5,151 research outputs found
The impact of cellular characteristics on the evolution of shape homeostasis
The importance of individual cells in a developing multicellular organism is
well known but precisely how the individual cellular characteristics of those
cells collectively drive the emergence of robust, homeostatic structures is
less well understood. For example cell communication via a diffusible factor
allows for information to travel across large distances within the population,
and cell polarisation makes it possible to form structures with a particular
orientation, but how do these processes interact to produce a more robust and
regulated structure? In this study we investigate the ability of cells with
different cellular characteristics to grow and maintain homeostatic structures.
We do this in the context of an individual-based model where cell behaviour is
driven by an intra-cellular network that determines the cell phenotype. More
precisely, we investigated evolution with 96 different permutations of our
model, where cell motility, cell death, long-range growth factor (LGF),
short-range growth factor (SGF) and cell polarisation were either present or
absent. The results show that LGF has the largest positive impact on the
fitness of the evolved solutions. SGF and polarisation also contribute, but all
other capabilities essentially increase the search space, effectively making it
more difficult to achieve a solution. By perturbing the evolved solutions, we
found that they are highly robust to both mutations and wounding. In addition,
we observed that by evolving solutions in more unstable environments they
produce structures that were more robust and adaptive. In conclusion, our
results suggest that robust collective behaviour is most likely to evolve when
cells are endowed with long range communication, cell polarisation, and
selection pressure from an unstable environment
Systems approaches to modelling pathways and networks.
Peer reviewedPreprin
QSSPN: dynamic simulation of molecular interaction networks describing gene regulation, signalling and whole-cell metabolism in human cells
Motivation: Dynamic simulation of genome-scale molecular interaction networks will enable the mechanistic prediction of genotype–phenotype relationships. Despite advances in quantitative biology, full parameterization of whole-cell models is not yet possible. Simulation methods capable of using available qualitative data are required to develop dynamic whole-cell models through an iterative process of modelling and experimental validation. Results: We formulate quasi-steady state Petri nets (QSSPN), a novel method integrating Petri nets and constraint-based analysis to predict the feasibility of qualitative dynamic behaviours in qualitative models of gene regulation, signalling and whole-cell metabolism. We present the first dynamic simulations including regulatory mechanisms and a genome-scale metabolic network in human cell, using bile acid homeostasis in human hepatocytes as a case study. QSSPN simulations reproduce experimentally determined qualitative dynamic behaviours and permit mechanistic analysis of genotype–phenotype relationships. Availability and implementation: The model and simulation software implemented in Cþþ are available in supplementary material and at http://sysbio3.fhms.surrey.ac.uk/qsspn/. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin
Modelling of glucose repression signalling in yeast Saccharomyces cerevisiae
Saccharomyces cerevisiae has a sophisticated signalling system that plays a crucial role in cellular adaptation to changing environments. The SNF1 pathway regulates energy homeostasis upon glucose derepression; hence, it plays an important role in various processes, such as metabolism, cell cycle and autophagy. To unravel its behaviour, SNF1 signalling has been extensively studied. However, the pathway components are strongly interconnected and inconstant; therefore, elucidating its dynamic behaviour based on experimental data only is challenging. To tackle this complexity, systems biology approaches have been successfully employed. This review summarizes the progress, advantages and disadvantages of the available mathematical modelling frameworks covering Boolean, dynamic kinetic, single-cell models, which have been used to study processes and phenomena ranging from crosstalks to sources of cell-to-cell variability in the context of SNF1 signalling. Based on the lessons from existing models, we further discuss how to develop a consensus dynamic mechanistic model of the entire SNF1 pathway that can provide novel insights into the dynamics of nutrient signalling
Colorectal Cancer Through Simulation and Experiment
Colorectal cancer has continued to generate a huge amount of research interest over several decades, forming a canonical example of tumourigenesis since its use in Fearon and Vogelstein’s linear model of genetic mutation. Over time, the field has witnessed a transition from solely experimental work to the inclusion of mathematical biology and computer-based modelling. The fusion of these disciplines has the potential to provide valuable insights into oncologic processes, but also presents the challenge of uniting many diverse perspectives. Furthermore, the cancer cell phenotype defined by the ‘Hallmarks of Cancer’ has been extended in recent times and provides an excellent basis for future research. We present a timely summary of the literature relating to colorectal cancer, addressing the traditional experimental findings, summarising the key mathematical and computational approaches, and emphasising the role of the Hallmarks in current and future developments. We conclude with a discussion of interdisciplinary work, outlining areas of experimental interest which would benefit from the insight that mathematical and computational modelling can provide
Discrete time piecewise affine models of genetic regulatory networks
We introduce simple models of genetic regulatory networks and we proceed to
the mathematical analysis of their dynamics. The models are discrete time
dynamical systems generated by piecewise affine contracting mappings whose
variables represent gene expression levels. When compared to other models of
regulatory networks, these models have an additional parameter which is
identified as quantifying interaction delays. In spite of their simplicity,
their dynamics presents a rich variety of behaviours. This phenomenology is not
limited to piecewise affine model but extends to smooth nonlinear discrete time
models of regulatory networks. In a first step, our analysis concerns general
properties of networks on arbitrary graphs (characterisation of the attractor,
symbolic dynamics, Lyapunov stability, structural stability, symmetries, etc).
In a second step, focus is made on simple circuits for which the attractor and
its changes with parameters are described. In the negative circuit of 2 genes,
a thorough study is presented which concern stable (quasi-)periodic
oscillations governed by rotations on the unit circle -- with a rotation number
depending continuously and monotonically on threshold parameters. These regular
oscillations exist in negative circuits with arbitrary number of genes where
they are most likely to be observed in genetic systems with non-negligible
delay effects.Comment: 34 page
Asymptotic analysis of noisy fitness maximization, applied to metabolism and growth
We consider a population dynamics model coupling cell growth to a diffusion
in the space of metabolic phenotypes as it can be obtained from realistic
constraints-based modelling. In the asymptotic regime of slow diffusion, that
coincides with the relevant experimental range, the resulting non-linear
Fokker-Planck equation is solved for the steady state in the WKB approximation
that maps it into the ground state of a quantum particle in an Airy potential
plus a centrifugal term. We retrieve scaling laws for growth rate fluctuations
and time response with respect to the distance from the maximum growth rate
suggesting that suboptimal populations can have a faster response to
perturbations.Comment: 24 pages, 6 figure
Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation
Langerhans cells (LCs) are able to orchestrate adaptive immune responses in the skin by interpreting the microenvironmental context in which they encounter foreign substances, but the regulatory basis for this has not been established. Utilising systems immunology approaches combining in silico modelling of a reconstructed gene regulatory network (GRN) with in vitro validation of the predictions, we sought to determine the mechanisms of regulation of immune responses in human primary LCs. The key role of Interferon regulatory factors (IRFs) as controllers of the human Langerhans cell response to epidermal cytokines was revealed by whole transcriptome analysis. Applying Boolean logic we assembled a Petri net-based model of the IRF-GRN which provides molecular pathway predictions for the induction of different transcriptional programmes in LCs. In silico simulations performed after model parameterisation with transcription factor expression values predicted that human LC activation of antigen-specific CD8 T cells would be differentially regulated by epidermal cytokine induction of specific IRF-controlled pathways. This was confirmed by in vitro measurement of IFN-g production by activated T cells. As a proof of concept, this approach shows that stochastic modelling of a specific immune networks renders transcriptome data valuable for the prediction of functional outcomes of immune responses
- …