Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. Nowadays the fibrillatory process is known to be provoked by the high-frequency reentrant activity of certain atrial regions that propagates the fibrillatory activity to the rest of the atrial tissue, and the electrical isolation of these key regions has demonstrated its effectiveness in terminating the fibrillatory process. The location of the dominant regions represents a major challenge in the diagnosis and treatment of this arrhythmia. With the aim to detect and locate the fibrillatory sources prior to surgical procedure, non-invasive methods have been developed such as body surface electrical mapping (BSPM) which allows to record with high spatial resolution the electrical activity on the torso surface or the electrocardiographic imaging (ECGI) which allows to non-invasively reconstruct the electrical activity in the atrial surface. Given the novelty of these systems, both technologies suffer from a lack of scientific knowledge about the physical and technical mechanisms that support their operation. Therefore, the aim of this thesis is to increase that knowledge, as well as studying the effectiveness of these technologies for the localization of dominant regions in patients with AF. First, it has been shown that BSPM systems are able to noninvasively identify atrial rotors by recognizing surface rotors after band-pass filtering. Furthermore, the position of such surface rotors is related to the atrial rotor location, allowing the distinction between left or right atrial rotors. Moreover, it has been found that the surface electrical maps in AF suffer a spatial smoothing effect by the torso conductor volume, so the surface electrical activity can be studied with a relatively small number of electrodes. Specifically, it has been seen that 12 uniformly distributed electrodes are sufficient for the correct identification of atrial dominant frequencies, while at least 32 leads are needed for non-invasive identification of atrial rotors. Secondly, the effect of narrowband filtering on the effectiveness of the location of reentrant patterns was studied. It has been found that this procedure allows isolating the reentrant electrical activity caused by the rotor, increasing the detection rate for both invasive and surface maps. However, the spatial smoothing caused by the regularization of the ECGI added to the temporal filtering causes a large increase in the spurious reentrant activity, making it difficult to detect real reentrant patterns. However, it has been found that maps provided by the ECGI without temporal filtering allow the correct detection of reentrant activity, so narrowband filtering should be applied for intracavitary or surface signal only. Finally, we studied the stability of the markers used to detect dominant regions in ECGI, such as frequency maps or the rotor presence. It has been found that in the presence of alterations in the conditions of the inverse problem, such as electrical or geometrical noise, these markers are significantly more stable than the ECGI signal morphology from which they are extracted. In addition, a new methodology for error reduction in the atrial spatial location based on the curvature of the curve L has been proposed. The results presented in this thesis showed that BSPM and ECGI systems allows to non-invasively locate the presence of high-frequency rotors, responsible for the maintenance of AF. This detection has been proven to be unambiguous and robust, and the physical and technical mechanisms that support this behavior have been studied. These results indicate that both non-invasive systems provide information of great clinical value in the treatment of AF, so their use can be helpful for selecting and planning atrial ablation procedures. / La fibrilación auricular (FA) es una de las arritmias cardiacas más frecuentes. Hoy en día se sabe que el proceso fibrilatorio está provocado por la actividad reentrante a alta frecuencia de ciertas regiones auriculares que propagan la actividad fibrilatoria en el resto del tejido auricular, y se ha demostrado que el aislamiento eléctrico de estas regiones dominantes permite detener el proceso fibrilatorio. La localización de las regiones dominantes supone un gran reto en el diagnóstico y tratamiento de la FA. Con el objetivo de poder localizar las fuentes fibrilatorias con anterioridad al procedimiento quirúrgico, se han desarrollado métodos no invasivos como la cartografía eléctrica de superficie (CES) que registra con gran resolución espacial la actividad eléctrica en la superficie del torso o la electrocardiografía por imagen (ECGI) que permite reconstruir la actividad eléctrica en la superficie auricular. Dada la novedad de estos sistemas, existe una falta de conocimiento científico sobre los mecanismos físicos y técnicos que sustentan su