Modelling the rheology of living cell cytoplasm: poroviscoelasticity and fluid-to-solid transition.

Eukaryotic cell rheology has important consequences for vital processes such as adhesion, migration, and differentiation. Experiments indicate that cell cytoplasm can exhibit both elastic and viscous characteristics in different regimes, while the transport of fluid (cytosol) through the cross-linked filamentous scaffold (cytoskeleton) is reminiscent of mass transfer by diffusion through a porous medium. To gain insights into this complex rheological behaviour, we construct a computational model for the cell cytoplasm as a poroviscoelastic material formulated on the principles of nonlinear continuum mechanics, where we model the cytoplasm as a porous viscoelastic scaffold with an embedded viscous fluid flowing between the pores to model the cytosol. Baseline simulations (neglecting the viscosity of the cytosol) indicate that the system exhibits seven different regimes across the parameter space spanned by the viscoelastic relaxation timescale of the cytoskeleton and the poroelastic diffusion timescale; these regimes agree qualitatively with experimental measurements. Furthermore, the theoretical model also allows us to elucidate the additional role of pore fluid viscosity, which enters the system as a distinct viscous timescale. We show that increasing this viscous timescale hinders the passage of the pore fluid (reducing the poroelastic diffusion) and makes the cytoplasm rheology increasingly incompressible, shifting the phase boundaries between the regimes.

Application and reduction of a nonlinear hyperelastic wall model capturing ex vivo relationships between fluid pressure, area, and wall thickness in normal and hypertensive murine left pulmonary arteries.

Pulmonary hypertension is a cardiovascular disorder manifested by elevated mean arterial blood pressure (>20 mmHg) together with vessel wall stiffening and thickening due to alterations in collagen, elastin, and smooth muscle cells. Hypoxia-induced (type 3) pulmonary hypertension can be studied in animals exposed to a low oxygen environment for prolonged time periods leading to biomechanical alterations in vessel wall structure. This study introduces a novel approach to formulating a reduced order nonlinear elastic structural wall model for a large pulmonary artery. The model relating blood pressure and area is calibrated using ex vivo measurements of vessel diameter and wall thickness changes, under controlled pressure conditions, in left pulmonary arteries isolated from control and hypertensive mice. A two-layer, hyperelastic, and anisotropic model incorporating residual stresses is formulated using the Holzapfel-Gasser-Ogden model. Complex relations predicting vessel area and wall thickness with increasing blood pressure are derived and calibrated using the data. Sensitivity analysis, parameter estimation, subset selection, and physical plausibility arguments are used to systematically reduce the 16-parameter model to one in which a much smaller subset of identifiable parameters is estimated via solution of an inverse problem. Our final reduced one layer model includes a single set of three elastic moduli. Estimated ranges of these parameters demonstrate that nonlinear stiffening is dominated by elastin in the control animals and by collagen in the hypertensive animals. The pressure-area relation developed in this novel manner has potential impact on one-dimensional fluids network models of vessel wall remodeling in the presence of cardiovascular disease.

Finite-element simulation of in-plane tear propagation in the dissected aorta: Implications for the propagation mechanism.

Computer modeling and numerical simulation are essential for understanding the progression of aortic dissection. However, tear propagation has not been properly modeled and simulated. The in-plane dissection propagation between concentrically distributed elastic lamellae is modeled using the cohesive zone method with a bilinear traction-separation law. The parameters of cohesive elements are calibrated for the three modes of interfacial damage in the media, enabling quantitative predictions of in-plane tear propagation. An idealized cylindrical tube-shaped bilayer thick-wall model of the aorta is employed to elucidate the influence of geometrical parameters, loading conditions and residual stress on the tear propagation. While the model is capable of replicating that deeper, larger tears are associated with lower critical pressure, new findings include: (i) Larger axial stretch leads to lower critical pressure; (ii) Increased magnitude of residual stress is associated with higher critical pressure; (iii) Pressure difference between true and false lumen alters the critical pressure; (iv) The interfacial damage is mostly opening mode in the axial direction, but shear-dominated in the circumferential direction; (v) Damage due to the opening mode is associated with smaller fracture energy, which makes it easier to propagate than the shear and the mixed modes. (vi) The deformed shape of the tear, which is related to its geometrical features and loading conditions, modulates the critical pressure via two pathways: (a) deformed shapes are associated with specific modes of damage, which influences the critical pressure, and (b) deformed shapes modulate the critical pressure directly via geometrical constraints.

Fluid-structure interaction in a fully coupled three-dimensional mitral-atrium-pulmonary model.

