diffusion barrier. Here, we explore this hypothesis using partial differential equation models with anisotropic ROP diffusion and show that a horizontal microtubule array acting as a vertical diffusion barrier to active ROP can yield a horizontally banded ROP pattern. We then study the underlying mechanism in more detail, finding that it can only orient curved pattern features but not straight lines. This implies that, once formed, banded and spiral patterns cannot be reoriented by this mechanism. Finally, we observe that ROPs and microtubules together only form ultimately static patterns if the interaction is implemented with sufficient biological realism.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Parede Celular/metabolismo , Microtúbulos/metabolismo , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
We present a new simulation model of the reactions in the photosynthetic electron transport chain of C3 species. We show that including recent insights about the regulation of the thylakoid proton motive force, ATP/NADPH balancing mechanisms (cyclic and noncyclic alternative electron transport), and regulation of Rubisco activity leads to emergent behaviors that may affect the operation and regulation of photosynthesis under different dynamic environmental conditions. The model was parameterized with experimental results in the literature, with a focus on Arabidopsis (Arabidopsis thaliana). A dataset was constructed from multiple sources, including measurements of steady-state and dynamic gas exchange, chlorophyll fluorescence, and absorbance spectroscopy under different light intensities and CO2, to test predictions of the model under different experimental conditions. Simulations suggested that there are strong interactions between cyclic and noncyclic alternative electron transport and that an excess capacity for alternative electron transport is required to ensure adequate redox state and lumen pH. Furthermore, the model predicted that, under specific conditions, reduction of ferredoxin by plastoquinol is possible after a rapid increase in light intensity. Further analysis also revealed that the relationship between ATP synthesis and proton motive force was highly regulated by the concentrations of ATP, ADP, and inorganic phosphate, and this facilitated an increase in nonphotochemical quenching and proton motive force under conditions where metabolism was limiting, such as low CO2, high light intensity, or combined high CO2 and high light intensity. The model may be used as an in silico platform for future research on the regulation of photosynthetic electron transport.
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Arabidopsis/fisiologia , Transporte de Elétrons/fisiologia , Modelos Biológicos , Plantas/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Dióxido de Carbono/metabolismo , Simulação por Computador , Ferredoxinas/metabolismo , Fluorescência , Concentração de Íons de Hidrogênio , Luz , NADP/metabolismo , Fotossíntese/fisiologia , Plastoquinona/análogos & derivados , Plastoquinona/metabolismoRESUMO
A dynamic model of leaf CO2 assimilation was developed as an extension of the canonical steady-state model, by adding the effects of energy-dependent non-photochemical quenching (qE), chloroplast movement, photoinhibition, regulation of enzyme activity in the Calvin cycle, metabolite concentrations, and dynamic CO2 diffusion. The model was calibrated and tested successfully using published measurements of gas exchange and chlorophyll fluorescence on Arabidopsis thaliana ecotype Col-0 and several photosynthetic mutants and transformants affecting the regulation of Rubisco activity (rca-2 and rwt43), non-photochemical quenching (npq4-1 and npq1-2), and sucrose synthesis (spsa1). The potential improvements on CO2 assimilation under fluctuating irradiance that can be achieved by removing the kinetic limitations on the regulation of enzyme activities, electron transport, and stomatal conductance were calculated in silico for different scenarios. The model predicted that the rates of activation of enzymes in the Calvin cycle and stomatal opening were the most limiting (up to 17% improvement) and that effects varied with the frequency of fluctuations. On the other hand, relaxation of qE and chloroplast movement had a strong effect on average low-irradiance CO2 assimilation (up to 10% improvement). Strong synergies among processes were found, such that removing all kinetic limitations simultaneously resulted in improvements of up to 32%.
