A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.

Cystic fibrosis (CF) is a genetic disease caused by the mutations of cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibrosis transmembrane conductance regulator gene. Cftr is a critical ion channel expressed in the apical membrane of mouse salivary gland striated duct cells. Although Cftr is primarily a Cl- channel, its knockout leads to higher salivary Cl- and Na+ concentrations and lower pH. Mouse experiments show that the activation of Cftr upregulates epithelial Na+ channel (ENaC) protein expression level and Slc26a6 (a 1Cl-:2[Formula: see text] exchanger of the solute carrier family) activity. Experimentally, it is difficult to predict how much the coregulation effects of CFTR contribute to the abnormal Na+, Cl-, and [Formula: see text] concentrations and pH in CF saliva. To address this question, we construct a wild-type mouse salivary gland model and simulate CFTR knockout by altering the expression levels of CFTR, ENaC, and Slc26a6. By reproducing the in vivo and ex vivo final saliva measurements from wild-type and CFTR knockout animals, we obtain computational evidence that ENaC and Slc26a6 activities are downregulated in CFTR knockout in salivary glands.NEW & NOTEWORTHY This paper describes a salivary gland mathematical model simulating the ion exchange between saliva and the salivary gland duct epithelium. The novelty lies in the implementation of CFTR regulating ENaC and Slc26a6 in a CFTR knockout gland. By reproducing the experimental saliva measurements in wild-type and CFTR knockout glands, the model shows that CFTR regulates ENaC and Slc26a6 anion exchanger in salivary glands. The method could be used to understand the various cystic fibrosis phenotypes.

MRI Derived Simulations of Flow Patterns in the Stomach.

A framework to simulate the flow in the stomach using subject-specific motility patterns and geometries was developed. Dynamic 2D magnetic resonance images (MRIs) were obtained. Motility parameters such as contraction speed and occlusion were quantified, and 3D stomach geometries were reconstructed using a semi-automated approach. Computational fluid dynamics (CFD) simulations were performed, and flow patterns were investigated. The stomach of both subjects had distinct anatomical features with computed volumes of 789 mL and 619 mL. For the one subject, the occlusion (i.e., normalized contraction size) was 12% while it was around 25% for the other subject. Contraction speeds were also different (1.9-2.8 mm/s vs 3.0-5.1 mm/s) for each subject. CFD simulations resulted in unsteady laminar flow for both subjects with average velocities of 2.1 and 3.2 mm/s. While antegrade flow was mainly observed in the simulations, a retropulsive jet was also present in both stomachs. The versatile framework developed within this study would allow the generation of CFD models of gastric motility from dynamic MRIs.Clinical Relevance- Subject-specific models of flow patterns informed by gastric motility features can elucidate the impact of contractions and anatomical variations on digestion. Such models can inform therapies to treat gastric dysfunctions and improve their efficacy.

In silico prediction of e-cigarette aerosol particle transport and deposition within the airways.

Electronic cigarettes (ECs) generate aerosols by heating up a liquid ('e-liquid') that typically consists of propylene glycol (PG), vegetable glycerol (VG), nicotine and flavouring agents. These aerosols transport through the airway tree, and lung and deposit non-uniformly in the bronchi and alveoli. Studying the transport of aerosols through lung airways is necessary because it provides information about the concentration and deposition of particles in the upper and lower airways. Here, particle transport and deposition were simulated within an anatomically-realistic airway model, which was constructed from computed tomography imaging. Particle transport was simulated using the advection-diffusion equations. Particle deposition was estimated using three different mechanisms; including sedimentation, impaction and Brownian diffusion. Results show that by increasing the particle size (PS) from 50 nm to 500 nm, the total deposition efficiency decreased from 50% to 10%, and then by increasing the PS to 3 µm, it increased to 60%. In addition, Brownian deposition was the dominant mechanism for nanoparticles (PS≪0.5µm), while the sedimentation deposition mechanism was the dominant one for microparticles (PS≫0.5µm).Clinical relevance-There is an urgent need to understand the risk that ECs pose to human health and to determine the safest methods for using these devices to support smoking cessation whilst also minimising harm. The results of this study will be used to simulate the conditions such as aerosol concentration and flow rate in airways and alveoli to use in in vitro studies.