This paper aims to investigate detailed mechanical interactions between the pulmonary haemodynamics and left heart function in pathophysiological situations (e.g. atrial fibrillation and acute mitral regurgitation). This is achieved by developing a complex computational framework for a coupled pulmonary circulation, left atrium and mitral valve model. The left atrium and mitral valve are modelled with physiologically realistic three-dimensional geometries, fibre-reinforced hyperelastic materials and fluid-structure interaction, and the pulmonary vessels are modelled as one-dimensional network ended with structured trees, with specified vessel geometries and wall material properties. This new coupled model reveals some interesting results which could be of diagnostic values. For example, the wave propagation through the pulmonary vasculature can lead to different arrival times for the second systolic flow wave (S2 wave) among the pulmonary veins, forming vortex rings inside the left atrium. In the case of acute mitral regurgitation, the left atrium experiences an increased energy dissipation and pressure elevation. The pulmonary veins can experience increased wave intensities, reversal flow during systole and increased early-diastolic flow wave (D wave), which in turn causes an additional flow wave across the mitral valve (L wave), as well as a reversal flow at the left atrial appendage orifice. In the case of atrial fibrillation, we show that the loss of active contraction is associated with a slower flow inside the left atrial appendage and disappearances of the late-diastole atrial reversal wave (AR wave) and the first systolic wave (S1 wave) in pulmonary veins. The haemodynamic changes along the pulmonary vessel trees on different scales from microscopic vessels to the main pulmonary artery can all be captured in this model. The work promises a potential in quantifying disease progression and medical treatments of various pulmonary diseases such as the pulmonary hypertension due to a left heart dysfunction.

Assessing model mismatch and model selection in a Bayesian uncertainty quantification analysis of a fluid-dynamics model of pulmonary blood circulation.

This study uses Bayesian inference to quantify the uncertainty of model parameters and haemodynamic predictions in a one-dimensional pulmonary circulation model based on an integration of mouse haemodynamic and micro-computed tomography imaging data. We emphasize an often neglected, though important source of uncertainty: in the mathematical model form due to the discrepancy between the model and the reality, and in the measurements due to the wrong noise model (jointly called 'model mismatch'). We demonstrate that minimizing the mean squared error between the measured and the predicted data (the conventional method) in the presence of model mismatch leads to biased and overly confident parameter estimates and haemodynamic predictions. We show that our proposed method allowing for model mismatch, which we represent with Gaussian processes, corrects the bias. Additionally, we compare a linear and a nonlinear wall model, as well as models with different vessel stiffness relations. We use formal model selection analysis based on the Watanabe Akaike information criterion to select the model that best predicts the pulmonary haemodynamics. Results show that the nonlinear pressure-area relationship with stiffness dependent on the unstressed radius predicts best the data measured in a control mouse.

Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

The Rundown of Dietary Supplements and Their Effects on Inflammatory Bowel Disease-A Review.

Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are a life-long, chronic, and relapsing problem affecting 11.2 million people worldwide. To date, there is pharmacological therapy to treat symptoms such as diarrhea, constipation, and abdominal cramping/pain. These medications also help to alleviate everyday discomfort; however, there are no curative therapies. Recent studies have investigated the combination of pharmacological treatment along with nutritional interventions to improve quality of life and risk of disease relapse. Dietary supplements, specifically probiotics, polyphenols, fibers, fatty acids and low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol diets (FODMAP diets), have been closely looked at to determine their effect, if any, on the development of inflammatory bowel disease and its course of progression. Approximately 30 studies were carefully reviewed and analyzed to appreciate the value of these above-mentioned supplements and their influence on this gastrointestinal disease. After analysis, it has been demonstrated that by implementing fibers, polyphenols, and fatty acids, as well as keeping a low-saccharide diet for those patients with Crohn's disease and ulcerative colitis can improve quality of life and invoke clinical remission. Some polyphenols, specifically curcumin and resveratrol, have proved to decrease disease activity in studies reviewed. Although these studies have become a topic of recent interest, it would be of great value to doctors and patients alike, to continue in this direction of research and to improve the findings for best treatment substances and dosages. This would lead to increased quality of life and disease control leading to fewer complications in the future.

A One-Dimensional Hemodynamic Model of the Coronary Arterial Tree.

