Computational modelling of human stem cell-derived cardiomyocytes - Texture descriptors for biological image processing

This thesis investigates two distinct research topics. The main topic (Part I) is the computational modelling of cardiomyocytes derived from human stem cells, both embryonic (hESC-CM) and induced-pluripotent (hiPSC-CM). The aim of this research line lies in developing models of the electrophysiology of hESC-CM and hiPSC-CM in order to integrate the available experimental data and getting in-silico models to be used for studying/making new hypotheses/planning experiments on aspects not fully understood yet, such as the maturation process, the functionality of the Ca2+ hangling or why the hESC-CM/hiPSC-CM action potentials (APs) show some differences with respect to APs from adult cardiomyocytes. Chapter I.1 introduces the main concepts about hESC-CMs/hiPSC-CMs, the cardiac AP, and computational modelling. Chapter I.2 presents the hESC-CM AP model, able to simulate the maturation process through two developmental stages, Early and Late, based on experimental and literature data. Chapter I.3 describes the hiPSC-CM AP model, able to simulate the ventricular-like and atrial-like phenotypes. This model was used to assess which currents are responsible for the differences between the ventricular-like AP and the adult ventricular AP. The secondary topic (Part II) consists in the study of texture descriptors for biological image processing. Chapter II.1 provides an overview on important texture descriptors such as Local Binary Pattern or Local Phase Quantization. Moreover the non-binary coding and the multi-threshold approach are here introduced. Chapter II.2 shows that the non-binary coding and the multi-threshold approach improve the classification performance of cellular/sub-cellular part images, taken from six datasets. Chapter II.3 describes the case study of the classification of indirect immunofluorescence images of HEp2 cells, used for the antinuclear antibody clinical test. Finally the general conclusions are reported.

Techniques for Lagrangian modelling of dispersion in geophysical flows

Basic concepts and definitions relative to Lagrangian Particle Dispersion Models (LPDMs)for the description of turbulent dispersion are introduced. The study focusses on LPDMs that use as input, for the large scale motion, fields produced by Eulerian models, with the small scale motions described by Lagrangian Stochastic Models (LSMs). The data of two different dynamical model have been used: a Large Eddy Simulation (LES) and a General Circulation Model (GCM). After reviewing the small scale closure adopted by the Eulerian model, the development and implementation of appropriate LSMs is outlined. The basic requirement of every LPDM used in this work is its fullfillment of the Well Mixed Condition (WMC). For the dispersion description in the GCM domain, a stochastic model of Markov order 0, consistent with the eddy-viscosity closure of the dynamical model, is implemented. A LSM of Markov order 1, more suitable for shorter timescales, has been implemented for the description of the unresolved motion of the LES fields. Different assumptions on the small scale correlation time are made. Tests of the LSM on GCM fields suggest that the use of an interpolation algorithm able to maintain an analytical consistency between the diffusion coefficient and its derivative is mandatory if the model has to satisfy the WMC. Also a dynamical time step selection scheme based on the diffusion coefficient shape is introduced, and the criteria for the integration step selection are discussed. Absolute and relative dispersion experiments are made with various unresolved motion settings for the LSM on LES data, and the results are compared with laboratory data. The study shows that the unresolved turbulence parameterization has a negligible influence on the absolute dispersion, while it affects the contribution of the relative dispersion and meandering to absolute dispersion, as well as the Lagrangian correlation.

Closed-loop investigation of the dynamical properties of cardiomyocyte electrophysiology by means of Dynamic clamp and Mathematical modelling