Landmark-free Shape Analysis of the Human Duodenum.

The primary function of the duodenum is to undertake chemical digestion by ensuring that the partially digested food received from the stomach is well-mixed with the enzymes and chemicals secreted into it. However, little is known about the anatomical variations in the shape of the duodenum within humans, and thus the effect of duodenum shape on the flow and mixing occurring within the lumen has not been studied. In this work, a methodology for analyzing shape variations in the normal duodenal anatomy has been developed and applied to a publicly available dataset of abdominal CT images. This method does not require the placement of landmarks as it is based on the underlying tubular 'C' shape of the duodenum. The average duodenal length and radius of this dataset (consisting of 34 subjects) were 212.8 ± 38 mm and 10.8 ± 2.5 mm respectively. A Principal Component Analysis (PCA) was conducted on a sample of 34 duodenums after normalizing their lengths and the first five principal components were found to contribute to 82 % of the total variation. The first shape component (accounting for 42 % of overall variation) consisted of variations in the radius along the duodenum with no deformations normal to the central plane, and the subsequent shape modes consisted of twists in the centerline either in and out of the central plane, and radial variations at either the inlet or outlet. This is the first study to analyze shape variations in the human duodenum and the results can be combined with flow modeling to analyze the effect of shape on the flow and mixing occurring within the duodenum.Clinical relevance- The methods developed in this study can be used by clinicians to diagnose abnormalities in an individual's duodenum shape.

Quantification of the Regional Properties of Gastric Motility Using Dynamic Magnetic Resonance Images.

Goal: To quantify the regional properties of gastric motility from free-breathing dynamic MRI data. Methods: Free-breathing MRI scans were performed on 10 healthy human subjects. Motion correction was applied to reduce the respiratory effect. A stomach centerline was automatically generated and used as a reference axis. Contractions were quantified and visualized as spatio-temporal contraction maps. Gastric motility properties were reported separately for the lesser and greater curvatures in the proximal and distal regions of the stomach. Results: Motility properties varied in different regions of the stomach. The mean contraction frequencies for the lesser and greater curvatures were both 3.1±0.4 cycles per minute. The contraction speed was significantly higher on the greater curvature than the lesser curvature (3.5±0.7 vs 2.5±0.4 mm/s, p<0.001) while contraction size on both curvatures was comparable (4.9±1.2 vs 5.7±2.4 mm, p = 0.326). The mean gastric motility index was significantly higher in the distal greater curvature (28.13±18.89 mm2/s) compared to the other regions of the stomach (11.16-14.12 mm2/s). Conclusions: The results showed the effectiveness of the proposed method for visualization and quantification of motility patterns from MRI data.

Likelihood-based estimation and prediction for a measles outbreak in Samoa.

Prediction of the progression of an infectious disease outbreak is important for planning and coordinating a response. Differential equations are often used to model an epidemic outbreak's behaviour but are challenging to parameterise. Furthermore, these models can suffer from misspecification, which biases predictions and parameter estimates. Stochastic models can help with misspecification but are even more expensive to simulate and perform inference with. Here, we develop an explicitly likelihood-based variation of the generalised profiling method as a tool for prediction and inference under model misspecification. Our approach allows us to carry out identifiability analysis and uncertainty quantification using profile likelihood-based methods without the need for marginalisation. We provide justification for this approach by introducing a new interpretation of the model approximation component as a stochastic constraint. This preserves the rationale for using profiling rather than integration to remove nuisance parameters while also providing a link back to stochastic models. We applied an initial version of this method during an outbreak of measles in Samoa in 2019-2020 and found that it achieved relatively fast, accurate predictions. Here we present the most recent version of our method and its application to this measles outbreak, along with additional validation.