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Arabidopsis/metabolismo , Dióxido de Carbono/metabolismo , Modelos Biológicos , Folhas de Planta/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Calibragem , Clorofila/metabolismo , Transporte de Elétrons , Luz , Complexos de Proteínas Captadores de Luz/genética , Complexos de Proteínas Captadores de Luz/metabolismo , Mutação , Fotossíntese/fisiologia , Complexo de Proteína do Fotossistema II/genética , Complexo de Proteína do Fotossistema II/metabolismo , Estômatos de Plantas/fisiologia , Ribulose-Bifosfato Carboxilase/economia , Ribulose-Bifosfato Carboxilase/metabolismoRESUMO
In many developing plant tissues and organs, differentiating cells switch from the classical cell cycle to an alternative partial cycle. This partial cycle bypasses mitosis and allows for multiple rounds of genome duplication without cell division, giving rise to cells with high ploidy numbers. This partial cycle is referred to as endoreduplication. Cell division and endoreduplication are important processes for biomass allocation and yield in tomato. Quantitative trait loci for tomato fruit size or weight are frequently associated with variations in the pericarp cell number, and due to the tight connection between endoreduplication and cell expansion and the prevalence of polyploidy in storage tissues, a functional correlation between nuclear ploidy number and cell growth has also been implicated (karyoplasmic ratio theory). In this paper, we assess the applicability of putative mechanisms for the onset of endoreduplication in tomato pericarp cells via development of a mathematical model for the cell cycle gene regulatory network. We focus on targets for regulation of the transition to endoreduplication by the phytohormone auxin, which is known to play a vital role in the onset of cell expansion and differentiation in developing tomato fruit. We show that several putative mechanisms are capable of inducing the onset of endoreduplication. This redundancy in explanatory mechanisms is explained by analysing system behaviour as a function of their combined action. Namely, when all these routes to endoreduplication are used in a combined fashion, robustness of the regulation of the transition to endoreduplication is greatly improved.
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Divisão Celular , Endorreduplicação , Frutas/citologia , Solanum lycopersicum/citologia , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Fatores de Transcrição E2F/metabolismo , Frutas/genética , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/metabolismo , Solanum lycopersicum/genética , Modelos BiológicosRESUMO
Brassinosteroid (BR) signaling is essential for plant growth and development. In Arabidopsis (Arabidopsis thaliana), BRs are perceived by the BRASSINOSTEROID INSENSITIVE1 (BRI1) receptor. Root growth and hypocotyl elongation are convenient downstream physiological outputs of BR signaling. A computational approach was employed to predict root growth solely on the basis of BRI1 receptor activity. The developed mathematical model predicts that during normal root growth, few receptors are occupied with ligand. The model faithfully predicts root growth, as observed in bri1 loss-of-function mutants. For roots, it incorporates one stimulatory and two inhibitory modules, while for hypocotyls, a single inhibitory module is sufficient. Root growth as observed when BRI1 is overexpressed can only be predicted assuming that a decrease occurred in the BRI1 half-maximum response values. Root growth appears highly sensitive to variation in BR concentration and much less to reduction in BRI1 receptor level, suggesting that regulation occurs primarily by ligand availability and biochemical activity.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Hipocótilo/crescimento & desenvolvimento , Modelos Teóricos , Raízes de Plantas/crescimento & desenvolvimento , Proteínas Quinases/metabolismo , Transdução de Sinais , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Brassinosteroides/farmacologia , Biologia Computacional/métodos , Meios de Cultura/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hipocótilo/efeitos dos fármacos , Hipocótilo/metabolismo , Ligantes , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Receptores de Superfície Celular/metabolismo , Esteroides Heterocíclicos/metabolismo , Esteroides Heterocíclicos/farmacologia , Triazóis/farmacologiaRESUMO
Biological systems are tremendously complex in their functioning and regulation. Studying the multifaceted behaviour and describing the performance of such complexity has challenged the scientific community for years. The reduction of real-world intricacy into simple descriptive models has therefore convinced many researchers of the usefulness of introducing mathematics into biological sciences. Predictive modelling takes such an approach another step further in that it takes advantage of existing knowledge to project the performance of a system in alternating scenarios. The ever growing amounts of available data generated by assessing biological systems at increasingly higher detail provide unique opportunities for future modelling and experiment design. Here we aim to provide an overview of the progress made in modelling over time and the currently prevalent approaches for iterative modelling cycles in modern biology. We will further argue for the importance of versatility in modelling approaches, including parameter estimation, model reduction and network reconstruction. Finally, we will discuss the difficulties in overcoming the mathematical interpretation of in vivo complexity and address some of the future challenges lying ahead.
