Computational modelling of molecular nexopathies

Neurodegenerative diseases are an ever-increasing health problem, requiring substantial human and financial resources. They are caused by pathogenic proteins, which accumulate and spread in the brain's neural network, causing neuronal loss and brain atrophy. However, the mechanisms that govern pathogenic protein accumulation, spread, and toxic effects are still poorly understood, and many competing hypotheses regarding them have been presented by researchers. A better understanding of these mechanisms can help inform which hypotheses are more likely to be true, improve prognosis tools, and assist in drug development. Clinically, brain atrophy follows specific spatiotemporal patterns in each neurodegenerative disease, and each disease is linked to specific pathogenic proteins. This observation led to the `molecular nexopathies' hypothesis, which states that clinical phenotypes can be predicted if the specific pathogenic protein variant and the neural network characteristics are both known. However, little computational work has been done that links pathogenic protein mechanisms, the brain's neural network, and clinical phenotypes. In this thesis, I developed computational models for a variety of hypotheses regarding pathogenic protein mechanisms of accumulation, spread, and toxic effects on the brain, which occur at the neuronal scale, while linking them to neuroimaging data, which is acquired at the brain scale. After running simulations with the modelled mechanisms within a neural network, I compared simulation results over time against empirical data for Alzheimer's disease and three genetic variants of frontotemporal dementia. For each disease, the model that best fitted its atrophy progression was found, discovering differences among diseases with regards to what degree each mechanism played a role. I also analysed how each mechanism affected disease progression, discovered each disease's seed location, and found mechanisms that showed potential as candidate targets for therapies, in particular, increasing the firing frequency of neurons

Image partition and video segmentation using the Mumford-Shah functional

2010 - 2011The aim of this Thesis is to present an image partition and video segmentation procedure, based on the minimization of a modified version of Mumford-Shah functional. The Mumford-Shah functional used for image partition has been then extended to develop a video segmentation procedure. Differently by the image processing, in video analysis besides the usual spatial connectivity of pixels (or regions) on each single frame, we have a natural notion of “temporal” connectivity between pixels (or regions) on consecutive frames given by the optical flow. In this case, it makes sense to extend the tree data structure used to model a single image with a graph data structure that allows to handle a video sequence. The video segmentation procedure is based on minimization of a modified version of a Mumford-Shah functional. In particular the functional used for image partition allows to merge neighboring regions with similar color without considering their movement. Our idea has been to merge neighboring regions with similar color and similar optical flow vector. Also in this case the minimization of Mumford-Shah functional can be very complex if we consider each possible combination of the graph nodes. This computation becomes easy to do if we take into account a hierarchy of partitions constructed starting by the nodes of the graph.[edited by author]X n.s

Le rôle de la reconnexion magnétique dans la formation de cordes de flux et "switchbacks" dans l'héliosphère