funcionamiento. Por lo tanto, el objetivo de esta tesis es aumentar dicho conocimiento, así como estudiar la eficacia de ambas tecnologías para la localización de regiones dominantes en pacientes con FA. En primer lugar, ha visto que los sistemas CES permiten identificar rotores auriculares mediante el reconocimiento de rotores superficiales tras el filtrado en banda estrecha. Además, la posición de los rotores superficiales está relacionada con la localización de dichos rotores, permitiendo la distinción entre rotores de aurícula derecha o izquierda. Por otra parte, se ha visto que los mapas eléctricos superficiales durante FA sufren una gran suavizado espacial por el efecto del volumen conductor del torso, lo que permite que la actividad eléctrica superficial pueda ser estudiada con un número relativamente reducido de electrodos. Concretamente, se ha visto que 12 electrodos uniformemente distribuidos son suficientes para una correcta identificación de frecuencias dominantes, mientras que son necesarios al menos 32 para una correcta identificación de rotores auriculares. Por otra parte, también se ha estudiado el efecto del filtrado en banda estrecha sobre la eficacia de la localización de patrones reentrantes. Así, se ha visto que este procedimiento permite aislar la actividad eléctrica reentrante provocada por el rotor, aumentando la tasa de detección tanto para señal obtenida de manera invasiva como para los mapas superficiales. No obstante, este filtrado temporal sobre la señal de ECGI provoca un gran aumento de la actividad reentrante espúrea que dificulta la detección de patrones reentrantes reales. Sin embargo, los mapas ECGI sin filtrado temporal permiten la detección correcta de la actividad reentrante, por lo el filtrado debería ser aplicado únicamente para señal intracavitaria o superficial. Por último, se ha estudiado la estabilidad de los marcadores utilizados en ECGI para detectar regiones dominantes, como son los mapas de frecuencia o la presencia de rotores. Se ha visto que en presencia de alteraciones en las condiciones del problema inverso, como ruido eléctrico o geométrico, estos marcadores son significativamente más estables que la morfología de la propia señal ECGI. Además, se ha propuesto una nueva metodología para la reducción del error en la localización espacial de la aurícula basado en la curvatura de la curva L. Los resultados presentados en esta tesis revelan que los sistemas de CES y ECGI permiten localizar de manera no invasiva la presencia de rotores de alta frecuencia. Esta detección es univoca y robusta, y se han estudiado los mecanismos físicos y técnicos que sustentan dicho comportamiento. Estos resultados indican que ambos sistemas no invasivos proporcionan información de gran valor clínico en el tratamiento de la FA, por lo que su uso puede ser de gran ayuda para la selección y planificaci / La fibril·lació auricular (FA) és una de les arítmies cardíaques més freqüents. Hui en dia es sabut que el procés fibrilatori està provocat per l'activitat reentrant de certes regions auriculars que propaguen l'activitat fibril·latoria a la resta del teixit auricular, i s'ha demostrat que l'aïllament elèctric d'aquestes regions dominants permet aturar el procés fibrilatori. La localització de les regions dominants suposa un gran repte en el diagnòstic i tractament d'aquesta arítmia. Amb l'objectiu de poder localitzar fonts fibril·latories amb anterioritat al procediment quirúrgic s'han desenvolupat mètodes no invasius com la cartografia elèctrica de superfície (CES) que registra amb gran resolució espacial l'activitat elèctrica en la superfície del tors o l'electrocardiografia per imatge (ECGI) que permet obtenir de manera no invasiva l'activitat elèctrica en la superfície auricular. Donada la relativa novetat d'aquests sistemes, existeix una manca de coneixement científic sobre els mecanismes físics i tècnics que sustenten el seu funcionament. Per tant, l'objectiu d'aquesta tesi és augmentar aquest coneixement, així com estudiar l'eficàcia d'aquestes tecnologies per a la localització de regions dominants en pacients amb FA. En primer lloc, s'ha vist que els sistemes CES permeten identificar rotors auriculars mitjançant el reconeixement de rotors superficials després del filtrat en banda estreta. A més, la posició dels rotors superficials està relacionada amb la localització d'aquests rotors, permetent la distinció entre rotors de aurícula dreta o esquerra. També s'ha vist que els mapes elèctrics superficials durant FA pateixen un gran suavitzat espacial per l'efecte del volum conductor del tors, el que permet que l'activitat elèctrica superficial pugui ser estudiada amb un nombre relativament reduït d'elèctrodes. Concretament, s'ha vist que 12 elèctrodes uniformement distribuïts són suficients per a una correcta identificació de freqüències dominants auriculars, mentre