RESUMEN
Dermal exposure to metal allergens can lead to irritant and allergic contact dermatitis (ACD). In this paper we present a mathematical model of the absorption of metal ions, hexavalent chromium and nickel, into the viable epidermis and compare the localised irritant and T-lymphocyte (T-cell) mediated immune responses. The model accounts for the spatial-temporal variation of skin health, extra and intracellular allergen concentrations, innate immune cells, T-cells, cytokine signalling and lymph node activity up to about 6 days after contact with these metals; repair processes associated with withdrawal of exposure to both metals is not considered in the current model, being assumed secondary during the initial phases of exposure. Simulations of the resulting system of PDEs are studied in one-dimension, i.e. across skin depth, and three-dimensional scenarios with the aim of comparing the responses to the two ions in the cases of first contact (no T-cells initially present) and second contact (T-cells initially present). The results show that on continuous contact, chromium ions elicit stronger skin inflammation, but for nickel, subsequent re-exposure stimulates stronger responses due to an accumulation of cytotoxic T-cell mediated responses which characterise ACD. Furthermore, the surface area of contact to these metals has little effect on the speed of response, whilst sensitivity is predicted to increase with the thickness of skin. The modelling approach is generic and should be applicable to describe contact dermatitis from a wide range of allergens.
Asunto(s)
Alérgenos/inmunología , Cromo/inmunología , Dermatitis Alérgica por Contacto/inmunología , Modelos Biológicos , Níquel/inmunología , Simulación por Computador , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inmunidad Innata , Piel/citología , Piel/inmunología , Piel/metabolismo , Análisis Espacio-Temporal , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismoRESUMEN
The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time.
Asunto(s)
Western Blotting/métodos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfolipasa C gamma/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Plaquetas/citología , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Western Blotting/instrumentación , Proteínas Portadoras/farmacología , Humanos , Inmunoprecipitación , Péptidos/farmacología , Fosforilación , Activación Plaquetaria/efectos de los fármacos , Cultivo Primario de Células , Quinasa SykRESUMEN
The chemotaxis pathway of Escherichia coli is one of the best studied and modelled biological signalling pathways. Here we extend existing modelling approaches by explicitly including a description of the formation and subcellular localization of intermediary complexes in the phosphotransfer pathway. The inclusion of these complexes shows that only about 60% of the total output response regulator (CheY) is uncomplexed at any moment and hence free to interact with its target, the flagellar motor. A clear strength of this model is its ability to predict the experimentally observable subcellular localization of CheY throughout a chemotactic response. We have found good agreement between the model output and experimentally determined CheY localization patterns.
Asunto(s)
Proteínas Bacterianas/metabolismo , Quimiotaxis , Escherichia coli/citología , Escherichia coli/metabolismo , Proteínas de la Membrana/metabolismo , Modelos Biológicos , Escherichia coli/genética , Proteínas de Escherichia coli , Regulación Bacteriana de la Expresión Génica , Proteínas Quimiotácticas Aceptoras de Metilo , Fosforilación , Factores de TiempoRESUMEN
A mathematical model describing the uptake of low density lipoprotein (LDL) and very low density lipoprotein (VLDL) particles by a single hepatocyte cell is formulated and solved. The model includes a description of the dynamic change in receptor density on the surface of the cell due to the binding and dissociation of the lipoprotein particles, the subsequent internalisation of bound particles, receptors and unbound receptors, the recycling of receptors to the cell surface, cholesterol dependent de novo receptor formation by the cell and the effect that particle uptake has on the cell's overall cholesterol content. The effect that blocking access to LDL receptors by VLDL, or internalisation of VLDL particles containing different amounts of apolipoprotein E (we will refer to these particles as VLDL-2 and VLDL-3) has on LDL uptake is explored. By comparison with experimental data we find that measures of cell cholesterol content are important in differentiating between the mechanisms by which VLDL is thought to inhibit LDL uptake. We extend our work to show that in the presence of both types of VLDL particle (VLDL-2 and VLDL-3), measuring relative LDL uptake does not allow differentiation between the results of blocking and internalisation of each VLDL particle to be made. Instead by considering the intracellular cholesterol content it is found that internalisation of VLDL-2 and VLDL-3 leads to the highest intracellular cholesterol concentration. A sensitivity analysis of the model reveals that binding, unbinding and internalisation rates, the fraction of receptors recycled and the rate at which the cholesterol dependent free receptors are created by the cell have important implications for the overall uptake dynamics of either VLDL or LDL particles and subsequent intracellular cholesterol concentration.
