Multiscale modelling of Potts shunt as a potential palliative treatment for suprasystemic idiopathic pulmonary artery hypertension: a paediatric case study

Potts shunt (PS) was suggested as palliation for patients with suprasystemic pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. PS, however, can result in poorly understood mortality. Here, a patient-specific geometrical multiscale model of PAH physiology and PS is developed for a paediatric PAH patient with stent-based PS. In the model, 7.6mm-diameter PS produces near-equalisation of the aortic and PA pressures and $$Q_p/Q_s$$ Q p / Q s (oxygenated vs deoxygenated blood flow) ratio of 0.72 associated with a 16% decrease of left ventricular (LV) output and 18% increase of RV output. The flow from LV to aortic arch branches increases by 16%, while LV contribution to the lower body flow decreases by 29%. Total flow in the descending aorta (DAo) increases by 18% due to RV contribution through the PS with flow into the distal PA branches decreasing. PS induces 18% increase of RV work due to its larger stroke volume pumped against lower afterload. Nonetheless, larger RV work does not lead to increased RV end-diastolic volume. Three-dimensional flow assessment demonstrates the PS jet impinging with a high velocity and wall shear stress on the opposite DAo wall with the most of the shunt flow being diverted to the DAo. Increasing the PS diameter from 5mm up to 10mm results in a nearly linear increase in post-operative shunt flow and a nearly linear decrease in shunt pressure-drop. In conclusion, this model reasonably represents patient-specific haemodynamics pre- and post-creation of the PS, providing insights into physiology of this complex condition, and presents a predictive tool that could be useful for clinical decision-making regarding suitability for PS in PAH patients with drug-resistant suprasystemic PAH.

Impact of Respiratory Fluctuation on Hemodynamics in Human Cardiovascular System: A 0-1D Multiscale Model

To explore hemodynamic interaction between the human respiratory system (RS) and cardiovascular system (CVS), here we propose an integrated computational model to predict the CVS hemodynamics with consideration of the respiratory fluctuation (RF). A submodule of the intrathoracic pressure (ITP) adjustment is developed and incorporated in a 0-1D multiscale hemodynamic model of the CVS specified for infant, adolescent, and adult individuals. The model is verified to enable reasonable estimation of the blood pressure waveforms accounting for the RF-induced pressure fluctuations in comparison with clinical data. The results show that the negative ITP caused by respiration increases the blood flow rates in superior and inferior vena cavae; the deep breathing improves the venous return in adolescents but has less influence on infants. It is found that a marked reduction in ITP under pathological conditions can excessively increase the flow rates in cavae independent of the individual ages, which may cause the hemodynamic instability and hence increase the risk of heart failure. Our results indicate that the present 0-1D multiscale CVS model incorporated with the RF effect is capable of providing a useful and effective tool to explore the physiological and pathological mechanisms in association with cardiopulmonary interactions and their clinical applications.

Escherichia coli chemotaxis to competing stimuli in a microfluidic device with a constant gradient

In natural systems bacteria are exposed to many chemical stimulants; some attract chemotactic bacteria as they promote survival, while others repel bacteria because they inhibit survival. When faced with a mixture of chemoeffectors, it is not obvious which direction the population will migrate. Predicting this direction requires an understanding of how bacteria process information about their surroundings. We used a multiscale mathematical model to relate molecular level details of their two-component signaling system to the probability that an individual cell changes its swimming direction to the chemotactic velocity of a bacterial population. We used a microfluidic device designed to maintain a constant chemical gradient to compare model predictions to experimental observations. We obtained parameter values for the multiscale model of Escherichia coli chemotaxis to individual stimuli, α-methylaspartate and nickel ion, separately. Then without any additional fitting parameters, we predicted the response to chemoeffector mixtures. Migration of E. coli toward α-methylaspartate was modulated by adding increasing concentrations of nickel ion. Thus, the migration direction was controlled by the relative concentrations of competing chemoeffectors in a predictable way. This study demonstrated the utility of a multiscale model to predict the migration direction of bacteria in the presence of competing chemoeffectors.

A probability-based multiscale model to quantify the impact of hydropeaking on mesohabitat suitability in rivers

One of the negative effects of hydropower on river environment includes rapid changes in flow and habitat conditions. Any sudden flow change could force fish to move towards a refuge area in a short period of time, causing serious disturbances in the life cycle of the fish. A probability-based multiscale model was developed to quantify the impact of hydropeaking on habitat suitability for two fish species. The model used habitat preference curves, river flow and depth to develop the suitability maps. The suitability index maps reveal that habitat suitability deteriorates as flow increases in this part of the river. The probability model showed that, on average, suitability indices are higher for adult grayling than juvenile trout in hydropeaking events in the studied area. In addition, the life stages of fish determine their response to the sudden flow change. The method developed shows the potential to be used in river management and the evaluation of hydropeaking impacts in river systems affected by hydropower.

