Parametric Sensitivity Analysis of the Most Recent Computational Models of Rabbit Cardiac Pacemaking

The cellular basis of cardiac pacemaking activity, and specifically the quantitative contributions of particular mechanisms, is still debated. Reliable computational models of sinoatrial nodal (SAN) cells may provide mechanistic insights, but competing models are built from different data sets and with different underlying assumptions. To understand quantitative differences between alternative models, we performed thorough parameter sensitivity analyses of the SAN models of Maltsev & Lakatta (2009) and Severi et al (2012). Model parameters were randomized to generate a population of cell models with different properties, simulations performed with each set of random parameters generated 14 quantitative outputs that characterized cellular activity, and regression methods were used to analyze the population behavior. Clear differences between the two models were observed at every step of the analysis. Specifically: (1) SR Ca2+ pump activity had a greater effect on SAN cell cycle length (CL) in the Maltsev model; (2) conversely, parameters describing the funny current (If) had a greater effect on CL in the Severi model; (3) changes in rapid delayed rectifier conductance (GKr) had opposite effects on action potential amplitude in the two models; (4) within the population, a greater percentage of model cells failed to exhibit action potentials in the Maltsev model (27%) compared with the Severi model (7%), implying greater robustness in the latter; (5) confirming this initial impression, bifurcation analyses indicated that smaller relative changes in GKr or Na+-K+ pump activity led to failed action potentials in the Maltsev model. Overall, the results suggest experimental tests that can distinguish between models and alternative hypotheses, and the analysis offers strategies for developing anti-arrhythmic pharmaceuticals by predicting their effect on the pacemaking activity.

How can cells sense the elasticity of a substrate? An analysis using a cell tensegrity model

A eukaryotic cell attaches and spreads on substrates, whether it is the extracellular matrix naturally produced by the cell itself, or artificial materials, such as tissue-engineered scaffolds. Attachment and spreading require the cell to apply forces in the nN range to the substrate via adhesion sites, and these forces are balanced by the elastic response of the substrate. This mechanical interaction is one determinant of cell morphology and, ultimately, cell phenotype. In this paper we use a finite element model of a cell, with a tensegrity structure to model the cytoskeleton of actin filaments and microtubules, to explore the way cells sense the stiffness of the substrate and thereby adapt to it. To support the computational results, an analytical 1D model is developed for comparison. We find that (i) the tensegrity hypothesis of the cytoskeleton is sufficient to explain the matrix-elasticity sensing, (ii) cell sensitivity is not constant but has a bell-shaped distribution over the physiological matrix-elasticity range, and (iii) the position of the sensitivity peak over the matrix-elasticity range depends on the cytoskeletal structure and in particular on the F-actin organisation. Our model suggests that F-actin reorganisation observed in mesenchymal stem cells (MSCs) in response to change of matrix elasticity is a structural-remodelling process that shifts the sensitivity peak towards the new value of matrix elasticity. This finding discloses a potential regulatory role of scaffold stiffness for cell differentiation.

Sensitivity analysis of vehicle tripped rollover model. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Identifying the critical parameters of a cyanobacterial growth and movement model by using generalised sensitivity analysis

Bloom-forming and toxin-producing cyanobacteria remain a persistent nuisance across the world. Modelling of cyanobacteria in freshwaters is an important tool for understanding their population dynamics and predicting the location and timing of the bloom events in lakes and rivers. A new deterministic-mathematical model was developed, which simulates the growth and movement of cyanobacterial blooms in river systems. The model focuses on the mathematical description of the bloom formation, vertical migration and lateral transport of colonies within river environments by taking into account the major factors that affect the cyanobacterial bloom formation in rivers including, light, nutrients and temperature. A technique called generalised sensitivity analysis was applied to the model to identify the critical parameter uncertainties in the model and investigates the interaction between the chosen parameters of the model. The result of the analysis suggested that 8 out of 12 parameters were significant in obtaining the observed cyanobacterial behaviour in a simulation. It was found that there was a high degree of correlation between the half-saturation rate constants used in the model.

Nutrient-limited toxin production and the dynamics of two phytoplankton in culture media: a mathematical model

In this paper we have proposed and analyzed a simple mathematical model consisting of four variables, viz., nutrient concentration, toxin producing phytoplankton (TPP), non-toxic phytoplankton (NTP), and toxin concentration. Limitation in the concentration of the extracellular nutrient has been incorporated as an environmental stress condition for the plankton population, and the liberation of toxic chemicals has been described by a monotonic function of extracellular nutrient. The model is analyzed and simulated to reproduce the experimental findings of Graneli and Johansson [Graneli, E., Johansson, N., 2003. Increase in the production of allelopathic Prymnesium parvum cells grown under N- or P-deficient conditions. Harmful Algae 2, 135–145]. The robustness of the numerical experiments are tested by a formal parameter sensitivity analysis. As the first theoretical model consistent with the experiment of Graneli and Johansson (2003), our results demonstrate that, when nutrient-deficient conditions are favorable for the TPP population to release toxic chemicals, the TPP species control the bloom of other phytoplankton species which are non-toxic. Consistent with the observations made by Graneli and Johansson (2003), our model overcomes the limitation of not incorporating the effect of nutrient-limited toxic production in several other models developed on plankton dynamics.