One-dimensional (1D) hemodynamic models of arteries have increasingly been applied to coronary circulation. In this study, we have adopted flow and pressure profiles in Olufsen's 1D structured tree as coronary boundary conditions, with terminals coupled to the dynamic pressure feedback resulting from the intra-myocardial stress because of ventricular contraction. We model a trifurcation structure of the example coronary tree as two adjacent bifurcations. The estimated results of blood pressure and flow rate from our simulation agree well with the clinical measurements and published data. Furthermore, the 1D model enables us to use wave intensity analysis to simulate blood flow in the developed coronary model. Six characteristic waves are observed in both left and right coronary flows, though the waves' magnitudes differ from each other. We study the effects of arterial wall stiffness on coronary blood flow in the left circumflex artery (LCX). Different diseased cases indicate that distinct pathological reactions of the cardiovascular system can be better distinguished through Wave Intensity analysis, which shows agreement with clinical observations. Finally, the feedback pressure in terminal vessels and measurement deviation are also investigated by changing parameters in the LCX. We find that larger feedback pressure increases the backward wave and decreases the forward one. Although simplified, this 1D model provides new insight into coronary hemodynamics in healthy and diseased conditions. We believe that this approach offers reference resources for studies on coronary circulation disease diagnosis, treatment and simulation.

Hemodynamic assessment of pulmonary hypertension in mice: a model-based analysis of the disease mechanism.

This study uses a one-dimensional fluid dynamics arterial network model to infer changes in hemodynamic quantities associated with pulmonary hypertension in mice. Data for this study include blood flow and pressure measurements from the main pulmonary artery for 7 control mice with normal pulmonary function and 5 mice with hypoxia-induced pulmonary hypertension. Arterial dimensions for a 21-vessel network are extracted from micro-CT images of lungs from a representative control and hypertensive mouse. Each vessel is represented by its length and radius. Fluid dynamic computations are done assuming that the flow is Newtonian, viscous, laminar, and has no swirl. The system of equations is closed by a constitutive equation relating pressure and area, using a linear model derived from stress-strain deformation in the circumferential direction assuming that the arterial walls are thin, and also an empirical nonlinear model. For each dataset, an inflow waveform is extracted from the data, and nominal parameters specifying the outflow boundary conditions are computed from mean values and characteristic timescales extracted from the data. The model is calibrated for each mouse by estimating parameters that minimize the least squares error between measured and computed waveforms. Optimized parameters are compared across the control and the hypertensive groups to characterize vascular remodeling with disease. Results show that pulmonary hypertension is associated with stiffer and less compliant proximal and distal vasculature with augmented wave reflections, and that elastic nonlinearities are insignificant in the hypertensive animal.

Modelling peeling- and pressure-driven propagation of arterial dissection.

An arterial dissection is a longitudinal tear in the vessel wall, which can create a false lumen for blood flow and may propagate quickly, leading to death. We employ a computational model for a dissection using the extended finite element method with a cohesive traction-separation law for the tear faces. The arterial wall is described by the anisotropic hyperelastic Holzapfel-Gasser-Ogden material model that accounts for collagen fibres and ground matrix, while the evolution of damage is governed by a linear cohesive traction-separation law. We simulate propagation in both peeling and pressure-loading tests. For peeling tests, we consider strips and discs cut from the arterial wall. Propagation is found to occur preferentially along the material axes with the greatest stiffness, which are determined by the fibre orientation. In the case of pressure-driven propagation, we examine a cylindrical model, with an initial tear in the shape of an arc. Long and shallow dissections lead to buckling of the inner wall between the true lumen and the dissection. The various buckling configurations closely match those seen in clinical CT scans. Our results also indicate that a deeper tear is more likely to propagate.

Propagation of dissection in a residually-stressed artery model.

This paper studies dissection propagation subject to internal pressure in a residually-stressed two-layer arterial model. The artery is assumed to be infinitely long, and the resultant plane strain problem is solved using the extended finite element method. The arterial layers are modelled using the anisotropic hyperelastic Holzapfel-Gasser-Ogden model, and the tissue damage due to tear propagation is described using a linear cohesive traction-separation law. Residual stress in the arterial wall is determined by an opening angle [Formula: see text] in a stress-free configuration. An initial tear is introduced within the artery which is subject to internal pressure. Quasi-static solutions are computed to determine the critical value of the pressure, at which the dissection starts to propagate. Our model shows that the dissection tends to propagate radially outwards. Interestingly, the critical pressure is higher for both very short and very long tears. The simulations also reveal that the inner wall buckles for longer tears, which is supported by clinical CT scans. In all simulated cases, the critical pressure is found to increase with the opening angle. In other words, residual stress acts to protect the artery against tear propagation. The effect of residual stress is more prominent when a tear is of intermediate length ([Formula: see text]90[Formula: see text] arc length). There is an intricate balance between tear length, wall buckling, fibre orientation, and residual stress that determines the tear propagation.