Multiscale Models in Heterogeneous Catalysis: Incorporating Dynamics into Reaction Kinetics

Modern operando spectroscopy and microscopy, and kinetic investigations have provided qualitative evidence for active site dynamics, catalyst surface dynamics, and charge transport. On the macroscale, intraparticle and interparticle mass and heat transfer can be tuned to optimise selectivity over heterogeneous catalysts. On the microscale, adsorbate-induced restructuring, adsorbate mobility, surface composition, oxidation states, charge transport, bandgap, and the degree of coordination of the active site have been identified for controlling product selectivity. There exist, however, limited physics-based and data-driven multiscale models that can assimilate these qualitative descriptors in an integrated manner to extract quantitative catalyst activity, stability, and product selectivity descriptors. A multiscale model, which describes the evolution of gas species, adspecie accumulation due to reactivity, stability, lifetime, and mobility, charge transport involving electrons and holes, heat transfer for non-isothermal conditions due to reaction exothermicity, and the changing catalyst states is provided. Dynamical effects are included in these models to bridge the gap between laboratory-scale studies and industrial technical reactors.

Multiscale model for forecasting Sabin 2 vaccine virus household and community transmission

Since the global withdrawal of Sabin 2 oral poliovirus vaccine (OPV) from routine immunization, the Global Polio Eradication Initiative (GPEI) has reported multiple circulating vaccine-derived poliovirus type 2 (cVDPV2) outbreaks. Here, we generated an agent-based, mechanistic model designed to assess OPV-related vaccine virus transmission risk in populations with heterogeneous immunity, demography, and social mixing patterns. To showcase the utility of our model, we present a simulation of mOPV2-related Sabin 2 transmission in rural Matlab, Bangladesh based on stool samples collected from infants and their household contacts during an mOPV2 clinical trial. Sabin 2 transmission following the mOPV2 clinical trial was replicated by specifying multiple, heterogeneous contact rates based on household and community membership. Once calibrated, the model generated Matlab-specific insights regarding poliovirus transmission following an accidental point importation or mass vaccination event. We also show that assuming homogeneous contact rates (mass action), as is common of poliovirus forecast models, does not accurately represent the clinical trial and risks overestimating forecasted poliovirus outbreak probability. Our study identifies household and community structure as an important source of transmission heterogeneity when assessing OPV-related transmission risk and provides a calibratable framework for expanding these analyses to other populations. Trial Registration: ClinicalTrials.gov This trial is registered with clinicaltrials.gov, NCT02477046.

The people behind the papers – Megan Rommelfanger and Adam MacLean

Cell fate decisions are dependent on both internal and external factors, but mathematical models of this process have often neglected the external signals. A new paper in Development describes a multiscale model that integrates intracellular gene regulatory networks with a cell-cell communication network at single-cell resolution. We caught up with the authors, PhD student Megan Rommelfanger and Adam MacLean, Assistant Professor at the University of Southern California, to find out more about their research.

A Multiscale computational model of YAP signaling in epithelial fingering behaviour

In epithelial-mesenchymal transition (EMT), cells organized into sheets break away and become motile mesenchymal cells. EMT plays a crucial role in wound healing, embryonic development, and cancer metastasis. Intracellular signaling in response to mechanical, topographic, or chemical stimuli can promote EMT. We present a multiscale model for EMT downstream of the protein YAP, which suppresses the cell-cell adhesion protein E-cadherin and activates the GTPase Rac1 that enhances cell migration. We first propose an ODE model for YAP/Rac1/E-cadherin interactions. The model dynamics are bistable, accounting for motile loose cells as for adherent slower cells. We implement this model in a cellular Potts model simulation of 2D wound-healing using the open source platform Morpheus. We show that, under suitable stimuli (depicting topographic cues) the sheet exhibits finger-like projections and EMT. Morphological, as well as quantitative differences in YAP levels as well as cell speed across the sheet are consistent with preexisting experimental observations of epithelial sheets grown on topographic features in vitro. The simulation is also consistent with experiments that knockdown or over-express YAP, inhibit Rac1, or block E-cadherin.