Simulation of Calcium Dynamics in Realistic Three-Dimensional Domains.

The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often critical. In a salivary gland acinar cell, a polarised epithelial cell, whose principal function is to transport water and thus secrete saliva, [Ca2+] controls the secretion of primary saliva, but increases in [Ca2+] are localised to the apical regions of the cell. Hence, any quantitative explanation of how [Ca2+] controls saliva secretion must take into careful account the spatial distribution of the various Ca2+ sources, Ca2+ sinks, and Ca2+-sensitive ion channels. Based on optical slices, we have previously constructed anatomically accurate three-dimensional models of seven salivary gland acinar cells, and thus shown that a model in which Ca2+ responses are confined to the apical regions of the cell is sufficient to provide a quantitative and predictive explanation of primary saliva secretion. However, reconstruction of such anatomically accurate cells is extremely time consuming and inefficient. Here, we present an alternative, mostly automated method of constructing three-dimensional cells that are approximately anatomically accurate and show that the new construction preserves the quantitative accuracy of the model.

A Mathematical Model of Salivary Gland Duct Cells.

Saliva is produced in two stages in the salivary glands: the secretion of primary saliva by the acinus and the modification of saliva composition to final saliva by the intercalated and striated ducts. In order to understand the saliva modification process, we develop a mathematical model for the salivary gland duct. The model utilises the realistic 3D structure of the duct reconstructed from an image stack of gland tissue. Immunostaining results show that TMEM16A and aquaporin are expressed in the intercalated duct cells and that ENaC is not. Based on this, the model predicts that the intercalated duct does not absorb Na[Formula: see text] and Cl[Formula: see text] like the striated duct but secretes a small amount of water instead. The input to the duct model is the time-dependent primary saliva generated by an acinar cell model. Our duct model produces final saliva output that agrees with the experimental measurements at various stimulation levels. It also shows realistic biological features such as duct cell volume, cellular concentrations and membrane potentials. Simplification of the model by omission of all detailed 3D structures of the duct makes a negligible difference to the final saliva output. This shows that saliva production is not sensitive to structural variation of the duct.

Development of closed-loop modelling framework for adaptive respiratory pacemakers.

OBJECTIVE: Ventilatory pacing by electrical stimulation of the phrenic nerve has many advantages compared to mechanical ventilation. However, commercially available respiratory pacing devices operate in an open-loop fashion, which require manual adjustment of stimulation parameters for a given patient. Here, we report the model development of a closed-loop respiratory pacemaker, which can automatically adapt to various pathological ventilation conditions and metabolic demands. METHODS: To assist the model design, we have personalized a computational lung model, which incorporates the mechanics of ventilation and gas exchange. The model can respond to the device stimulation where the gas exchange model provides biofeedback signals to the device. We use a pacing device model with a proportional integral (PI) controller to illustrate our approach. RESULTS: The closed-loop adaptive pacing model can provide superior treatment compared to open-loop operation. The adaptive pacing stimuli can maintain physiological oxygen levels in the blood under various simulated breathing disorders and metabolic demands. CONCLUSION: We demonstrate that the respiratory pacing devices with the biofeedback can adapt to individual needs, while the lung model can be used to validate and parametrize the device. SIGNIFICANCE: The closed-loop model-based framework paves the way towards an individualized and autonomous respiratory pacing device development.

Quantification of Gastric Contractions Using MRI with a Natural Contrast Agent.