que són necessaris almenys 32 per a una correcta identificació de rotors auriculars. D'altra banda, també s'ha estudiat l'efecte del filtrat en banda estreta sobre l'eficàcia de la localització de patrons reentrants. Així, s'ha vist que aquest procediment permet aïllar l'activitat elèctrica reentrant provocada pel rotor, augmentant la taxa de detecció tant pel senyal obtingut de manera invasiva com per als mapes superficials. No obstant això, aquest filtrat temporal sobre el senyal de ECGI provoca un gran augment de l'activitat reentrant espúria que dificulta la detecció de patrons reentrants reals. A més, els mapes proporcionats per la ECGI sense filtrat temporal permeten la detecció correcta de l'activitat reentrant, per la qual cosa el filtrat hauria de ser aplicat únicament per a senyal intracavitària o superficial. Per últim, s'ha estudiat l'estabilitat dels marcadors utilitzats en ECGI per a detectar regions auriculars dominants, com són els mapes de freqüència o la presència de rotors. S'ha vist que en presència d'alteracions en les condicions del problema invers, com soroll elèctric o geomètric, aquests marcadors són significativament més estables que la morfologia del mateix senyal ECGI. A més, s'ha proposat una nova metodologia per a la reducció de l'error en la localització espacial de l'aurícula basat en la curvatura de la corba L. Els resultats presentats en aquesta tesi revelen que els sistemes de CES i ECGI permeten localitzar de manera no invasiva la presència de rotors d'alta freqüència. Aquesta detecció és unívoca i robusta, i s'han estudiat els mecanismes físics i tècnics que sustenten aquest comportament. Aquests resultats indiquen que els dos sistemes no invasius proporcionen informació de gran valor clínic en el tractament de la FA, pel que el seu ús pot ser de gran ajuda per a la selecció i planificació de procediments d'ablació auricular. / Rodrigo Bort, M. (2016). Non-invasive identification of atrial fibrillation drivers [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/75346 / Premios Extraordinarios de tesis doctorales

In this dissertation, we describe a novel method that we call Diffusing Colloidal Probe Microscopy (DCPM), which integrates Total Internal Reflection Microscopy (TIRM) and Video Microscopy (VM) methods to monitor three dimensional trajectories in colloidal ensembles levitated above macroscopic surfaces. TIRM and VM are well established optical microscopy techniques for measuring normal and lateral colloidal excursions near macroscopic planar surfaces. The interactions between particle-particle and particle-substrate in colloidal interfacial systems are interpreted by statistical analyses from distributions of colloidal particles; dynamic properties of colloidal assembly are also determined from particle trajectories. Our studies show that DCPM is able to detect many particle-surface interactions simultaneously and provides an ensemble average measurement of particle-surface interactions on a homogeneous surface to allow direct comparison of distributed and average properties. A benefit of ensemble averaging of many particles is the diminished need for time averaging, which can produce orders of magnitude faster measurement times at higher interfacial particle concentrations. The statistical analyses (Ornstein- Zernike and three dimensional Monte Carlo analyses) are used to obtain particle-particle interactions from lateral distribution functions and to understand the role of nonuniformities in interfacial colloidal systems. An inconsistent finding is the observation of an anomalous long range particle-particle attraction and recovery of the expected DLVO particle-wall interactions for all concentrations examined. The possible influence of charge heterogeneity and particle size polydispersity on measured distribution functions is discussed in regard to inconsistent particle-wall and particle-particle potentials. In the final part of this research, the ability of DCPM is demonstrated to map potential energy landscapes on patterned surfaces by monitoring interactions between diffusing colloidal probes with Au pattern features. Absolute separation is obtained from theoretical fits to measured potential energy profiles and direct measurement by sticking silica colloids to Au surfaces via electrophoretic deposition. Initial results indicate that, as colloidal probe and pattern feature dimensions become comparable, measured potential energy profiles suffer some distortion due to the increased probability of probes interacting with surfaces at the edges of adjacent pattern features. Measurements of lateral diffusion via analysis of mean square displacements also indicated lateral diffusion coefficients in excellent agreement with rigorous theoretical predictions.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2009. / Härtill 4 uppsatser.