The research field of my PhD concerns mathematical modeling and numerical simulation, applied to the cardiac electrophysiology analysis at a single cell level. This is possible thanks to the development of mathematical descriptions of single cellular components, ionic channels, pumps, exchangers and subcellular compartments. Due to the difficulties of vivo experiments on human cells, most of the measurements are acquired in vitro using animal models (e.g. guinea pig, dog, rabbit). Moreover, to study the cardiac action potential and all its features, it is necessary to acquire more specific knowledge about single ionic currents that contribute to the cardiac activity. Electrophysiological models of the heart have become very accurate in recent years giving rise to extremely complicated systems of differential equations. Although describing the behavior of cardiac cells quite well, the models are computationally demanding for numerical simulations and are very difficult to analyze from a mathematical (dynamical-systems) viewpoint. Simplified mathematical models that capture the underlying dynamics to a certain extent are therefore frequently used. The results presented in this thesis have confirmed that a close integration of computational modeling and experimental recordings in real myocytes, as performed by dynamic clamp, is a useful tool in enhancing our understanding of various components of normal cardiac electrophysiology, but also arrhythmogenic mechanisms in a pathological condition, especially when fully integrated with experimental data.

Computational Modelling of Cardiac Electrophysiology: from Cell to Bedside

Heart diseases are the leading cause of death worldwide, both for men and women. However, the ionic mechanisms underlying many cardiac arrhythmias and genetic disorders are not completely understood, thus leading to a limited efficacy of the current available therapies and leaving many open questions for cardiac electrophysiologists. On the other hand, experimental data availability is still a great issue in this field: most of the experiments are performed in vitro and/or using animal models (e.g. rabbit, dog and mouse), even when the final aim is to better understand the electrical behaviour of in vivo human heart either in physiological or pathological conditions. Computational modelling constitutes a primary tool in cardiac electrophysiology: in silico simulations, based on the available experimental data, may help to understand the electrical properties of the heart and the ionic mechanisms underlying a specific phenomenon. Once validated, mathematical models can be used for making predictions and testing hypotheses, thus suggesting potential therapeutic targets. This PhD thesis aims to apply computational cardiac modelling of human single cell action potential (AP) to three clinical scenarios, in order to gain new insights into the ionic mechanisms involved in the electrophysiological changes observed in vitro and/or in vivo. The first context is blood electrolyte variations, which may occur in patients due to different pathologies and/or therapies. In particular, we focused on extracellular Ca2+ and its effect on the AP duration (APD). The second context is haemodialysis (HD) therapy: in addition to blood electrolyte variations, patients undergo a lot of other different changes during HD, e.g. heart rate, cell volume, pH, and sympatho-vagal balance. The third context is human hypertrophic cardiomyopathy (HCM), a genetic disorder characterised by an increased arrhythmic risk, and still lacking a specific pharmacological treatment.

Numerical modelling and structural optimization of multifunctional maritime structures aimed to protect harbours and produce energy

The main objective of this PhD thesis is to optimize a specific multifunctional maritime structure for harbour protection and energy production, named Overtopping Breakwater for Energy Conversion (OBREC), developed by the team of the University of Campania. This device is provided with a sloping plate followed by a unique reservoir, which is linked with the machine room (where the energy conversion occurs) by means of a pipe passing through the crown wall, provided with a parapet on top of it. Therefore, the potential energy of the overtopping waves, collected inside the reservoir located above the still water level, is then converted by means of low – head turbines. In order to improve the understanding of the wave – structure interactions with OBREC, several methodologies have been used and combined together: i. analysis of recent experimental campaigns on wave overtopping discharges and pressures at the crown wall on small – scale OBREC cross sections, carried out in other laboratories by the team of the University of Campania; ii. new experiments on cross sections similar to the OBREC device, planned and carried out in the hydraulic lab at the University of Bologna in the framework of this PhD work; iii. numerical modelling with a 1 – phase incompressible fluid model IH – 2VOF, developed by the University of Cantabria, and with a 2 – phase incompressible fluid model OpenFOAM, both available from the literature; iv. numerical modelling with a new 2 – phase compressible fluid model developed in the OpenFOAM environment within this PhD work; v. analysis of the data gained from the monitoring of the OBREC prototype installation.