Gastric motility has an essential role in mixing and the breakdown of ingested food. It can affect the digestion process and the efficacy of the orally administered drugs. There are several methods to image, measure, and quantify gastric motility. MRI has been shown to be a suitable non-invasive method for gastric motility imaging. However, in most studies, gadolinium-based agents have been used as an oral contrast agent, making it less desirable for general usage. In this study, MRI scans were performed on 4 healthy volunteers, where pineapple juice was used as a natural contrast agent for imaging gastric motility. A novel method was developed to automatically estimate a curved centerline of the stomach. The centerline was used as a reference to quantify contraction magnitudes. The results were visualized as contraction magnitude-maps. The mean speed of each contraction wave on the lesser and greater curvatures of the stomach was calculated, and the variation of the speeds in 4 regions of the stomach were quantified. There were 3-4 contraction waves simultaneously present in the stomach for all cases. The mean speed of all contractions was 2.4±0.9 mm/s, and was in agreement with previous gastric motility studies. The propagation speed of the contractions in the greater curvature was higher in comparison to the lesser curvature (2.9±0.8 vs 1.9±0.5 mm/s); however, the speeds were more similar near to the pylorus. This study shows the feasibility of using pineapple juice as a natural oral contrast agent for the MRI measurements of gastric motility. Also, it demonstrated the viability of the proposed method for automatic curved centerline estimation, which enables practical clinical translation.Clinical Relevance- MRI is able to non-invasively provide dynamic images of the contraction patterns of the stomach, providing a novel clinical tool for assessing functional motility disorders. The use of a natural oral contrast agent such as pineapple juice, as opposed to a gadolinium-based contrast agent, makes MRI more widely accessible. Our semi-automated methods for quantifying contraction magnitude and speed will streamline analysis and clinical diagnosis.

Computational Modelling of Glucose Uptake by SGLT1 and Apical GLUT2 in the Enterocyte.

It has been suggested that glucose absorption in the small intestine depends on both constitutively expressed SGLT1 and translocated GLUT2 in the brush border membrane, especially in the presence of high levels of luminal glucose. Here, we present a computational model of non-isotonic glucose uptake by small intestinal epithelial cells. The model incorporates apical uptake via SGLT1 and GLUT2, basolateral efflux into the blood via GLUT2, and cellular volume changes in response to non-isotonic conditions. The dependence of glucose absorption on luminal glucose, blood flow rate, and inlet blood glucose concentration is studied. Uptake via apical GLUT2 is found to be sensitive to all these factors. Under a range of conditions, the maximum apical GLUT2 flux is about half of the SGLT1 flux and is achieved at high luminal glucose (> 50 mM), high blood flow rates, and low inlet blood concentrations. In contrast, SGLT1 flux is less sensitive to these factors. When luminal glucose concentration is less than 10 mM, apical GLUT2 serves as an efflux pathway for glucose to move from the blood to the lumen. The model results indicate that translocation of GLUT2 from the basolateral to the apical membrane increases glucose uptake into the cell; however, the reduction of efflux capacity results in a decrease in net absorption. Recruitment of GLUT2 from a cytosolic pool elicits a 10-20% increase in absorption for luminal glucose levels in the a 20-100 mM range. Increased SGLT1 activity also leads to a roughly 20% increase in absorption. A concomitant increase in blood supply results in a larger increase in absorption. Increases in apical glucose transporter activity help to minimise cell volume changes by reducing the osmotic gradient between the cell and the lumen.

Permeability Properties of an In Vitro Model of the Alveolar Epithelium.

Cell culture models of epithelial barriers in the body are widely used to study the permeation of nutrients, drugs, infectious agents and pollutants into the body tissues and circulation. The NCI-H441 cell line cultured at the air-liquid interface mimics certain phenotypic and functional characteristics of the human alveolar epithelium. Here the permeability properties of the NCI-H441 model were characterised and compared against published data using experimental measurements and mathematical modelling. Cells were cultured under air-liquid interface conditions and trans-epithelial electrical resistance (TEER) and apparent permeability (P app) to sodium fluorescein (MW 383 Da) and fluorescently labelled dextrans (MW 4000-150,000 Da) was measured. It was found that TEER was independent of cell seeding density while P app decreased with higher seeding density and plateaued beyond a density of 500,000 cells/cm2. Using the framework of functional pore analysis, a mathematical model was fitted to P app values measured in this work as well as previously published datasets from human cell lines and primary human and rat cells. It was found that the air-liquid interface NCI-H441 model most closely matched the primary cell line results in contrast to published data using A549 and liquid-interface NCI-H441 cell cultures, supporting the use of this model to study the permeability of the alveolar epithelium to large molecules.