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Produtos Agrícolas/fisiologia , Modelos Biológicos , Biologia de Sistemas , Transdução de Sinais , Estatística como AssuntoRESUMO
The conversion of supplemental greenhouse light energy into biomass is not always optimal. Recent trends in global energy prices and discussions on climate change highlight the need to reduce our energy footprint associated with the use of supplemental light in greenhouse crop production. This can be achieved by implementing "smart" lighting regimens which in turn rely on a good understanding of how fluctuating light influences photosynthetic physiology. Here, a simple fit-for-purpose dynamic model is presented. It accurately predicts net leaf photosynthesis under natural fluctuating light. It comprises two ordinary differential equations predicting: 1) the total stomatal conductance to CO2 diffusion and 2) the CO2 concentration inside a leaf. It contains elements of the Farquhar-von Caemmerer-Berry model and the successful incorporation of this model suggests that for tomato (Solanum lycopersicum L.), it is sufficient to assume that Rubisco remains activated despite rapid fluctuations in irradiance. Furthermore, predictions of the net photosynthetic rate under both 400ppm and enriched 800ppm ambient CO2 concentrations indicate a strong correlation between the dynamic rate of photosynthesis and the rate of electron transport. Finally, we are able to indicate whether dynamic photosynthesis is Rubisco or electron transport rate limited.
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Solanum lycopersicum , Dióxido de Carbono/metabolismo , Ribulose-Bifosfato Carboxilase/metabolismo , Fotossíntese/fisiologia , Folhas de Planta/metabolismoRESUMO
The complexity of biochemical systems, stemming from both the large number of components and the intricate interactions between these components, may hinder us in understanding the behavior of these systems. Therefore, effective methods are required to capture their key components and interactions. Here, we present a novel and efficient reduction method to simplify mathematical models of biochemical systems. Our method is based on the exploration of the so-called admissible region, that is the set of parameters for which the mathematical model yields some required output. From the shape of the admissible region, parameters that are really required in generating the output of the system can be identified and hence retained in the model, whereas the rest is removed. To describe the idea, first the admissible region of a very small artificial network with only three nodes and three parameters is determined. Despite its simplicity, this network reveals all the basic ingredients of our reduction method. The method is then applied to an epidermal growth factor receptor (EGFR) network model. It turns out that only about 34% of the network components are required to yield the correct response to the epidermal growth factor (EGF) that was measured in the experiments, whereas the rest could be considered as redundant for this purpose. Furthermore, it is shown that parameter sensitivity on its own is not a reliable tool for model reduction, because highly sensitive parameters are not always retained, whereas slightly sensitive parameters are not always removable.
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Fenômenos Bioquímicos/fisiologia , Modelos Biológicos , Biologia de Sistemas/métodos , Algoritmos , Receptores ErbB/metabolismo , Redes e Vias Metabólicas/fisiologia , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Proteína Son Of Sevenless de Drosófila/metabolismoRESUMO
Structural identifiability is a binary property that determines whether or not unique parameter values can, in principle, be estimated from error-free input-output data. The many papers that have been written on this topic collectively stress the importance of this a priori analysis in the model development process. The story however, often ends with a structurally unidentifiable model. This may leave a model developer with no plan of action on how to address this potential issue. We continue this model exploration journey by identifying one of the possible sources of a model's unidentifiability: problematic initial conditions. It is well-known that certain initial values may result in the loss of local structural identifiability. Nevertheless, literature on this topic has been limited to the analysis of small toy models. Here, we present a systematic approach to detect problematic initial conditions of real-world systems biology models, that are usually not small. A model's identifiability can often be reinstated by changing the value of such problematic initial conditions. This provides modellers an option to resolve the "unidentifiable model" problem. Additionally, a good understanding of which initial values should rather be avoided can be very useful during experimental design. We show how our approach works in practice by applying it to five models. First, two small benchmark models are studied to get the reader acquainted with the method. The first one shows the effect of a zero-valued problematic initial condition. The second one illustrates that the approach also yields correct results in the presence of input signals and that problematic initial conditions need not be zero-values. For the remaining three examples, we set out to identify key initial values which may result in the structural unidentifiability. The third and fourth examples involve a systems biology Epo receptor model and a JAK/STAT model, respectively. In the final Pharmacokinetics model, of which its global structural identifiability has only recently been confirmed, we indicate that there are still sets of initial values for which this property does not hold.