Reframing the concept of alternative livelihoods.

Alternative livelihood project (ALP) is a widely used term for interventions that aim to reduce the prevalence of activities deemed to be environmentally damaging by substituting them with lower impact livelihood activities that provide at least equivalent benefits. ALPs are widely implemented in conservation, but in 2012, an International Union for Conservation of Nature resolution called for a critical review of such projects based on concern that their effectiveness was unproven. We focused on the conceptual design of ALPs by considering their underlying assumptions. We placed ALPs within a broad category of livelihood-focused interventions to better understand their role in conservation and their intended impacts. We dissected 3 flawed assumptions about ALPs based on the notions of substitution, the homogenous community, and impact scalability. Interventions based on flawed assumptions about people's needs, aspirations, and the factors that influence livelihood choice are unlikely to achieve conservation objectives. We therefore recommend use of a sustainable livelihoods approach to understand the role and function of environmentally damaging behaviors within livelihood strategies; differentiate between households in a community that have the greatest environmental impact and those most vulnerable to resource access restrictions to improve intervention targeting; and learn more about the social-ecological system within which household livelihood strategies are embedded. Rather than using livelihood-focused interventions as a direct behavior-change tool, it may be more appropriate to focus on either enhancing the existing livelihood strategies of those most vulnerable to conservation-imposed resource access restrictions or on use of livelihood-focused interventions that establish a clear link to conservation as a means of building good community relations. However, we recommend that the term ALP be replaced by the broader term livelihood-focused intervention. This avoids the implicit assumption that alternatives can fully substitute for natural resource-based livelihood activities.

Investigation of the optimal collagen fibre orientation in human iliac arteries.

The distribution of collagen fibres plays a significant role in the mechanical behaviour of artery walls. Experimental data show that in most artery wall layers there are two (or more) in-plane symmetrically disposed families of fibres. However, a recent investigation revealed that some artery wall layers have only one preferred fibre direction, notably in the medial layer of human common iliac arteries. This paper aims to provide a possible explanation for this intriguing phenomenon. An invariant-based constitutive model is utilized to characterize the mechanical behaviour of tissues. We then use three different hypotheses to determine the 'optimal fibre angle' in an iliac artery model. All three hypotheses lead to the same result that the optimal fibre angle in the medial layer of the iliac artery is close to the circumferential direction. The axial pre-stretch, in particular, is found to play an essential role in determining the optimal fibre angle.

The interaction between seaweed farming as an alternative occupation and fisher numbers in the central Philippines.

Alternative occupations are frequently promoted as a means to reduce the number of people exploiting declining fisheries. However, there is little evidence that alternative occupations reduce fisher numbers. Seaweed farming is frequently promoted as a lucrative alternative occupation for artisanal fishers in Southeast Asia. We examined how the introduction of seaweed farming has affected village-level changes in the number of fishers on Danajon Bank, central Philippines, where unsustainable fishing has led to declining fishery yields. To determine how fisher numbers had changed since seaweed farming started, we interviewed the heads of household from 300 households in 10 villages to examine their perceptions of how fisher numbers had changed in their village and the reasons they associated with these changes. We then asked key informants (people with detailed knowledge of village members) to estimate fisher numbers in these villages before seaweed farming began and at the time of the survey. We compared the results of how fisher numbers had changed in each village with the wealth, education, seaweed farm sizes, and other attributes of households in these villages, which we collected through interviews, and with village-level factors such as distance to markets. We also asked people why they either continued to engage in or ceased fishing. In four villages, respondents thought seaweed farming and low fish catches had reduced fisher numbers, at least temporarily. In one of these villages, there was a recent return to fishing due to declines in the price of seaweed and increased theft of seaweed. In another four villages, fisher numbers increased as human population increased, despite the widespread uptake of seaweed farming. Seaweed farming failed for technical reasons in two other villages. Our results suggest seaweed farming has reduced fisher numbers in some villages, a result that may be correlated with socioeconomic status, but the heterogeneity of outcomes is consistent with suggestions that alternative occupations are not a substitute for more direct forms of resource management.

A multiscale maximum entropy moment closure for locally regulated space-time point process models of population dynamics.