Orientador: Monica Alonso Cotta / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-11T21:43:56Z (GMT). No. of bitstreams: 1 NarvaezGonzalez_AngelaCarolina_M.pdf: 14145813 bytes, checksum: 31ac8f1ebde240684c9bbe88b9c9b7a7 (MD5) Previous issue date: 2008 / Resumo: As propriedades elétricas de nanofios (InAs, InP, InP-InAs-InP, InAsP) individuais e em junções foram estudadas implementando simultaneamente as técnicas Non Contact Atomic Force Microscopy NC-AFM (para aquisição da topografia) e Amplitude-sensitive Modulated Kelvin Probe Microscopy AM-KPFM (fornece medidas do Potencial de Superfície), permitindo correlacionar as propriedades elétricas com a estrutura da amostra. Em particular, o comportamento do Potencial de Superfície (PS) em função do diâmetro do nanofio foi investigado e utilizado na identificação do material que o compõe. Em uma primeira etapa, a técnica AM-KPFM foi caracterizada, principalmente em termos de resolução para análise de nano-objetos. Nossos resultados evidenciaram um fator de escala presente associado à eletrônica do equipamento, que somente permitiu realizar uma análise qualitativa dos dados adquiridos. Além disso, foi observada uma diminuição no contraste nas medidas elétricas quando o tamanho do objeto analisado diminui. Medidas em nanofios individuais de InP e InAs permitiram estabelecer que há uma queda no PS quando o diâmetro do fio diminui. Este comportamento é o resultado de duas contribuições: a perda no contraste (efeito de tamanho na medida) e o incremento local da função trabalho, que poderíamos associar ao aumento da proporção entre a carga superficial e a carga no interior do fio. Nas junções, há um aumento no PS na região da junção, indicando a formação de uma barreira de energia associada à acumulção de carga. Isto isola as junções do comportamento típico observado em nanofios individuais. Medidas em junções montadas em dispositivos poderiam complementar o estudo deste tipo de configurações. A caracterização do PS em função do diâmetro para os nanofios de InP e InAs permitiu a identificação do material (InAs ou InP) presente ao longo dos fios heteroestruturados de InP-InAs-InP, mostrando também a presença da nanopartícula de ouro usada como catalisador no crescimento. Os contrastes no PS ao longo do fio não se correlacionam diretamente às imagens de Microscopia Eletrônica de Transmissão, sugerindo que a interface elétrica é diferente da metalúrgica. Nos nanofios de InAsP, pelo contrário, os dados obtidos indicam a formação de uma liga ternária / Abstract: The electric properties of InAs, InP, InP-InAs-InP and InAsP nanowires (NWs) -assembled both individually and in junctions - were studied by simultaneous imple-mentation of Non Contact Atomic Force Microscopy NC-AFM (for topography) and Amplitude-sensitive Modulated Kelvin Probe Microscopy AM-KPFM (for Surface Potential distribution), obtaining spatially resolved electrical measurements of the sample structure. In particular, the SP vs NW diameter behavior was investigated and used to identify the material composing the nanowires. In a first approach, AM-KPFM was characterized mainly in terms of resolution for the analysis of the nano-objects. Our results suggest there is a scale factor on our measurements associated to the equipment electronics, that limited our discussion to a qualitative interpretation of the acquired data. Also, a contrast decrease on SP measurements was observed when the size of the object is reduced, comparatively to the tip. The experimental results on individual InAs and InP nanowires showed a SP saturation level (SPsat) below which SP drops with the NW diameter. This behavior came from at least two contributions: a loss of SP contrast due to object/tip size effects and a local increment on work function, that we associate to the larger surface/volume ratio close to the NW tip which makes the material more intrinsic. For NWs on junctions, a larger SP value is correlated to the regions where the junction is formed, possibly due to charge accumulation. Measurements of junctions assembled on devices could complement the study of this kind of structures. The SP vs diameter characterization of InAs and InP nanowires also allowed the identification of the material along the heterostructured InP-InAs-InP nanowire, showing the presence of the Au nanoparticle used to catalyze the growth. The SP image is not directly correlated with HR-TEM images, suggesting that electric and metallurgic interfaces are not the same. For InAsP nanowires, the acquired data indicate the formation of an homogeneous ternary alloy / Mestrado / Física da Matéria Condensada / Mestre em Física

