Intra-cardiac transfer of fatty acids from capillary to cardiomyocyte.

Blood-borne fatty acids (Fa) are important substrates for energy conversion in the mammalian heart. After release from plasma albumin, Fa traverse the endothelium and the interstitial compartment to cross the sarcolemma prior to oxidation in the cardiomyocytal mitochondria. The aims of the present study were to elucidate the site with lowest Fa permeability (i.

Equations for O and CO solubilities in saline and plasma: combining temperature and density dependences.

Solubilities of respiratory gasses in water, saline, and plasma decrease with rising temperatures and solute concentrations. Henry's Law, C = α·P, states that the equilibrium concentration of a dissolved gas is solubility times partial pressure. Solubilities in the water of a solution depend on temperature and the content of other solutes.

Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance.

Ageing and lifespan are strongly affected by metabolism. The maximal possible uptake of oxygen is not only a good predictor of performance in endurance sports, but also of life expectancy. Figuratively speaking, healthy ageing is a competitive sport.

The Pathway for Oxygen: Tutorial Modelling on Oxygen Transport from Air to Mitochondrion: The Pathway for Oxygen.

The 'Pathway for Oxygen' is captured in a set of models describing quantitative relationships between fluxes and driving forces for the flux of oxygen from the external air source to the mitochondrial sink at cytochrome oxidase. The intervening processes involve convection, membrane permeation, diffusion of free and heme-bound O2 and enzymatic reactions. While this system's basic elements are simple: ventilation, alveolar gas exchange with blood, circulation of the blood, perfusion of an organ, uptake by tissue, and consumption by chemical reaction, integration of these pieces quickly becomes complex.

Modeling Fatty Acid Transfer from Artery to Cardiomyocyte.

Despite the importance of oxidation of blood-borne long-chain fatty acids (Fa) in the cardiomyocytes for contractile energy of the heart, the mechanisms underlying the transfer of Fa from the coronary plasma to the cardiomyocyte is still incompletely understood. To obtain detailed insight into this transfer process, we designed a novel model of Fa transfer dynamics from coronary plasma through the endothelial cells and interstitium to the cardiomyocyte, applying standard physicochemical principles on diffusion and on the chemical equilibrium of Fa binding to carrier proteins Cp, like albumin in plasma and interstitium and Fatty Acid-Binding Proteins within endothelium and cardiomyocytes. Applying these principles, the present model strongly suggests that in the heart, binding and release of Fa to and from Cp in the aqueous border zones on both sides of the cell membranes form the major hindrance to Fa transfer.

Semi-automated Modular Program Constructor for physiological modeling: Building cell and organ models.

The Modular Program Constructor (MPC) is an open-source Java based modeling utility, built upon JSim's Mathematical Modeling Language (MML) ( http://www.physiome.org/jsim/) that uses directives embedded in model code to construct larger, more complicated models quickly and with less error than manually combining models.

Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy.

Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs.

Simple accurate mathematical models of blood HbO2 and HbCO2 dissociation curves at varied physiological conditions: evaluation and comparison with other models.

Purpose: Equations for blood oxyhemoglobin (HbO2) and carbaminohemoglobin (HbCO2) dissociation curves that incorporate nonlinear biochemical interactions of oxygen and carbon dioxide with hemoglobin (Hb), covering a wide range of physiological conditions, are crucial for a number of practical applications. These include the development of physiologically-based computational models of alveolar-blood and blood-tissue O2–CO2 transport, exchange, and metabolism, and the analysis of clinical and in vitro data.

Methods And Results: To this end, we have revisited, simplified, and extended our previous models of blood HbO2 and HbCO2 dissociation curves (Dash and Bassingthwaighte, Ann Biomed Eng 38:1683–1701, 2010), validated wherever possible by available experimental data, so that the models now accurately fit the low HbO2 saturation (SHbO2) range over a wide range of values of PCO2, pH, 2,3-DPG, and temperature.

Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance.

This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a "consilience" of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions.

JSim, an open-source modeling system for data analysis.

JSim is a simulation system for developing models, designing experiments, and evaluating hypotheses on physiological and pharmacological systems through the testing of model solutions against data. It is designed for interactive, iterative manipulation of the model code, handling of multiple data sets and parameter sets, and for making comparisons among different models running simultaneously or separately. Interactive use is supported by a large collection of graphical user interfaces for model writing and compilation diagnostics, defining input functions, model runs, selection of algorithms solving ordinary and partial differential equations, run-time multidimensional graphics, parameter optimization (8 methods), sensitivity analysis, and Monte Carlo simulation for defining confidence ranges.

Left ventricular finite element model bounded by a systemic circulation model.

A series of models were developed in which a circulatory system model was coupled to an existing series of finite element (FE) models of the left ventricle (LV). The circulatory models were used to provide realistic boundary conditions for the LV models. This was developed for the JSim analysis package and was composed of a systemic arterial, capillary, and venous system in a closed loop with a varying elastance LV and left atria to provide the driving pressures and flows matching those of the FE model.

