Investigating a simple model of cutaneous wound healing angiogenesis

A simple model of wound healing angiogenesis is presented, and investigated using numerical and asymptotic techniques. The model captures many key qualitative features of the wound healing angiogenic response, such as the propagation of a structural unit into the wound centre. A detailed perturbative study is pursued, and is shown to capture all features of the model. This enables one to show that the level of the angiogenic response predicted by the model is governed to a good approximation by a small number of parameter groupings. Further investigation leads to predictions concerning how one should select between potential optimal means of stimulating cell proliferation in order to increase the level of the angiogenic response

A mass action model of a fibroblast growth factor signaling pathway and its simplification

We consider a kinetic law of mass action model for Fibroblast Growth Factor (FGF) signaling, focusing on the induction of the RAS-MAP kinase pathway via GRB2 binding. Our biologically simple model suffers a combinatorial explosion in the number of differential equations required to simulate the system. In addition to numerically solving the full model, we show that it can be accurately simplified. This requires combining matched asymptotics, the quasi-steady state hypothesis, and the fact subsets of the equations decouple asymptotically. Both the full and simplified models reproduce the qualitative dynamics observed experimentally and in previous stochastic models. The simplified model also elucidates both the qualitative features of GRB2 binding and the complex relationship between SHP2 levels, the rate SHP2 induces dephosphorylation and levels of bound GRB2. In addition to providing insight into the important and redundant features of FGF signaling, such work further highlights the usefulness of numerous simplification techniques in the study of mass action models of signal transduction, as also illustrated recently by Borisov and co-workers (Borisov et al. in Biophys. J. 89, 951–66, 2005, Biosystems 83, 152–66, 2006; Kiyatkin et al. in J. Biol. Chem. 281, 19925–9938, 2006). These developments will facilitate the construction of tractable models of FGF signaling, incorporating further biological realism, such as spatial effects or realistic binding stoichiometries, despite a more severe combinatorial explosion associated with the latter

Mode doubling and tripling in reaction-diffusion patterns on growing domains: A piece-wise linear model

Reaction-diffusion equations are ubiquitous as models of biological pattern formation. In a recent paper [4] we have shown that incorporation of domain growth in a reaction-diffusion model generates a sequence of quasi-steady patterns and can provide a mechanism for increased reliability of pattern selection. In this paper we analyse the model to examine the transitions between patterns in the sequence. Introducing a piecewise linear approximation we find closed form approximate solutions for steady-state patterns by exploiting a small parameter, the ratio of diffusivities, in a singular perturbation expansion. We consider the existence of these steady-state solutions as a parameter related to the domain length is varied and predict the point at which the solution ceases to exist, which we identify with the onset of transition between patterns for the sequence generated on the growing domain. Applying these results to the model in one spatial dimension we are able to predict the mechanism and timing of transitions between quasi-steady patterns in the sequence. We also highlight a novel sequence behaviour, mode-tripling, which is a consequence of a symmetry in the reaction term of the reaction-diffusion system

Leaky vessels as a potential source of stromal acidification in tumours

Malignant tumours are characterised by higher rates of acid production and a lower extracellular pH than normal tissues. Previous mathematical modelling has indicated that the tumour-derived production of acid leads to a gradient of low pH in the interior of the tumour extending to a normal pH in the peritumoural tissue. This paper uses mathematical modelling to examine the potential of leaky vessels as an additional source of stromal acidification in tumours. We explore whether and to what extent increasing vascular permeability in vessels can lead to the breakdown of the acid gradient from the core of the tumour to the normal tissue, and a progressive acidification of the peritumoural stroma. We compare our mathematical simulations to experimental results found in vivo with a tumour implanted in the mammary fat pad of a mouse in a window chamber construct. We find that leaky vasculature can cause a net acidification of the normal tissue away from the tumour boundary, though not a progressive acidification over time as seen in the experiments. Only through progressively increasing the leakiness can the model qualitatively reproduce the experimental results. Furthermore, the extent of the acidification predicted by the mathematical model is less than as seen in the window chamber, indicating that although vessel leakiness might be acting as a source of acid, it is not the only factor contributing to this phenomenon. Nevertheless, tumour destruction of vasculature could result in enhanced stromal acidification and invasion, hence current therapies aimed at buffering tumour pH should also examine the possibility of preventing vessel disruption

Case management training needs to support vocational rehabilitation for case managers and general practitioners: a survey study

<b>Background</b><p></p> The use of the biopsychosocial model of health and case management for effective vocational rehabilitation (VR) has been confirmed for many health conditions. While Case and Condition Managers (CCMPs) use this approach in their everyday work, little is known about their views on training needs. A review of the training curriculum for General Practitioners’ (GPs) revealed little training in VR and the biopsychosocial model of care. This study aims to identify Case and Condition Managers and GPs perceptions of their training needs in relation to employability and VR.<p></p> <b>Methods</b><p></p> 80 Case and Condition Managers and 304 GPs working in NHS Lanarkshire, providing a comparison group, were invited to participate in this study. A self-completion questionnaire was developed and circulated for online completion with a second round of hardcopy questionnaires distributed.<p></p> <b>Results</b><p></p> In total 45 responses were obtained from CCMPs, 5 from occupational health nurses (62% response rate) and 60 from GPs (20% response rate). CCMPs and the nursing group expressed a need for training but to a lesser extent than GP’s. The GP responses demonstrated a need for high levels of training in case/condition management, the biopsychosocial model, legal and ethical issues associated with employment and VR, and management training.<p></p> <b>Conclusions</b><p></p> This survey confirms a need for further training of CCMPs and that respondent GPs in one health board are not fully equipped to deal with patients employability and vocational needs. GPs also reported a lack of understanding about the role of Case and Condition managers. Training for these professional groups and others involved in multidisciplinary VR could improve competencies and mutual understanding among those advising patients on return-to-work