Virus-sized colloid transport in a single pore: Model development and sensitivity analysis

A mathematical model is developed to simulate the transport and deposition of virus-sized colloids in a cylindrical pore throat considering various processes such as advection, diffusion, colloid-collector surface interactions and hydrodynamic wall effects. The pore space is divided into three different regions, namely, bulk, diffusion and potential regions, based on the dominant processes acting in each of these regions. In the bulk region, colloid transport is governed by advection and diffusion whereas in the diffusion region, colloid mobility due to diffusion is retarded by hydrodynamic wall effects. Colloid-collector interaction forces dominate the transport in the potential region where colloid deposition occurs. The governing equations are non-dimensionalized and solved numerically. A sensitivity analysis indicates that the virus-sized colloid transport and deposition is significantly affected by various pore-scale parameters such as the surface potentials on colloid and collector, ionic strength of the solution, flow velocity, pore size and colloid size. The adsorbed concentration and hence, the favorability of the surface for adsorption increases with: (i) decreasing magnitude and ratio of surface potentials on colloid and collector, (ii) increasing ionic strength and (iii) increasing pore radius. The adsorbed concentration increases with increasing Pe, reaching a maximum value at Pe = 0.1 and then decreases thereafter. Also, the colloid size significantly affects particle deposition with the adsorbed concentration increasing with increasing particle radius, reaching a maximum value at a particle radius of 100 nm and then decreasing with increasing radius. System hydrodynamics is found to have a greater effect on larger particles than on smaller ones. The secondary minimum contribution to particle deposition has been found to increase as the favorability of the surface for adsorption decreases. The sensitivity of the model to a given parameter will be high if the conditions are favorable for adsorption. The results agree qualitatively with the column-scale experimental observations available in the literature. The current model forms the building block in upscaling colloid transport from pore scale to Darcy scale using Pore-Network Modeling. (C) 2014 Elsevier By. All rights reserved.

Sensitivity analysis of a cyanobacterial growth and movement model under two different flow regimes

Bloom-forming and toxin-producing cyanobacteria remain a persistent nuisance across the world. Modelling cyanobacterial behaviour in freshwaters is an important tool for understanding their population dynamics and predicting the location and timing of the bloom events in lakes, reservoirs and rivers. A new deterministic–mathematical model was developed, which simulates the growth and movement of cyanobacterial blooms in river systems. The model focuses on the mathematical description of the bloom formation, vertical migration and lateral transport of colonies within river environments by taking into account the major factors that affect the cyanobacterial bloom formation in rivers including light, nutrients and temperature. A parameter sensitivity analysis using a one-at-a-time approach was carried out. There were two objectives of the sensitivity analysis presented in this paper: to identify the key parameters controlling the growth and movement patterns of cyanobacteria and to provide a means for model validation. The result of the analysis suggested that maximum growth rate and day length period were the most significant parameters in determining the population growth and colony depth, respectively.

Asymptotic stability of a mathematical model of cell population

We consider a simplified system of a growing colony of cells described as a free boundary problem. The system consists of two hyperbolic equations of first order coupled to an ODE to describe the behavior of the boundary. The system for cell populations includes non-local terms of integral type in the coefficients. By introducing a comparison with solutions of an ODE's system, we show that there exists a unique homogeneous steady state which is globally asymptotically stable for a range of parameters under the assumption of radially symmetric initial data.

Stability and sensitivity analysis of Be-CoDiS, an epidemiological model to predict the spread of human diseases between countries. Validation with data from the 2014-16 West African Ebola Virus Disease epidemic.

Ebola virus disease is a lethal human and primate disease that requires a particular attention from the international health authorities due to important recent outbreaks in some Western African countries and isolated cases in European and North-America continents. Regarding the emergency of this situation, various decision tools, such as mathematical models, were developed to assist the authorities to focus their efforts in important factors to eradicate Ebola. In a previous work, we have proposed an original deterministic spatial-temporal model, called Be-CoDiS (Between-Countries Disease Spread), to study the evolution of human diseases within and between countries by taking into consideration the movement of people between geographical areas. This model was validated by considering numerical experiments regarding the 2014-16 West African Ebola Virus Disease epidemic. In this article, we propose to perform a stability analysis of Be-CoDiS. Our first objective is to study the equilibrium states of simplified versions of this model, limited to the cases of one an two countries, and to determine their basic reproduction ratios. Then, in order to give some recommendations for the allocation of resources used to control the disease, we perform a sensitivity analysis of those basic reproduction ratios regarding the model parameters. Finally, we validate the obtained results by considering numerical experiments based on data from the 2014-16 West African Ebola Virus Disease epidemic.