Les processus de transfert de charge sont très importants dans de nombreux domaines de la physique et de la chimie. Ils interviennent en particulier dans la conception ds plasmas astrophysiques ainsi que des plasmas de fusion. Les particules secondaires, électrons lents ou ions, générés le long du trajet des radiations jouent également un rôle crucial dans l’action des radaitions sur le milieu biologique, en relation en particulier avec les traitements du cancer. Il est donc fondamental d’avoir une connaissance approfondie des mécanismes mis en jeu dans ce type de processus, à l’échelle moléculaire. Pour cela, nous avons étudié dans cette thèse deux systèmes voisins, la collision des ions C2+ avec les molécules HF et HCI afin d’ananllyser en détail le mécanisme de transfert de charge dans ces deux réactions en d’en déduire des éléments permettant d’avoir une vue plus générals de ce type de processus. Nous nous sommes en particulier intéressés à l’anisotropie de la réaction de transfert de charge ainsi qu’aux effets dus à la vibration de la molécule diatomique cible lors de la collision. Une étude comparée des ces deux système a montré un mécanisme différent dans chaque cas liés aux interactions non-adiabatiques mises en jeu / Collisiosns of slow multiply charged ions with molecular species have been widely investigated in the past few years. Imortant experimental and theoretical effort has been focused on reactions with simple targets. Consideration of more complex molecular targets are now of increasing interest, in particular with regardto possible direect or indirect processes occuring in the irradiation of the biological medium.. In these reactions generally at relativity low energies, different processes have to be considered: exitation and fragmentation on the molecule, ionization of the gaseous target, and also possible charge transfer from the multicharged ion toward the biomolecule..Charge transfer can be investigated theoretically in the framework of the molecular representation of the collision. Such studies provides important information on the mecanism as well as on the electronic structure of the projectile and target during the reaction. The charge-transfer process in collisions on C2+ ions with hydrogen halide molecule (HF, HCI) has been studied by means of ab initio quantum chemistry molecular methods followed by semiclassical dynamical treatment in the keV collision energy range. The mechanism has been investigated in detail in each reaction, in connection with nonadiabatic interactions around avoided crodssings between states involved in the process.

La démarche expérimentale menée dans cette thèse a eu comme objectif l'étude des facteurs qui influent l'efficacité de collecte des médias non-tissés chargés par décharge couronne, utilisés pour la filtration de l'air. Les recherches se sont focalisées sur les techniques faisant appel à la décharge couronne en configuration fil-plan et en configuration triode (électrode duale + grille + plan de masse). L'étude s'est déroulée en trois phases : (1) mise au point de dispositifs expérimentaux pour générer la décharge couronne et mesurer le potentiel électrique à la surface des échantillons chargés ; (2) caractérisation de l'état de charge des médias ; (3) évaluation de l'efficacité de collecte, en corrélation avec les résultats des mesures de charge. La distribution de charges a été plus homogène en configuration triode et le niveau de charge a été meilleur en polarité positive. Le déplacement de l'échantillon dans la zone de décharge électrique permet de mieux uniformiser la distribution de la charge. L'augmentation du courant de décharge et du potentiel de grille permet d'amplifier le niveau de charge des médias, suite à l'intensification du champ électrique moyen entre l'électrode active et le plan de masse (en configuration fil – plan), ou entre la grille et le plan de masse (en configuration triode). L'efficacité de la collecte est meilleure si la charge est uniformément déposée, sous l'action d'un champ électrique plus intense. Elle est plus élevée pour les configurations dites « multicouches » où la captation des particules est améliorée par l'association de plusieurs mécanismes physiques, mettant en jeux des forces électriques et mécaniques. / The experimental approach undertaken in this thesis was aimed at the study of the factors affecting the collection efficiency of nonwoven media charged by corona discharge, used for air filtration. Research was focused on techniques using the corona discharge generated by wire-plane and triode configurations (dual electrode + grid + ground plane). The study was conducted in three phases: (1) development of experimental devices to generate corona discharge and measure the electrical potential on the surface of charged samples; (2) characterization of the electrostatic charge state of the media; (3) evaluation of the collection efficiency, correlated with the results of charge measurements. The charge distribution was more homogeneous in triode configuration and the charge level was higher in positive polarity. The sample movement in the electric discharge zone allowed for more uniform distribution of the charge. The increase of the discharge current and gate voltage amplifies the charge level of the media, due to the intensification of the average electric field between the active electrode and the ground plane (configuration wire - plane) or between the gate and the ground plane (in triode configuration). The collection efficiency is better when the charge is uniformly deposited, under the action of a strong electric field. It is higher for the so-called "multi-layer" configurations where the capture of the particles is improved by the combination of several physical mechanisms, involving electrical and mechanical forces.