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Many biological processes have to occur at specific locations on the cell membrane. These locations are often specified by the localised activity of small GTPase proteins. Some processes require the formation of a single cluster of active GTPase, also called unipolar polarisation (here "polarisation"), whereas others need multiple coexisting clusters. Moreover, sometimes the pattern of GTPase clusters is dynamically regulated after its formation. This raises the question how the same interacting protein components can produce such a rich variety of naturally occurring patterns. Most currently used models for GTPase-based patterning inherently yield polarisation. Such models may at best yield transient coexistence of at most a few clusters, and hence fail to explain several important biological phenomena. These existing models are all based on mass conservation of total GTPase and some form of direct or indirect positive feedback. Here, we show that either of two biologically plausible modifications can yield stable coexistence: including explicit GTPase turnover, i.e., breaking mass conservation, or negative feedback by activation of an inhibitor like a GAP. Since we start from two different polarising models our findings seem independent of the precise self-activation mechanism. By studying the net GTPase flows among clusters, we provide insight into how these mechanisms operate. Our coexistence models also allow for dynamical regulation of the final pattern, which we illustrate with examples of pollen tube growth and the branching of fungal hyphae. Together, these results provide a better understanding of how cells can tune a single system to generate a wide variety of biologically relevant patterns.
Assuntos
Modelos Moleculares , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Animais , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Fungos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/químicaRESUMO
We have developed an algorithm for a particle-based model for the growth of plant tissues in three dimensions in which each cell is represented by a single particle, and connecting cell walls are represented as permanent bonds between particles. A sample of plant tissue is represented by a fixed network of bonded particles. If, and only if a cell divides, this network is updated locally. The update algorithm is implemented in a model where cell growth and division gives rise to forces between the cells, which are relaxed in steepest descent minimization. The same forces generate a pressure inside the cells, which moderates growth. The local nature of the algorithm makes it efficient computationally, so the model can deal with a large number of cells. We used the model to study the growth of plant tissues for a variety of model parameters, to show the viability of the algorithm.
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The appropriate timing of flowering is crucial for the reproductive success of plants. Hence, intricate genetic networks integrate various environmental and endogenous cues such as temperature or hormonal statues. These signals integrate into a network of floral pathway integrator genes. At a quantitative level, it is currently unclear how the impact of genetic variation in signaling pathways on flowering time is mediated by floral pathway integrator genes. Here, using datasets available from literature, we connect Arabidopsis thaliana flowering time in genetic backgrounds varying in upstream signalling components with the expression levels of floral pathway integrator genes in these genetic backgrounds. Our modelling results indicate that flowering time depends in a quite linear way on expression levels of floral pathway integrator genes. This gradual, proportional response of flowering time to upstream changes enables a gradual adaptation to changing environmental factors such as temperature and light.
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Adaptation of agents through learning or evolution is an important component of the resilience of Complex Adaptive Systems (CAS). Without adaptation, the flexibility of such systems to cope with outside pressures would be much lower. To study the capabilities of CAS to adapt, social simulations with agent-based models (ABMs) provide a helpful tool. However, the value of ABMs for studying adaptation depends on the availability of methodologies for sensitivity analysis that can quantify resilience and adaptation in ABMs. In this paper we propose a sensitivity analysis methodology that is based on comparing time-dependent probability density functions of output of ABMs with and without agent adaptation. The differences between the probability density functions are quantified by the so-called earth-mover's distance. We use this sensitivity analysis methodology to quantify the probability of occurrence of critical transitions and other long-term effects of agent adaptation. To test the potential of this new approach, it is used to analyse the resilience of an ABM of adaptive agents competing for a common-pool resource. Adaptation is shown to contribute positively to the resilience of this ABM. If adaptation proceeds sufficiently fast, it may delay or avert the collapse of this system.
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Adaptação Fisiológica , Algoritmos , Ecossistema , Modelos Teóricos , Animais , Simulação por Computador , Conservação dos Recursos Naturais , Atividades Humanas , Humanos , Comportamento SocialRESUMO
We study the glycosylation processes that convert initially toxic substrates to nutritionally valuable metabolites in the flavonoid biosynthesis pathway of tomato (Solanum lycopersicum) seedlings. To estimate the reaction rates we use ordinary differential equations (ODEs) to model the enzyme kinetics. A popular choice is to use a system of linear ODEs with constant kinetic rates or to use Michaelis-Menten kinetics. In reality, the catalytic rates, which are affected among other factors by kinetic constants and enzyme concentrations, are changing in time and with the approaches just mentioned, this phenomenon cannot be described. Another problem is that, in general these kinetic coefficients are not always identifiable. A third problem is that, it is not precisely known which enzymes are catalyzing the observed glycosylation processes. With several hundred potential gene candidates, experimental validation using purified target proteins is expensive and time consuming. We aim at reducing this task via mathematical modeling to allow for the pre-selection of most potential gene candidates. In this article we discuss a fast and relatively simple approach to estimate time varying kinetic rates, with three favorable properties: firstly, it allows for identifiable estimation of time dependent parameters in networks with a tree-like structure. Secondly, it is relatively fast compared to usually applied methods that estimate the model derivatives together with the network parameters. Thirdly, by combining the metabolite concentration data with a corresponding microarray data, it can help in detecting the genes related to the enzymatic processes. By comparing the estimated time dynamics of the catalytic rates with time series gene expression data we may assess potential candidate genes behind enzymatic reactions. As an example, we show how to apply this method to select prominent glycosyltransferase genes in tomato seedlings.