Peristaltic flow in the glymphatic system.

The flow inside the perivascular space (PVS) is modeled using a first-principles approach in order to investigate how the cerebrospinal fluid (CSF) enters the brain through a permeable layer of glial cells. Lubrication theory is employed to deal with the flow in the thin annular gap of the perivascular space between an impermeable artery and the brain tissue. The artery has an imposed peristaltic deformation and the deformable brain tissue is modeled by means of an elastic Hooke's law. The perivascular flow model is solved numerically, discovering that the peristaltic wave induces a steady streaming to/from the brain which strongly depends on the rigidity and the permeability of the brain tissue. A detailed quantification of the through flow across the glial boundary is obtained for a large parameter space of physiologically relevant conditions. The parameters include the elasticity and permeability of the brain, the curvature of the artery, its length and the amplitude of the peristaltic wave. A steady streaming component of the through flow due to the peristaltic wave is characterized by an in-depth physical analysis and the velocity across the glial layer is found to flow from and to the PVS, depending on the elasticity and permeability of the brain. The through CSF flow velocity is quantified to be of the order of micrometers per seconds.

A Novel Method for Time-Dependent Numerical Modeling of Gastric Motility Directly from Magnetic Resonance Imaging.

Gastric motility has a critical role in disintegration and mixing of the ingested food inside the stomach. Several studies have been conducted to quantify and analyze the effect of the contractions of gastric musculature on the stomach contents. Despite the anatomical variation in stomach shape and motility patterns, previous numerical studies employed generalized geometries of the stomach as the computational domain for simulations. To model realistic gastric muscular contractions, the variation in stomach geometries need to be accounted for in numerical simulations. In the current study, a novel method was developed to utilize the recent advances in magnetic resonance imaging (MRI) technology and computational power expansion to build anatomically and physiologically realistic subject specific models of human gastric motility. In this method, MRI scans of the stomach were used to construct two and three dimensional geometry models of gastric motility. MRI was performed on 4 healthy participants. Using the developed method, dynamic numerical geometry models of gastric motility for each participant were constructed and related geometrical calculations were presented. Different combinations of solid and liquid test meals were consumed prior to the scans. The volume of the stomach ranged between 0.36 - 1.10 L in the fed state. The stomach models had an average length of 184 to 226 mm and a maximum diameter of 65 to 102 mm. Contraction propagation speed calculated from the models and MRI data were in good agreement, measuring around 2 mm/s.Clinical relevance- Clinicians can benefit from the proposed method for diagnostic purposes as the method is semi-automatic and can provide dynamic three-dimensional visualization of gastric motility of patients.

Modelling Flow and Mixing in the Proximal Small Intestine.

The small intestine is the primary site of enzymatic digestion and nutrient absorption in humans. Intestinal contractions facilitate digesta mixing, transport and contact with the absorptive surfaces. These motility patterns are regulated by an underlying electrical activity, termed slow waves. In this study, we use computational fluid dynamics simulation of flow and mixing of intestinal contents in the human duodenum with anatomically realistic geometry and contraction patterns. Parameters including the amplitude of contraction (10-50% reduction of radius) and the rheology of the digesta (Newtonian vs Non-Newtonian power law fluid) were altered in-order to study their effects on mixing. Interesting flow features such as stagnation points and reversed flow were observed with digesta. Increases in the amplitude of contraction lead to increased propulsion of digesta along the intestine and increased mixing.