[EN] Atrial tachyarrhythmias present a high prevalence in the developed world, and several studies predict that in the coming decades it will be increased. Micro or macro-reentrant mechanisms of the electrical wavefronts that govern the mechanical behavior of the heart are one of the main responsibles for the maintenance of these arrhythmias. Atrial flutter is maintained by a macro-reentry around an anatomical or functional obstacle located in the atria. In the case of atrial fibrillation, the hypothesis which describes high frequency rotors as dominant sources of the fibrillation and responsible for the maintenance of the arrhythmia, has been gaining relevance in the last years. However, the therapies that target high frequency sources have a limited efficacy with current techniques. Radiofrequency ablation allows the destruction of parts of the cardiac tissue resulting in the interruption of the reentrant circuit in case of macro-reentries or the isolation of micro-reentrant circuits. The non-invasive location of reentrant circuits would increment the efficacy of these therapies and would shorten surgery interventions. In parallel, pharmacological therapies modify ionic expressions associated to the excitability and electrical refractoriness of the cardiac tissue with the objective of hindering the maintenance of reentrant behaviors. These therapies require a deep knowledge of the ionic mechanisms underlying the reentrant behavior and its properties in order to be effective. The research in these mechanisms allows the evaluation of new targets for the treatment and thus may improve the efficacy in atrial fibrillation termination. In this thesis, mathematical modeling is used to go forward in the minimization of the limitations associated to these treatments. Body surface potential mapping has been evaluated, both clinically and by means of mathematical simulations for the diagnosis and location of macro-reentrant circuits. The analysis of phase maps obtained from multiple lead electrocardiographic recordings distributed in the whole torso allowed the discrimination between different reentrant circuits. It is the reason why this technique is presented as a tool for the non-invasive location of macro and micro-reentrant circuits. A population of mathematical models designed in this thesis based on the action potentials recordings of atrial cardiomyocites from 149 patients, allowed the evaluation of the ionic mechanisms defining the properties of reentrant behaviors. This study has allowed us defining the blockade of ICaL as a target for the pharmacological treatment. The blockade of this current is associated with the increase of the movement in the core of the rotor which easies the collision of the rotor with other wavefronts or anatomical obstacles promoting the extinction of the reentry. The variability observed between patients modeled in our population has allowed showing and explaining the mechanisms promoting divergent results of a single treatment. This is why the introduction of populations of models will allow the prevention of side effects associated to inter-subject variability and to go forward in the development of individualized therapies. These works are built through a simulation platform of cardiac electrophysiology based in Graphic Processing Units (GPUs) and developed in this thesis. The platform allows the simulation of cellular models, tissues and organs with a realistic geometry and shows features comparable to that of the platforms used by the most relevant electrophysiology research groups at the moment. / [ES] Las taquiarritmias auriculares tienen una alta prevalencia en el mundo desarrollado, además diversos estudios poblacionales indican que en las próximas décadas ésta se verá incrementada. Los mecanismos de micro o macro-reentrada de los frentes de onda eléctricos que rigen el comportamiento mecánico del corazón, se presentan como una de las principales causas del mantenimiento de estas arritmias. El flutter auricular es mantenido por un macro-reentrada alrededor de un obstáculo anatómico o funcional en las aurículas, mientras que en el caso de la fibrilación auricular la hipótesis que define a los rotores de alta frecuencia como elementos dominantes y responsables del mantenimiento de la arritmia se ha ido imponiendo al resto en los últimos años. Sin embargo, las terapias que tienen como objetivo finalizar o aislar estas reentradas tienen todavía una eficacia limitada. La ablación por radiofrecuencia permite eliminar zonas del tejido cardiaco resultando en la interrupción del circuito de reentrada en el caso de macro-reentradas o el aislamiento de comportamientos micro-reentrantes. La localización no invasiva de los circuitos reentrantes incrementaría la eficacia de estas terapias y reduciría la duración de las intervenciones quirúrgicas. Por otro lado, las terapias farmacológicas alteran las expresiones iónicas asociadas a la excitabilidad y la refractoriedad del tejido con el fin de dificultar el mantenimiento de comportamientos reentrantes. Este tipo de terapias exigen incrementar el conocimiento de los mecanismos subyacentes que explican el proceso de reentrada y sus propiedades, la investigación de estos mecanismos permite definir las dianas terapéuticas que mejoran la eficacia en la extinción