Power spectra methods for a stochastic description of diffusion on deterministically growing domains

A central challenge in developmental biology is understanding the creation of robust spatiotemporal heterogeneity. Generally, the mathematical treatments of biological systems have used continuum, mean-field hypotheses for their constituent parts, which ignores any sources of intrinsic stochastic effects. In this paper we consider a stochastic space-jump process as a description of diffusion, i.e., particles are able to undergo a random walk on a discretized domain. By developing analytical Fourier methods we are able to probe this probabilistic framework, which gives us insight into the patterning potential of diffusive systems. Further, an alternative description of domain growth is introduced, with which we are able to rigorously link the mean-field and stochastic descriptions. Finally, through combining these ideas, it is shown that such stochastic descriptions of diffusion on a deterministically growing domain are able to support the nucleation of states that are far removed from the deterministic mean-field steady state

Influence of stochastic domain growth on pattern nucleation for diffusive systems with internal noise

Numerous mathematical models exploring the emergence of complexity within developmental biology incorporate diffusion as the dominant mechanism of transport. However, self-organizing paradigms can exhibit the biologically undesirable property of extensive sensitivity, as illustrated by the behavior of the French-flag model in response to intrinsic noise and Turing’s model when subjected to fluctuations in initial conditions. Domain growth is known to be a stabilizing factor for the latter, though the interaction of intrinsic noise and domain growth is underexplored, even in the simplest of biophysical settings. Previously, we developed analytical Fourier methods and a description of domain growth that allowed us to characterize the effects of deterministic domain growth on stochastically diffusing systems. In this paper we extend our analysis to encompass stochastically growing domains. This form of growth can be used only to link the meso- and macroscopic domains as the “box-splitting” form of growth on the microscopic scale has an ill-defined thermodynamic limit. The extension is achieved by allowing the simulated particles to undergo random walks on a discretized domain, while stochastically controlling the length of each discretized compartment. Due to the dependence of diffusion on the domain discretization, we find that the description of diffusion cannot be uniquely derived. We apply these analytical methods to two justified descriptions, where it is shown that, under certain conditions, diffusion is able to support a consistent inhomogeneous state that is far removed from the deterministic equilibrium, without additional kinetics. Finally, a logistically growing domain is considered. Not only does this show that we can deal with nonmonotonic descriptions of stochastic growth, but it is also seen that diffusion on a stationary domain produces different effects to diffusion on a domain that is stationary “on average.

Stochastic reaction & diffusion on growing domains: understanding the breakdown of robust pattern formation

Many biological patterns, from population densities to animal coat markings, can be thought of as heterogeneous spatiotemporal distributions of mobile agents. Many mathematical models have been proposed to account for the emergence of this complexity, but, in general, they have consisted of deterministic systems of differential equations, which do not take into account the stochastic nature of population interactions. One particular, pertinent criticism of these deterministic systems is that the exhibited patterns can often be highly sensitive to changes in initial conditions, domain geometry, parameter values, etc. Due to this sensitivity, we seek to understand the effects of stochasticity and growth on paradigm biological patterning models. In this paper, we extend spatial Fourier analysis and growing domain mapping techniques to encompass stochastic Turing systems. Through this we find that the stochastic systems are able to realize much richer dynamics than their deterministic counterparts, in that patterns are able to exist outside the standard Turing parameter range. Further, it is seen that the inherent stochasticity in the reactions appears to be more important than the noise generated by growth, when considering which wave modes are excited. Finally, although growth is able to generate robust pattern sequences in the deterministic case, we see that stochastic effects destroy this mechanism for conferring robustness. However, through Fourier analysis we are able to suggest a reason behind this lack of robustness and identify possible mechanisms by which to reclaim it

Tumour angiogenesis: The gap between theory and experiment

A common experimental technique for viewing in vivo angiogenesis utilises tumours implanted into a test animal cornea. The cornea is avascular but the tumour promotes vascularisation from the limbus and the new blood vessels can be readily observed through the transparent cornea. Many of the early mathematical models for tumour angiogenesis used this scenario as their experimental template and as such assumed that there is a large gap, of the order of 2 mm, between the tumour and neighbouring vasculature at the onset of angiogenesis. In this work we consider whether the assumption that there is a significant gap between the tumour and neighbouring vasculature is unique to intra-cornea tumour implants, or whether this characterises avascular tumour growth more generally. To do this we utilise a simple scaling argument, derive a multi-compartment model for tumour growth, and consider in vivo images. This analysis demonstrates that the corneal implant experiments and the corresponding mathematical models cannot generally be applied to a clinical setting

A note on the effectiveness of selenium supplementation of Irish-grown Allium crops.

peer-reviewedThis study is funded by the Department of Agriculture and Food through the Network and Team Building Initiative of the Food Institutional Research Measure (FIRM Reference Number 06/NITARFC6).Onions and other Allium crops contain high levels of dietary phenolics and, unlike many other crops, accumulate the beneficial mineral selenium. Selenium-enhanced Allium crops are of interest both from a public good perspective and as a market positioning strategy for growers. Field trials were carried out to i) identify onion and scallion varieties that contain high levels of health-promoting phenolic and flavonoid compounds as potential targets for selenium supplementation and ii) investigate selenium supplementation in the widely-grown commercial onion variety ‘Hyskin’ at different application rates of nitrogen fertilizer. Levels of selenium in onion bulbs were significantly increased from 0.5–5.9 μg/g dry weight (DW) to 40.6–70.0 μg/g DW.Department of Agriculture, Food and the Marin