Make it simple: long-term stable gradient generation in a microfluidic microdevice.

Microfluidics-based gradient generators have been used for various biological applications, specifically chemotaxis in cell culture. However, the ability to generate and maintain long term gradients alongside the ability to quickly switch solutions is a challenge of the current microfabricated systems. In this study, a simple flow-driven microfluidic system was developed to achieve long-term stable concentration gradients. Computational modelling was performed to highlight the fluid dynamics as well as to verify the ability of maintaining stable gradients over 7 days. Numerical simulation was analysed to evaluate the static pressure, velocity magnitude and wall shear stress distribution in the chamber. A microdevice fabricated with polydimethylsiloxane (PDMS), using a standard soft lithography technique is presented. It consists of eight parallel microchannels (5 µm × 30 µm × 1,800 µm) linking source and sink chambers; a syringe pump drives fluid through the sink chamber, advection/diffusion from source to sink establishes a gradient. A gradient of a fluorescent dye was generated under the low flow control at 1-10 µl/h of a simple syringe pump equipped with a pulsation damper that was comparable to a pulseless microfluidic pump. Concentration gradients were formed in 1 h and stable from 2 h out to 5 days and consuming less than 1.0 ml of solution. This study focuses on a novel solution to achieve a long-term microfluidic gradient generator using simple engineering techniques of biomedical microdevices.

Computational Modeling of Glucose Uptake in the Enterocyte.

Absorption of glucose across the epithelial cells of the small intestine is a key process in human nutrition and initiates signaling cascades that regulate metabolic homeostasis. Validated and predictive mathematical models of glucose transport in intestinal epithelial cells are essential for interpreting experimental data, generating hypotheses, and understanding the contributions of and interactions between transport pathways. Here we report on the development of such a model that, in contrast to existing models, incorporates mechanistic descriptions of all relevant transport proteins and is implemented in the CellML framework. The model is validated against experimental and simulation data from the literature. It is then used to elucidate the relative contributions of the sodium-glucose cotransporter (SGLT1) and the glucose transporter type 2 (GLUT2) proteins in published measurements of glucose absorption from human intestinal epithelial cell lines. The model predicts that the contribution of SGLT1 dominates at low extracellular glucose concentrations (<20 mM) and short exposure times (<60 s) while the GLUT2 contribution is more significant at high glucose concentrations and long durations. Implementation in CellML permitted a modular structure in which the model was composed by reusing existing models of the individual transporters. The final structure also permits transparent changes of the model components and parameter values in order to facilitate model reuse, extension, and customization (for example, to simplify, or add complexity to specific transporter/pathway models, or reuse the model as a component of a larger framework) and carry out parameter sensitivity studies.

Computational modeling of epithelial fluid and ion transport in the parotid duct after transfection of human aquaporin-1.

Previous studies have shown that localized delivery of the aquaporin-1 (AQP1) gene to the parotid duct can restore saliva flow in minipigs following irradiation-induced salivary hypofunction. The resulting flow rate and electrochemistry of secreted saliva contradicts current understanding of ductal fluid transport. We hypothesized that changes in expression of ion transport proteins have occurred following AQP1 transfection. We use a mathematical model of ion and fluid transport across the parotid duct epithelial cells to predict the expression profile of ion transporters that are consistent with the experimental measurements of saliva composition and secretion rates. Using a baseline set of parameters, the model reproduces the data for the irradiated, non-AQP1-transfected case. We propose three scenarios which may have occurred after transfection, which differ in the location of the AQP1 gene. The first scenario places AQP1 within nonsecretory cells, and requires that epithelial sodium channel (ENaC) expression is greatly reduced (1.3% of baseline), and ductal bicarbonate concentration is increased from 40.6 to 137.0 mM, to drive water secretion into the duct. The second scenario introduces the AQP1 gene into all ductal cells. The final scenario has AQP1 primarily in the proximal duct cells which secrete water under baseline conditions. We find the change in the remaining cells includes a 95.8% reduction in ENaC expression, enabling us to reproduce all experimental ionic concentrations within 9 mM. These findings provide a mechanistic basis for the observations and will guide the further development of gene transfer therapy for salivary hypofunction. NEW & NOTEWORTHY: Following transfection of aquaporin into the parotid ducts of minipigs with salivary hypofunction, the resulting increase in salivary flow rates contradicts current understanding of ductal fluid transport. We show that the change in saliva electrochemistry and flow rate can be explained by changes in expression of ion transporters in the ductal cell membranes, using a mathematical model replicating a single parotid duct.