En physique des plasmas, la reconnexion magnétique est un processus fondamental, omniprésent dans les systèmes astrophysiques. Ce mécanisme remarquable convertit l'énergie magnétique en énergie cinétique et thermique sur des échelles cinétiques, de ce fait accélérant et chauffant le plasma tout en permettant une reconfiguration globale de la topologie du champ magnétique. De façon spectaculaire, les changements induits à l'échelle microscopique conduisent, par exemple, à un remodelage complet et à grande échelle du champ magnétique d'une planète ou d'une étoile. De par son accessibilité, l'environnement proche de la Terre est un parfait laboratoire astrophysique pour étudier les plasmas spatiaux. Ces dernières années, de nombreuses missions spatiales ont été lancées pour étudier les propriétés in situ des plasmas dans l'environnement Soleil-Terre, ainsi que le processus de reconnexion magnétique. Equipées pour dévoiler de nouvelles caractéristiques sur ces milieux, elles ont notamment mis en lumière des structures qui n'avaient pas été observées auparavant de part une résolution instrumentale insuffisante ou une absence de données antérieures. Ce manuscrit se concentre sur des structures observées à la magnétopause terrestre d'une part et dans le vent solaire d'autre part, et qui ont un impact significatif sur leur environnement. Notre approche a pour but d'expliquer les processus de formation en jeu pour ces structures à travers des études statistiques. Dans une première partie, nous étudions des structures magnétiques qui se propagent le long de la magnétopause terrestre, transportant des quantités importantes d'énergie et appelées Evènements de Transfert de Flux (FTE). Plus particulièrement, des FTE d'un nouveau genre ont été observées ces dernières années, présentant une signature de reconnexion magnétique en leur centre. Une telle observation remet en cause les modèles classiquement mis en avant pour expliquer leur structure interne. A travers une étude statistique des FTEs, nous avons pu mieux comprendre leur topologie magnétique et déterminer les facteurs environnementaux jouant un rôle dans leur apparition. Ces analyses nous renseignent sur les mécanismes de formation des FTE qui implique le processus de reconnexion magnétique sur le côté jour de la magnétopause. Nous présentons également des observations de structures similaires dans le vent solaire, soulignant que le processus en jeu à la magnétopause terrestre est probablement également à l'œuvre dans le vent solaire. Dans une seconde partie, nous passons de l'environnement terrestre à l'héliosphère interne, où les switchbacks magnétiques sont omniprésents dans le vent solaire proche du Soleil. Les switchbacks sont des déflections du champs magnétique qui vont jusqu'à renverser sa composante radiale, et qui sont de plus accélérées par rapport au vent solaire de fond. A travers une étude systématique de leurs échelles caractéristiques ainsi que de leur orientation, nous montrons que les switchbacks sont probablement liés à des structures de surfaces tels que la granulation ou la supergranulation. Nous concluons que leurs propriétés sont cohérentes avec une formation dans la basse atmosphère à travers le processus de reconnexion d'interchange. La reconnexion magnétique est un fil conducteur dans ce travail, omniprésente à la magnétopause terrestre et dans le vent solaire, et menant à la formation de structures impactant significativement leur environnement. Dans la dernière partie du manuscrit, nous présentons une nouvelle méthode prometteuse de détection automatique des signatures de jets de reconnexion, inspirée du processus d'identification visuelle de ces jets. Un tel algorithme de détection automatique permet d'envisager des études statistiques de jets de reconnexion observés dans le vent solaire, ce qui serait une avancée importante dans la compréhension du phénomène de la reconnexion magnétique.Plasmas are ubiquitous in the universe where most matter is in such a state, constituting stars, the interplanetary, interstellar and intergalactic medium, nebulae, and so forth. In the solar system for instance, a plasma sphere (the Sun) continuously ejects into the interplanetary medium a plasma (the solar wind) that interacts with the plasma (magnetospheres) surrounding the Earth or other planets. This makes the near-Earth environment a perfect astrophysical laboratory to study space plasmas. In plasma physics, magnetic reconnection is a fundamental process omnipresent in astrophysical systems. This unique mechanism converts magnetic energy into kinetic and thermal energy at kinetic scales, accelerating and heating the plasma while allowing a global reconfiguration of the magnetic topology. Spectacularly, changes induced on microscopic scales lead for instance to the drastic large-scale remodeling of a planet's or a star's magnetic field. In the past decades, various space missions have been launched to investigate the in-situ properties of astrophysical plasmas in the Sun-Earth environment, as well as to study the process of magnetic reconnection. They were equipped to unveil new features of their surrounding media, and in that they succeeded, particularly in bringing to light structures that were not observed before, either due to a lack of instrumental resolution or to the absence of previous data. In this manuscript, we focus on structures observed at the Earth's magnetopause and in the solar wind, and of significant importance to the dynamics of their environment. In our approach, we aim to shed light on the physical processes at stake for the formation of these structures, using modeling and statistical analysis to infer their properties and potential formation models. In the first part of the manuscript, we present the investigation of a type of coherent magnetic structure often observed traveling along the Earth's magnetopause and carrying a significant amount of energy, called Flux Transfer Events (FTE). Particularly, a new type of FTE was observed with magnetic reconnection resolved in its core. Such a signature questions the usual model put forward to explain the internal structure of FTEs. Through a statistical analysis of FTE, we were able to better understand their magnetic topology and determine the factors playing a role in their occurrence, gaining insights on how they may be produced through magnetic reconnection at the dayside magnetopause. We also report on observations of similar structures in the solar wind, underlining that the process at work at the magnetopause is probably occurring in the solar wind as well. In the second part of the manuscript, we move from the near-Earth environment to the inner heliosphere, focusing on magnetic switchbacks that are a key feature of the near-Sun solar wind. Magnetic switchbacks are deflections of the magnetic field, sometimes reversing the radial component of the field, and made of accelerated plasma relative to the background solar wind. Through a systematic study of their characteristic scales and orientation, we highlight that switchbacks are probably linked to solar surface features like granulation and supergranulation, and we show that their properties are consistent with a formation through the process of interchange reconnection in the low solar atmosphere. Magnetic reconnection is a common thread of this work, being ubiquitous at the Earth's magnetopause and in the solar wind, and most probably involved in the formation of switchbacks in the low corona as well. In the last part of the manuscript, we describe a new promising approach, based on visual identification, that permits to automatically detect magnetic reconnection exhausts in-situ in the solar wind. An automated detection algorithm may lead to large statistical analysis of reconnection jets in the solar wind, a significant step forward in understanding the process of magnetic reconnection