Ship performance modelling for least-CO2 emission routes

Decarbonization of maritime transport requires immediate action. In the short term, ship weather routing can provide greenhouse gas emission reductions, even for existing ships and without retrofitting them. Weather routing is based on making optimal use of both envi- ronmental information and knowledge about vessel seakeeping and performance. Combining them at a state-of-the-art level and making use of path planning in realistic conditions can be challenging. To address these topics in an open-source framework, this thesis led to the development of a new module called bateau , and to its combination with the ship routing model VISIR. bateau includes both hull geometry and propulsion modelling for various vessel types. It has two objectives: to predict the sustained speed in a seaway and to estimate the CO2 emission rate during the voyage. Various semi-empirical approaches were used in bateau to predict the ship hydro- and aerodynamical resistance in both head and oblique seas. Assuming that the ship sails at a constant engine load, the involuntary speed loss due to waves was estimated. This thesis also attempted to clarify the role played by the actual representation of the sea state. In particular, the influence of the wave steepness parameter was assessed. For dealing with ships with a greater superstructure, the wind added resistance was also estimated. Numerical experiments via bateau were conducted for both a medium and a large-size container ships, a bulk-carrier, and a tanker. The simulations of optimal routes were carried out for a feeder containership during voyages in the North Indian Ocean and in the South China Sea. Least-CO2 routes were compared to the least-distance ones, assessing the relative CO2 savings. Analysis fields from the Copernicus Marine Service were used in the numerical experiments.

Numerical and physical modelling of axially loaded piles for offshore wind turbines

The scope of the thesis is to broaden the knowledge about axially loaded pipe piles, that can play as foundations for offshore wind turbines based on jacket structures. The goal of the work was pursued by interpreting experimental data on large-scale model piles and by developing numerical tools for the prediction of their monotonic response to tensile and compressive loads to failure. The availability of experimental results on large scale model piles produced in two different campaigns at Fraunhofer IWES (Hannover, Germany) represented the reference for the whole work. Data from CPTs, blow counts during installation and load-displacement curves allowed to develop considerations on the experimental results and comparison with empirical methods from literature, such as CPT-based methods and Load Transfer methods. The understanding of soil-structure interaction mechanisms has been involved in the study in order to better assess the mechanical response of the sand with the scope to help in developing predictive tools of the experiments. A lack of information on the response of Rohsand 3152 when in contact with steel was highlighted, so the necessity of better assessing its response was fulfilled with a comprehensive campaign of interface shear test. It was found how the response of the sand to ultimate conditions evolve with the roughness of the steel, which is a precious information to take account of when attempting the prediction of a pile capacity. Parallel to this topic, the work has developed a numerical modelling procedure that was validated on the available large-scale model piles at IWES. The modelling strategy is intended to build a FE model whose mechanical properties of the sand come from an interpretation of commonly available geotechnical tests. The results of the FE model were compared with other predictive tools currently used in the engineering practice.

Modelling and classification with quantile-based distributions

In this work, we explore and demonstrate the potential for modeling and classification using quantile-based distributions, which are random variables defined by their quantile function. In the first part we formalize a least squares estimation framework for the class of linear quantile functions, leading to unbiased and asymptotically normal estimators. Among the distributions with a linear quantile function, we focus on the flattened generalized logistic distribution (fgld), which offers a wide range of distributional shapes. A novel naïve-Bayes classifier is proposed that utilizes the fgld estimated via least squares, and through simulations and applications, we demonstrate its competitiveness against state-of-the-art alternatives. In the second part we consider the Bayesian estimation of quantile-based distributions. We introduce a factor model with independent latent variables, which are distributed according to the fgld. Similar to the independent factor analysis model, this approach accommodates flexible factor distributions while using fewer parameters. The model is presented within a Bayesian framework, an MCMC algorithm for its estimation is developed, and its effectiveness is illustrated with data coming from the European Social Survey. The third part focuses on depth functions, which extend the concept of quantiles to multivariate data by imposing a center-outward ordering in the multivariate space. We investigate the recently introduced integrated rank-weighted (IRW) depth function, which is based on the distribution of random spherical projections of the multivariate data. This depth function proves to be computationally efficient and to increase its flexibility we propose different methods to explicitly model the projected univariate distributions. Its usefulness is shown in classification tasks: the maximum depth classifier based on the IRW depth is proven to be asymptotically optimal under certain conditions, and classifiers based on the IRW depth are shown to perform well in simulated and real data experiments.