Asunto(s)
Hepatocitos/metabolismo , Lipoproteínas LDL/metabolismo , Modelos Biológicos , Receptores de LDL/metabolismo , Animales , Apolipoproteínas E/metabolismo , Unión Competitiva , Colesterol/metabolismo , Endocitosis/fisiología , Lipoproteínas VLDL/metabolismoRESUMEN
A mathematical model is presented to understand heat transfer processes during the cooling and re-warming of patients during cardiac surgery. Our compartmental model is able to account for many of the qualitative features observed in the cooling of various regions of the body including the central core containing the majority of organs, the rectal region containing the intestines and the outer peripheral region of skin and muscle. In particular, we focus on the issue of afterdrop: a drop in core temperature following patient re-warming, which can lead to serious post-operative complications. Model results for a typical cooling and re-warming procedure during surgery are in qualitative agreement with experimental data in producing the afterdrop effect and the observed dynamical variation in temperature between the core, rectal and peripheral regions. The influence of heat transfer processes and the volume of each compartmental region on the afterdrop effect is discussed. We find that excess fat on the peripheral and rectal regions leads to an increase in the afterdrop effect. Our model predicts that, by allowing constant re-warming after the core temperature has been raised, the afterdrop effect will be reduced.
Asunto(s)
Regulación de la Temperatura Corporal/fisiología , Puente Cardiopulmonar/métodos , Modelos Biológicos , Humanos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & controlRESUMEN
We review the application of mathematical modeling to understanding the behavior of populations of chemotactic bacteria. The application of continuum mathematical models, in particular generalized Keller-Segel models, is discussed along with attempts to incorporate the microscale (individual) behavior on the macroscale, modeling the interaction between different species of bacteria, the interaction of bacteria with their environment, and methods used to obtain experimentally verified parameter values. We allude briefly to the role of modeling pattern formation in understanding collective behavior within bacterial populations. Various aspects of each model are discussed and areas for possible future research are postulated.
Asunto(s)
Fenómenos Fisiológicos Bacterianos , Quimiotaxis/fisiología , Modelos Biológicos , Algoritmos , Biodiversidad , Ecosistema , Ambiente , Escherichia coli/crecimiento & desarrollo , Escherichia coli/fisiologíaRESUMEN
Mathematical modeling of bacterial chemotaxis systems has been influential and insightful in helping to understand experimental observations. We provide here a comprehensive overview of the range of mathematical approaches used for modeling, within a single bacterium, chemotactic processes caused by changes to external gradients in its environment. Specific areas of the bacterial system which have been studied and modeled are discussed in detail, including the modeling of adaptation in response to attractant gradients, the intracellular phosphorylation cascade, membrane receptor clustering, and spatial modeling of intracellular protein signal transduction. The importance of producing robust models that address adaptation, gain, and sensitivity are also discussed. This review highlights that while mathematical modeling has aided in understanding bacterial chemotaxis on the individual cell scale and guiding experimental design, no single model succeeds in robustly describing all of the basic elements of the cell. We conclude by discussing the importance of this and the future of modeling in this area.
Asunto(s)
Fenómenos Fisiológicos Bacterianos , Quimiotaxis/fisiología , Modelos Biológicos , Algoritmos , Escherichia coli/citología , Escherichia coli/fisiología , Transducción de Señal/fisiologíaRESUMEN
A mathematical model describing the main mechanistic processes involved in keratinocyte response to chromium and nickel has been developed and compared to experimental in vitro data. Accounting for the interactions between the metal ions and the keratinocytes, the law of mass action was used to generate ordinary differential equations which predict the time evolution and ion concentration dependency of keratinocyte viability, the amount of metal associated with the keratinocytes and the release of cytokines by the keratinocytes. Good agreement between model predictions and existing experimental data of these endpoints was observed, supporting the use of this model to explore physiochemical parameters that influence the toxicological response of keratinocytes to these two metals.
Asunto(s)
Cromo/toxicidad , Queratinocitos/efectos de los fármacos , Modelos Teóricos , Níquel/toxicidad , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Dermatitis por Contacto/etiología , Humanos , Queratinocitos/metabolismo , Exposición ProfesionalRESUMEN
The mechanisms underlying the formation of necrotic regions within avascular tumours are not well understood. In this paper, we examine the relative roles of nutrient deprivation and of cell death, from both the proliferating phase of the cell cycle via apoptosis and from the quiescent phase via necrosis, in changing the structure within multicellular tumour spheroids and particularly the accumulation of dead cell material in the centre. A mathematical model is presented and studied that accounts for nutrient diffusion, changes in cell cycling rates, the two different routes to cell death as well as active motion of cells and passive motion of the dead cell material. In studying the accumulation of dead cell matter we do not distinguish between the route by which each was formed. The resulting mathematical model is examined for a number of scenarios. Results show that in many cases the size of the necrotic core is closely correlated with low levels in nutrient concentration. However, in certain cases, particularly where the rate of necrosis is large, the resulting necrotic core can lead to regions of non-negligible nutrient concentration-dependent upon the mode of cell death.