The prevalence of structure in biological populations challenges fundamental assumptions at the heart of continuum models of population dynamics based only on mean densities (local or global). Individual-based models (IBMs) were introduced during the last decade in an attempt to overcome this limitation by following explicitly each individual in the population. Although the IBM approach has been quite useful, the capability to follow each individual usually comes at the expense of analytical tract ability, which limits the generality of the statements that can be made. For the specific case of spatial structure in populations of sessile (and identical) organisms, space-time point processes with local regulation seem to cover the middle ground between analytical tract ability and a higher degree of biological realism. This approach has shown that simplified representations of fecundity, local dispersal and density-dependent mortality weighted by the local competitive environment are sufficient to generate spatial patterns that mimic field observations. Continuum approximations of these stochastic processes try to distill their fundamental properties, and they keep track of not only mean densities, but also higher order spatial correlations. However, due to the non-linearities involved they result in infinite hierarchies of moment equations. This leads to the problem of finding a 'moment closure'; that is, an appropriate order of (lower order) truncation, together with a method of expressing the highest order density not explicitly modelled in the truncated hierarchy in terms of the lower order densities. We use the principle of constrained maximum entropy to derive a closure relationship for truncation at second order using normalisation and the product densities of first and second orders as constraints, and apply it to one such hierarchy. The resulting 'maxent' closure is similar to the Kirkwood superposition approximation, or 'power-3' closure, but it is complemented with previously unknown correction terms that depend mainly on the avoidance function of an associated Poisson point process over the region for which third order correlations are irreducible. This domain of irreducible triplet correlations is found from an integral equation associated with the normalisation constraint. This also serves the purpose of a validation check, since a single, non-trivial domain can only be found if the assumptions of the closure are consistent with the predictions of the hierarchy. Comparisons between simulations of the point process, alternative heuristic closures, and the maxent closure show significant improvements in the ability of the truncated hierarchy to predict equilibrium values for mildly aggregated spatial patterns. However, the maxent closure performs comparatively poorly in segregated ones. Although the closure is applied in the context of point processes, the method does not require fixed locations to be valid, and can in principle be applied to problems where the particles move, provided that their correlation functions are stationary in space and time.

Co-activation differences in lower limb muscles between asymptomatic controls and those with varying degrees of knee osteoarthritis during walking.

BACKGROUND: Increased muscle co-activation during gait has been identified as a neuromuscular alteration associated with knee osteoarthritis, however levels of co-activation among different osteoarthritis severity have not been established. The purpose of this study was to determine if differences in co-activation could be detected among asymptomatic controls, those with moderate and those with severe osteoarthritis using a co-activation index and a pattern recognition technique. METHODS: Surface electromyograms from vastus lateralis and medialis, lateral and medial hamstring and gastrocnemius pairs were recorded from 63 asymptomatic, 59 moderate and 48 severe osteoarthritic subjects during self-selected walking. A co-activation index was calculated over the initial stance for four medial and lateral muscle pairs. The four co-activation indices were tested among groups using a one factor ANOVA (alpha=0.05). Gait waveform pattern recognition procedures were applied to yield a principal pattern, scored for each muscle site and subject. A mixed model ANOVA (group-muscle) tested for principal pattern score differences. FINDINGS: A significant group effect was found (P<0.05) for all four co-activation indices. Principal pattern one captured the amplitude and general shape of activity throughout the entire stance phase. ANOVA revealed a significant (P<0.05) group by muscle interaction for the principal pattern scores. Significant differences were found among all three groups and between the two osteoarthritic groups for both measures. INTERPRETATION: The co-activation indices and principal patterns identified that lateral site differences occurred among all three groups with medial site differences between the two osteoarthritic groups. These findings suggest that measures of muscle co-activity provide additional information related to knee osteoarthritis severity.

Dynamic 3D ultrasound and MR image registration of the beating heart.

Real-time three-dimensional ultrasound (RT3D US) is an ideal imaging modality for the diagnosis of cardiac disease. RT3D US is a flexible, inexpensive, non-invasive tool that provides important diagnostic information related to cardiac function. Unfortunately, RT3D US suffers from inherent shortcomings, such as low signal-to-noise ratio and limited field of view, producing images that are difficult to interpret. Multi-modal dynamic cardiac image registration is a well-recognized approach that compensates for these deficiencies while retaining the advantages of RT3D US imaging. The clinical application of multi-modal image registration methods is difficult, and there are a number of implementation issues to be resolved. In this work, we present a method for the rapid registration of RT3D US images of the beating heart to high-resolution magnetic resonance (MR) images. This method was validated using a volunteer image set. Validation results demonstrate that this approach can achieve rapid registration of images of the beating heart with fiducial landmark and registration errors of 1.25 +/- 0.63 and 1.76 mm respectively. This technique can potentially be used to improve the diagnosis of cardiac disease by augmenting RT3D US images with high-resolution MR images and to facilitate intra-operative image fusion for minimally invasive cardio-thoracic surgical navigation.