A mathematical model of integrin-mediated haptotactic cell migration

Haptotactic cell migration, a directed response to gradients of cell—extracellular matrix adhesion, is an important process in a number of biological phenomena such as wound healing and tumour cell invasion. Previously, mathematical models of haptotaxis have been developed on the premise that cells migrate in response to gradients in the density of the extracellular matrix. In this paper, we develop a novel mathematical model of haptotaxis which includes the adhesion receptors known as integrins and a description of their functional activation, local recruitment and protrusion as part of lamellipodia. Through the inclusion of integrins, the modelled cell matter is able to respond to a true gradient of cell–matrix adhesion, represented by functionally active integrins. We also show that previous matrix-mediated models are in fact a subset of the novel integrin-mediated models, characterised by specific choices of diffusion and haptotaxis coefficients in their model equations. Numerical solutions suggest the existence of travelling waves of cell migration that are confirmed via a phase plane analysis of a simplified model.

Single diode model parameters analysis of photovoltaic cell

In this paper it is proposed to obtain enhanced and more efficient parameters model from generalized five parameters (single diode) model of PV cells. The paper also introduces, describes and implements a seven parameter model for photovoltaic cell (PV cell) which includes two internal parameters and five external parameters. To obtain the model the mathematical equations and an equivalent circuit consisting of a photo generated current source, a series resistor, a shunt resistor and a diode is used. The fundamental equation of PV cell is used to analyse and best fit the observation data. Especially bisection iteration method is used to obtain the expected result and to understand the deviation of changes in different parameters situation at various conditions respectively. The produced model can be used of measuring and understanding the actions of photovoltaic cells for certain changes and parameters extraction. The effect is also studied with I-V and P-V characteristics of PV cells though it is a challenge to optimize the output with real time simulation. The working procedure is also discussed and an experiment presented to get the closure and insight about the produced model and to decide upon the model validity. At the end, we observed that the result of the simulation is very close to the produced model.

Analytical modeling and sensitivity analysis for travel time estimation on signalized urban networks

This paper presents a model for estimation of average travel time and its variability on signalized urban networks using cumulative plots. The plots are generated based on the availability of data: a) case-D, for detector data only; b) case-DS, for detector data and signal timings; and c) case-DSS, for detector data, signal timings and saturation flow rate. The performance of the model for different degrees of saturation and different detector detection intervals is consistent for case-DSS and case-DS whereas, for case-D the performance is inconsistent. The sensitivity analysis of the model for case-D indicates that it is sensitive to detection interval and signal timings within the interval. When detection interval is integral multiple of signal cycle then it has low accuracy and low reliability. Whereas, for detection interval around 1.5 times signal cycle both accuracy and reliability are high.

Towards a model for the analysis and description of mathematical knowledge and understanding

Mathematics education literature has called for an abandonment of ontological and epistemological ideologies that have often divided theory-based practice. Instead, a consilience of theories has been sought which would leverage the strengths of each learning theory and so positively impact upon contemporary educational practice. This research activity is based upon Popper’s notion of three knowledge worlds which differentiates the knowledge shared in a community from the personal knowledge of the individual, and Bereiter’s characterisation of understanding as the individual’s relationship to tool-like knowledge. Using these notions, a re-conceptualisation of knowledge and understanding and a subsequent re-consideration of learning theories are proposed as a way to address the challenge set by literature. Referred to as the alternative theoretical framework, the proposed theory accounts for the scaffolded transformation of each individual’s unique understanding, whilst acknowledging the existence of a body of domain knowledge shared amongst participants in a scientific community of practice. The alternative theoretical framework is embodied within an operational model that is accompanied by a visual nomenclature with which to describe consensually developed shared knowledge and personal understanding. This research activity has sought to iteratively evaluate this proposed theory through the practical application of the operational model and visual nomenclature to the domain of early-number counting, addition and subtraction. This domain of mathematical knowledge has been comprehensively analysed and described. Through this process, the viability of the proposed theory as a tool with which to discuss and thus improve the knowledge and understanding with the domain of mathematics has been validated. Putting of the proposed theory into practice has lead to the theory’s refinement and the subsequent achievement of a solid theoretical base for the future development of educational tools to support teaching and learning practice, including computer-mediated learning environments. Such future activity, using the proposed theory, will advance contemporary mathematics educational practice by bringing together the strengths of cognitivist, constructivist and post-constructivist learning theories.