Asunto(s)
Apoptosis , Modelos Biológicos , Neoplasias/patología , Algoritmos , Animales , Recuento de Células , Ciclo Celular/fisiología , Movimiento Celular , Proliferación Celular , Humanos , Cinética , Necrosis , Neoplasias/metabolismo , Neoplasias/fisiopatología , Esferoides Celulares/metabolismo , Esferoides Celulares/patologíaRESUMEN
This paper analyses a recent mathematical model of avascular tumour spheroid growth which accounts for both cell cycle dynamics and chemotactic driven cell movement. The model considers cells to exist in one of two compartments: proliferating and quiescent, as well as accounting for necrosis and apoptosis. One particular focus of this paper is the behaviour created when proliferating and quiescent cells have different chemotactic responses to an extracellular nutrient supply. Two very different steady-state behaviours are identified corresponding to those cases where proliferating cells move either more quickly or more slowly than quiescent cells in response to a gradient in the extracellular nutrient supply. The case where proliferating cells move more rapidly leads to the commonly accepted spheroid structure of a thin layer of proliferating cells surrounding an inner quiescent core. In the case where proliferating cells move more slowly than quiescent cells the model predicts an interesting structure of a thin layer of quiescent cells surrounding an inner core of proliferating and quiescent cells. The sensitivity of this tumour structure to the cell cycle model parameters is also discussed. In particular variations in the steady-state size of the tumour and the types of transient behaviour are explored. The model reveals interesting transient behaviour with sharply delineated regions of proliferating and quiescent cells.
Asunto(s)
Ciclo Celular/fisiología , Movimiento Celular/fisiología , Modelos Biológicos , Neoplasias/patología , Procesos de Crecimiento Celular/fisiología , Quimiotaxis , Análisis Numérico Asistido por Computador , Esferoides CelularesRESUMEN
We present a model for the regulation of the G(1)/S transition by cell growth in budding yeast. The model includes a description of cell size, the extracellular nutrient concentration and a simplified model of the G(1)/S transition as originally reported by Chen et al. [Mol. Biol. Cell 11:369-391, 2000]. By considering cell growth proportional to cell size we show that the cell grows exponentially. In the case where cell growth is considered proportional to the concentration of a sizer protein within the cell, our model exhibits both exponential and linear cell growth for varying parameter values. The effects of varying nutrient concentration and initial cell size are considered in the context of whether progression through the cell-size checkpoint occurs. We consider our results in relation to recent experimental evidence and discuss possible experiments for testing our theoretical predictions.
Asunto(s)
Fase G1/fisiología , Modelos Biológicos , Fase S/fisiología , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/crecimiento & desarrollo , Simulación por Computador , Saccharomyces cerevisiae/metabolismoRESUMEN
A mathematical model is proposed to explain the observed internalization of microspheres and 3H-thymidine labelled cells in steady-state multicellular spheroids. The model uses the conventional ideas of nutrient diffusion and consumption by the cells. In addition, a very simple model of the progress of the cells through the cell cycle is considered. Cells are divided into two classes, those proliferating (being in G1, S, G2 or M phases) and those that are quiescent (being in G0). Furthermore, the two categories are presumed to have different chemotactic responses to the nutrient gradient. The model accounts for the spatial and temporal variations in the cell categories together with mitosis, conversion between categories and cell death. Numerical solutions demonstrate that the model predicts the behavior similar to existing models but has some novel effects. It allows for spheroids to approach a steady-state size in a non-monotonic manner, it predicts self-sorting of the cell classes to produce a thin layer of rapidly proliferating cells near the outer surface and significant numbers of cells within the spheroid stalled in a proliferating state. The model predicts that overall tumor growth is not only determined by proliferation rates but also by the ability of cells to convert readily between the classes. Moreover, the steady-state structure of the spheroid indicates that if the outer layers are removed then the tumor grows quickly by recruiting cells stalled in a proliferating state. Questions are raised about the chemotactic response of cells in differing phases and to the dependency of cell cycle rates to nutrient levels.