de estos comportamientos. En esta tesis el modelado matemático se utiliza para dar un paso importante en la minimización de las limitaciones asociadas a estos tratamientos. La cartografía eléctrica de superficie ha sido testada, clínicamente y con simulaciones matemática,s como técnica de diagnóstico y localización de circuitos macro-reentrantes. El análisis de mapas de fase obtenidos a partir de los registros multicanal de derivaciones electrocardiográficas distribuidas en la superficie del torso permite diferenciar distintos circuitos de reentrada. Es por ello que esta técnica de registro y análisis se presenta como una herramienta para la localización no invasiva de circuitos macro y micro-reentrantes. Una población de modelos matemáticos, diseñada en esta tesis a partir de los registros de los potenciales de acción de 149 pacientes, ha permitido evaluar los mecanismos iónicos que definen las propiedades asociadas a los procesos de reentrada. Esto ha permitido apuntar al bloqueo de la corriente ICaL como diana terapéutica. Ésta se asocia al incremento del movimiento del núcleo que facilita el impacto del rotor con otros frentes de onda u obstáculos extinguiéndose así el comportamiento reentrante. La variabilidad entre pacientes reflejada en la población de modelos ha permitido además mostrar los mecanismos por los cuales un mismo tratamiento puede mostrar efectos divergentes, así el uso de poblaciones de modelos matemáticos permitirá prevenir efectos secundarios asociados a la variabilidad entre pacientes y profundizar en el desarrollo de terapias individualizadas. Estos trabajos se cimientan sobre una plataforma de simulación de electrofisiología cardiaca de basado en Unidades de Procesado Gráfico (GPUs) y desarrollada en esta tesis. La plataforma permite la simulación de modelos celulares cardiacos así como de tejidos u órganos con geometría realista, mostrando unas prestaciones comparables con las de las utilizadas por los grupos de investigación más potentes en el campo de la electrofisiología. / [CA] Les taquiarítmies auriculars tenen una alta prevalença en el món desenvolupat, a més diversos estudis poblacionals indiquen que en les pròximes dècades aquesta es veurà incrementada. Els mecanismes de micro o macro-reentrada dels fronts d'ona elèctrics que regeixen el comportament mecànic del cor, es presenten com una de les principals causes del manteniment d'aquestes arítmies. El flutter auricular és mantingut per una macro-reentrada al voltant d'un obstacle anatòmic o funcional en les aurícules, mentre que en el cas de la fibril·lació auricular la hipòtesi que defineix als rotors d'alta freqüència com a elements dominants i responsables del manteniment de l'arítmia s'ha anat imposant a la resta en els últims anys. No obstant això, les teràpies que tenen com a objectiu finalitzar o aïllar aquestes reentrades tenen encara una eficàcia limitada. L'ablació per radiofreqüència permet eliminar zones del teixit cardíac resultant en la interrupció del circuit de reentrada en el cas de macro-reentrades o l'aïllament de comportaments micro-reentrants. La localització no invasiva dels circuits reentrants incrementaria l'eficàcia d'aquestes teràpies i reduiria la durada de les intervencions quirúrgiques. D'altra banda, les teràpies farmacològiques alteren les expressions iòniques associades a la excitabilitat i la refractaritat del teixit amb la finalitat de dificultar el manteniment de comportaments reentrants. Aquest tipus de teràpies exigeixen incrementar el coneixement dels mecanismes subjacents que expliquen el procés de reentrada i les seues propietats, la recerca d'aquests mecanismes permet definir les dianes terapèutiques que milloren l'eficàcia en l'extinció d'aquests comportaments. En aquesta tesi el modelatge matemàtic s'utilitza per a fer un pas important en la minimització de les limitacions associades a aquests tractaments. La cartografia elèctrica de superfície ha sigut testada, clínicament i amb simulacions matemàtiques com a tècnica de diagnòstic i localització de circuits macro-reentrants. L'anàlisi de mapes de fase obtinguts a partir dels registres multicanal de derivacions electrocardiogràfiques distribuïdes en la superfície del tors permet diferenciar diferents circuits de reentrada. És per açò que aquesta tècnica de registre i anàlisi es presenta com una eina per a la localització no invasiva de circuits macro i micro-reentrants. Una població de models matemàtics, dissenyada en aquesta tesi a partir dels registres dels potencials d'acció de 149 pacients, ha permès avaluar els mecanismes iònics que defineixen les propietats associades als processos de reentrada. Açò ha permès apuntar al bloqueig del corrent ICaL com a diana terapèutica. Aquesta s'associa a l'increment del moviment del nucli que facilita l'impacte del rotor amb altres fronts d'ona o obstacles extingint-se així el comportament reentrant. La variabilitat entre pacients reflectida en la població de models ha permès a més mostrar els mecanismes pels quals un mateix tractament pot mostrar efectes divergents, així l'ús de poblacions de models matemàtics permetrà prevenir efectes secundaris associats a la variabilitat entre pacients i aprofundir en el desenvolupament de teràpies individualitzades. Aquests treballs es fonamenten sobre una plataforma de simulació de electrofisiologia cardíaca basat en Unitats de Processament Gràfic (GPUs) i desenvolupada en aquesta tesi. La plataforma permet la simulació de models cel·lulars cardíacs així com de teixits o òrgans amb geometria realista, mostrant unes prestacions comparables amb les de les utilitzades per els grups de recerca més importants en aquesta área. / Liberos Mascarell, A. (2016). Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166