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Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1) mutation has a larger impact on APETALA1 (AP1), which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY) which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1) by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time.
Assuntos
Arabidopsis/genética , Flores/genética , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Flores/crescimento & desenvolvimento , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Modelos Genéticos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
A simple molecular model is studied to explain wall slip in a polymer melt. We consider a tube model for tethered chains in which the most important relaxation mechanisms: convective constraint release and chain stretching (retraction), are incorporated. Furthermore, we take the interactions between tethered chains and bulk flow self-consistently into account. Numerical simulations show that our model exhibits an entanglement-disentanglement transition, leading to a jump in the slip velocity which increases with the number of entanglements and the grafting density. The wall shear stress is found to be a nonmonotonic function of the slip and plate velocity, yielding the possibility of hysteresis and spurt instabilities. In a simplified version of the model we show via an analytical approach that the stick-slip transition is asymmetrical: the transition from stick to slip is much faster than the slip to stick transition. Our analysis reveals the existence of a dimensionless parameter that determines the time scale of the dynamics for the slowing down of the bulk flow. The relative rate at which relaxation of the tethered chains and slowing down of the bulk take place, seems to be quintessential for the slip behavior of the melt.
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Microarray data is often utilized in inferring regulatory networks. Quantile normalization (QN) is a popular method to reduce array-to-array variation. We show that in the context of time series measurements QN may not be the best choice for this task, especially not if the inference is based on continuous time ODE model. We propose an alternative normalization method that is better suited for network inference from time series data.
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Biochemical systems involving a high number of components with intricate interactions often lead to complex models containing a large number of parameters. Although a large model could describe in detail the mechanisms that underlie the system, its very large size may hinder us in understanding the key elements of the system. Also in terms of parameter identification, large models are often problematic. Therefore, a reduced model may be preferred to represent the system. Yet, in order to efficaciously replace the large model, the reduced model should have the same ability as the large model to produce reliable predictions for a broad set of testable experimental conditions. We present a novel method to extract an "optimal" reduced model from a large model to represent biochemical systems by combining a reduction method and a model discrimination method. The former assures that the reduced model contains only those components that are important to produce the dynamics observed in given experiments, whereas the latter ensures that the reduced model gives a good prediction for any feasible experimental conditions that are relevant to answer questions at hand. These two techniques are applied iteratively. The method reveals the biological core of a model mathematically, indicating the processes that are likely to be responsible for certain behavior. We demonstrate the algorithm on two realistic model examples. We show that in both cases the core is substantially smaller than the full model.
Assuntos
Modelos Biológicos , Biologia de Sistemas , Arabidopsis/genética , Arabidopsis/fisiologia , Receptores ErbB/metabolismo , Flores/genética , Flores/fisiologia , Redes Reguladoras de Genes , Genes de Plantas , Reprodutibilidade dos TestesRESUMO
Multi-parameter models in systems biology are typically 'sloppy': some parameters or combinations of parameters may be hard to estimate from data, whereas others are not. One might expect that parameter uncertainty automatically leads to uncertain predictions, but this is not the case. We illustrate this by showing that the prediction uncertainty of each of six sloppy models varies enormously among different predictions. Statistical approximations of parameter uncertainty may lead to dramatic errors in prediction uncertainty estimation. We argue that prediction uncertainty assessment must therefore be performed on a per-prediction basis using a full computational uncertainty analysis. In practice this is feasible by providing a model with a sample or ensemble representing the distribution of its parameters. Within a Bayesian framework, such a sample may be generated by a Markov Chain Monte Carlo (MCMC) algorithm that infers the parameter distribution based on experimental data. Matlab code for generating the sample (with the Differential Evolution Markov Chain sampler) and the subsequent uncertainty analysis using such a sample, is supplied as Supplemental Information.