An Optimised Human Cell Culture Model for Alveolar Epithelial Transport.

Robust and reproducible in vitro models are required for investigating the pathways involved in fluid homeostasis in the human alveolar epithelium. We performed functional and phenotypic characterisation of ion transport in the human pulmonary epithelial cell lines NCI-H441 and A549 to determine their similarity to primary human alveolar type II cells. NCI-H441 cells exhibited high expression of junctional proteins ZO-1, and E-cadherin, seal-forming claudin-3, -4, -5 and Na+-K+-ATPase while A549 cells exhibited high expression of pore-forming claudin-2. Consistent with this phenotype NCI-H441, but not A549, cells formed a functional barrier with active ion transport characterised by higher electrical resistance (529 ± 178 Ω cm2 vs 28 ± 4 Ω cm2), lower paracellular permeability ((176 ± 42) ×10-8 cm/s vs (738 ± 190) ×10-8 cm/s) and higher transepithelial potential difference (11.9 ± 4 mV vs 0 mV). Phenotypic and functional properties of NCI-H441 cells were tuned by varying cell seeding density and supplement concentrations. The cells formed a polarised monolayer typical of in vivo epithelium at seeding densities of 100,000 cells per 12-well insert while higher densities resulted in multiple cell layers. Dexamethasone and insulin-transferrin-selenium supplements were required for the development of high levels of electrical resistance, potential difference and expression of claudin-3 and Na+-K+-ATPase. Treatment of NCI-H441 cells with inhibitors and agonists of sodium and chloride channels indicated sodium absorption through ENaC under baseline and forskolin-stimulated conditions. Chloride transport was not sensitive to inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) under either condition. Channels inhibited by 5-nitro-1-(3-phenylpropylamino) benzoic acid (NPPB) contributed to chloride secretion following forskolin stimulation, but not at baseline. These data precisely define experimental conditions for the application of NCI-H441 cells as a model for investigating ion and water transport in the human alveolar epithelium and also identify the pathways of sodium and chloride transport.

Roadmap for cardiovascular circulation model.

Computational models of many aspects of the mammalian cardiovascular circulation have been developed. Indeed, along with orthopaedics, this area of physiology is one that has attracted much interest from engineers, presumably because the equations governing blood flow in the vascular system are well understood and can be solved with well-established numerical techniques. Unfortunately, there have been only a few attempts to create a comprehensive public domain resource for cardiovascular researchers. In this paper we propose a roadmap for developing an open source cardiovascular circulation model. The model should be registered to the musculo-skeletal system. The computational infrastructure for the cardiovascular model should provide for near real-time computation of blood flow and pressure in all parts of the body. The model should deal with vascular beds in all tissues, and the computational infrastructure for the model should provide links into CellML models of cell function and tissue function. In this work we review the literature associated with 1D blood flow modelling in the cardiovascular system, discuss model encoding standards, software and a model repository. We then describe the coordinate systems used to define the vascular geometry, derive the equations and discuss the implementation of these coupled equations in the open source computational software OpenCMISS. Finally, some preliminary results are presented and plans outlined for the next steps in the development of the model, the computational software and the graphical user interface for accessing the model.