SBML and CellML translation in antimony and JSim.

Motivation: The creation and exchange of biologically relevant models is of great interest to many researchers. When multiple standards are in use, models are more readily used and re-used if there exist robust translators between the various accepted formats.

Summary: Antimony 2.

Modeling serotonin uptake in the lung shows endothelial transporters dominate over cleft permeation.

A four-region (capillary plasma, endothelium, interstitial fluid, cell) multipath model was configured to describe the kinetics of blood-tissue exchange for small solutes in the lung, accounting for regional flow heterogeneity, permeation of cell membranes and through interendothelial clefts, and intracellular reactions. Serotonin uptake data from the Multiple indicator dilution "bolus sweep" experiments of Rickaby and coworkers (Rickaby DA, Linehan JH, Bronikowski TA, Dawson CA. J Appl Physiol 51: 405-414, 1981; Rickaby DA, Dawson CA, and Linehan JH.

Reexamining Michaelis-Menten enzyme kinetics for xanthine oxidase.

Abbreviated expressions for enzyme kinetic expressions, such as the Michaelis-Menten (M-M) equations, are based on the premise that enzyme concentrations are low compared with those of the substrate and product. When one does progress experiments, where the solute is consumed during conversion to form a series of products, the idealized conditions are violated. Here, we analyzed data of xanthine oxidase in vitro from Escribano et al.

Validation of an axially distributed model for quantification of myocardial blood flow using ¹³N-ammonia PET.

Background: Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary.

Compartmental modeling in the analysis of biological systems.

Compartmental models are composed of sets of interconnected mixing chambers or stirred tanks. Each component of the system is considered to be homogeneous, instantly mixed, with uniform concentration. The state variables are concentrations or molar amounts of chemical species.

Modeling to link regional myocardial work, metabolism and blood flows.

Given the mono-functional, highly coordinated processes of cardiac excitation and contraction, the observations that regional myocardial blood flows, rMBF, are broadly heterogeneous has provoked much attention, but a clear explanation has not emerged. In isolated and in vivo heart studies the total coronary flow is found to be proportional to the rate-pressure product (systolic mean blood pressure times heart rate), a measure of external cardiac work. The same relationship might be expected on a local basis: more work requires more flow.

Multiscale modeling and data integration in the virtual physiological rat project.

It has become increasingly evident that the descriptions of many complex diseases are only possible by taking into account multiple influences at different physiological scales. To do this with computational models often requires the integration of several models that have overlapping scales (genes to molecules, molecules to cells, cells to tissues). The Virtual Physiological Rat (VPR) Project, a National Institute of General Medical Sciences (NIGMS) funded National Center of Systems Biology, is tasked with mechanistically describing several complex diseases and is therefore identifying methods to facilitate the process of model integration across physiological scales.

Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs.

Large-scale models accounting for the processes supporting metabolism and function in an organ or tissue with a marked heterogeneity of flows and metabolic rates are computationally complex and tedious to compute. Their use in the analysis of data from positron emission tomography (PET) and magnetic resonance imaging (MRI) requires model reduction since the data are composed of concentration-time curves from hundreds of regions of interest (ROI) within the organ. Within each ROI, one must account for blood flow, intracapillary gradients in concentrations, transmembrane transport, and intracellular reactions.

Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels.

New mathematical model equations for O(2) and CO(2) saturations of hemoglobin (S(HbO)(2) and S(HbCO)(2) are developed here from the equilibrium binding of O(2) and CO(2) with hemoglobin inside RBCs. They are in the form of an invertible Hill-type equation with the apparent Hill coefficients KHbO(2) and KHbCO(2) in the expressions for SHbO(2) and SHbCO(2) dependent on the levels of O(2) and CO(2) partial pressures (P(O)(2) and P(CO)(2)), pH, 2,3-DPG concentration, and temperature in blood. The invertibility of these new equations allows PO(2) and PCO(2) to be computed efficiently from S(HbO)(2) and S(HbCO)(2) and vice versa.

Predictive Modeling and Integrative Physiology: The Physiome Projects.

The fundamental paradigm in physiological research is integration. Biological researchers are now ready to define for a species a mathematical construct, the Physiome, the all-encompassing quantitative model of an organism. The goal of the human Physiome project is improved health care, through deep understanding of the organism, all the way down to the genes, reconciling contradictions and clarifying cause and effect.

Quantitative imaging of coronary blood flow.

Positron emission tomography (PET) is a nuclear medicine imaging modality based on the administration of a positron-emitting radiotracer, the imaging of the distribution and kinetics of the tracer, and the interpretation of the physiological events and their meaning with respect to health and disease. PET imaging was introduced in the 1970s and numerous advances in radiotracers and detection systems have enabled this modality to address a wide variety of clinical tasks, such as the detection of cancer, staging of Alzheimer's disease, and assessment of coronary artery disease (CAD). This review provides a description of the logic and the logistics of the processes required for PET imaging and a discussion of its use in guiding the treatment of CAD.