Cell polarity under extreme morphological conditions

Cell polarity is an important phenomenon in a multitude of cellular and developmental processes. The cellular contexts that polarity occurs in include a wide array of morphological properties such as size, shape, and growth. An important, conserved system of cell polarity depends on the intracellular localisation of proteins that act as diffusive molecular switches. Since the localisation of these proteins depends on their reactive and diffusive properties, cell size and growth may alter polarity induced by localisation. My work contributes extensive analyses of an established protein localisation model under extreme morphological conditions such as extremely small and rapidly growing cells. My work also uncovers non-trivial, biologically relevant behaviour caused by the inclusion of these morphological properties and further discusses the mechanisms underlying the observed behaviour. In addition, I contribute and discuss a novel computational tool that can continue to aid the research community in understanding cell polarity under extreme morphological conditions

The PMC Turbo Experiment: Design, Development, and Results

In the middle and upper atmosphere, dynamics of scales from tens of meters to thousands of kilometers primary arise due to the influence of gravity waves propagating from lower altitudes. In order to understand the structure and variability of these regions of our planet's atmosphere, we must understand the propagation, influences, and dissipation of gravity waves. However, gravity waves and their influences are difficult to measure. Their largest and most observable effects occur in the remote mesosphere and lower thermosphere and the relevant spatial scales extend across many orders of magnitude. The EBEX group discovered a novel method to observe polar mesospheric clouds, which are a sensitive tracer of gravity waves and their associated dynamics. This discovery motivated the Polar Mesospheric Cloud Turbulence (PMC Turbo) experiment. Polar mesospheric clouds form an extremely thin but bright layer at roughly 80 kilometer altitude in which we can observe brightness fluctuations created by gravity wave dynamics and the resulting instabilities. PMC Turbo included seven pressure vessels, each of which contained an optical camera, hard drives, and computers that controlled the image capture, flight control, and communication with ground stations. The cameras captured spatial scales from gravity waves with wavelengths of roughly 10-100 kilometers, instability dynamics at scales from about 1-10 kilometers, and the fine structure at the inner scale of turbulence down to 20 meters. PMC Turbo flew at 38 kilometer altitude and remained afloat for nearly six days. During this time, it travelled from Esrange Space Center in Sweden to the Northwest Passage in Canada. Complementary data from other instruments provides additional atmospheric context to the PMC Turbo measurements. During flight, the PMC Turbo cameras captured images of polar mesospheric clouds tracing Kelvin-Helmholtz instabilities with a high signal-to-noise ratio. Kelvin-Helmholtz instabilities play major roles in energy dissipation and structure of geophysical fluids, and they have a close relationship with gravity waves. The PMC Turbo images include complicated interactions and secondary instabilities leading to turbulence. These dynamics provide insight into the atmospheric conditions and rate of energy dissipation in the mesosphere and lower thermosphere

Skeletonization and segmentation of binary voxel shapes

Preface. This dissertation is the result of research that I conducted between January 2005 and December 2008 in the Visualization research group of the Technische Universiteit Eindhoven. I am pleased to have the opportunity to thank a number of people that made this work possible. I owe my sincere gratitude to Alexandru Telea, my supervisor and first promotor. I did not consider pursuing a PhD until my Master’s project, which he also supervised. Due to our pleasant collaboration from which I learned quite a lot, I became convinced that becoming a doctoral student would be the right thing to do for me. Indeed, I can say it has greatly increased my knowledge and professional skills. Alex, thank you for our interesting discussions and the freedom you gave me in conducting my research. You made these four years a pleasant experience. I am further grateful to Jack vanWijk, my second promotor. Our monthly discussions were insightful, and he continuously encouraged me to take a more formal and scientific stance. I would also like to thank Prof. Jan de Graaf from the department of mathematics for our discussions on some of my conjectures. His mathematical rigor was inspiring. I am greatly indebted to the Netherlands Organisation for Scientific Research (NWO) for funding my PhD project (grant number 612.065.414). I thank Prof. Kaleem Siddiqi, Prof. Mark de Berg, and Dr. Remco Veltkamp for taking part in the core doctoral committee and Prof. Deborah Silver and Prof. Jos Roerdink for participating in the extended committee. Our Visualization group provides a great atmosphere to do research in. In particular, I would like to thank my fellow doctoral students Frank van Ham, Hannes Pretorius, Lucian Voinea, Danny Holten, Koray Duhbaci, Yedendra Shrinivasan, Jing Li, NielsWillems, and Romain Bourqui. They enabled me to take my mind of research from time to time, by discussing political and economical affairs, and more trivial topics. Furthermore, I would like to thank the senior researchers of our group, Huub van de Wetering, Kees Huizing, and Michel Westenberg. In particular, I thank Andrei Jalba for our fruitful collaboration in the last part of my work. On a personal level, I would like to thank my parents and sister for their love and support over the years, my friends for providing distractions outside of the office, and Michelle for her unconditional love and ability to light up my mood when needed

Variational methods and its applications to computer vision

Many computer vision applications such as image segmentation can be formulated in a ''variational'' way as energy minimization problems. Unfortunately, the computational task of minimizing these energies is usually difficult as it generally involves non convex functions in a space with thousands of dimensions and often the associated combinatorial problems are NP-hard to solve. Furthermore, they are ill-posed inverse problems and therefore are extremely sensitive to perturbations (e.g. noise). For this reason in order to compute a physically reliable approximation from given noisy data, it is necessary to incorporate into the mathematical model appropriate regularizations that require complex computations. The main aim of this work is to describe variational segmentation methods that are particularly effective for curvilinear structures. Due to their complex geometry, classical regularization techniques cannot be adopted because they lead to the loss of most of low contrasted details. In contrast, the proposed method not only better preserves curvilinear structures, but also reconnects some parts that may have been disconnected by noise. Moreover, it can be easily extensible to graphs and successfully applied to different types of data such as medical imagery (i.e. vessels, hearth coronaries etc), material samples (i.e. concrete) and satellite signals (i.e. streets, rivers etc.). In particular, we will show results and performances about an implementation targeting new generation of High Performance Computing (HPC) architectures where different types of coprocessors cooperate. The involved dataset consists of approximately 200 images of cracks, captured in three different tunnels by a robotic machine designed for the European ROBO-SPECT project.Open Acces

Modelling angiogenesis in three dimensions

The process through which new blood vessels are formed within the body is known as angiogenesis. An essential part of our survival, it has also been implicated more recently in many diseases both in terms of induced growth, and abnormal vascular structure. Angiogenesis is characterized as two processes, the development of a vascular network during embryonic growth and the production of new blood vessels. This work focuses on the latter, and seeks to develop a robust, three-dimensional model for simulating blood vessel growth and the attendant processes of blood flow and mass transfer within the simulated system. A system was developed which utilises medical imaging scan data (specifically, MicroCT) as the initial conditions from which a network of vessels is grown. This is combined with GPU accelerated simulations of fluid dynamics, with the intention of providing a technique for future use in predictive medicine and therapeutic simulation