The sequence-dependent curvature and flexibility of DNA is critical for many biochemically important processes. However, few experimental methods are available for directly probing these properties at the base-pair level. One promising way to predict these properties as a function of sequence is to model DNA with a set of base-pair parameters that describe the local stacking of the different possible base-pair step combinations. In this dissertation research, we develop and study a computational model for predicting the diffusion coefficients of short, relatively rigid DNA fragments from the sequence and the base-pair parameters. We focus on diffusion coefficients because various experimental methods have been developed to measure them. Moreover, these coefficients can also be computed numerically from the Stokes equations based on the three-dimensional shape of the macromolecule. By comparing the predicted diffusion coefficients with experimental measurements, we can potentially obtain refined estimates of various base-pair parameters for DNA. Our proposed model consists of three sub-models. First, we consider the geometric model of DNA, which is sequence-dependent and controlled by a set of base-pair parameters. We introduce a set of new base-pair parameters, which are convenient for computation and lead to a precise geometric interpretation. Initial estimates for these parameters are adapted from crystallographic data. With these parameters, we can translate a DNA sequence into a curved tube of uniform radius with hemispherical end caps, which approximates the effective hydrated surface of the molecule. Second, we consider the solvent model, which captures the hydrodynamic properties of DNA based on its geometric shape. We show that the Stokes equations are the leading-order, time-averaged equations in the particle body frame assuming that the Reynolds number is small. We propose an efficient boundary element method with a priori error estimates for the solution of the exterior Stokes equations. Lastly, we consider the diffusion model, which relates our computed results from the solvent model to relevant measurements from various experimental methods. We study the diffusive dynamics of rigid particles of arbitrary shape which often involves arbitrary cross- and self-coupling between translational and rotational degrees of freedom. We use scaling and perturbation analysis to characterize the dynamics at time scales relevant to different classic experimental methods and identify the corresponding diffusion coefficients. In the end, we give rigorous proofs for the convergence of our numerical scheme and show numerical evidence to support the validity of our proposed models by making comparisons with experimental data. / text

α-Tocopherol has a well known antioxidant action but is also considered likely to exert significant non-antioxidant effects in cell membranes. Due to its lipophilic nature α-tocopherol inserts into biological membranes where it influences the organisation of the component lipids and may therefore influence biophysical parameters including the membrane dipole potential. The dipole potential has been demonstrated to modulate the function of several membrane associated proteins and perturbation of this physical parameter by α-tocopherol may prove to be a significant non-antioxidant mechanism underlying several of its cellular effects. This study investigates the influence of α-tocopherol, and the non-antioxidant structural analogue α-tocopherol succinate, on the membrane dipole potential employing fluorescence spectroscopy techniques with the dipole potential sensitive probe Di-8-ANEPPS. Similar techniques are utilised with the surface potential sensitive probe FPE to investigate the interaction of the charged α-tocopherol succinate molecule with membranes. α-Tocopherol and α-tocopherol succinate are shown to decrease the dipole potential of egg-phosphatidylcholine vesicles and Jurkat T-lymphocyte cell membranes. This effect is placed in the context of the significant influence of membrane cholesterol oxidation on the dipole potential. 7-ketocholesterol, an oxidised form of cholesterol, significantly influences several cellular processes and is thought to mediate these effects, in part, through its physical effects on the cell membrane. These include altering the composition, and therefore biophysical properties, of rafts; structures which are considered to support the function of a host of membrane proteins. This study attempts to correlate the effect of 7-ketocholesterol on the dipole potential of microdomains with the influence of the oxysterol on the function of two microdomains associated receptors: P-glycoprotein and the insulin receptor, assessed by determining the extent of ligand binding using flow fluorocytometry. α-Tocopherol has been suggested to inhibit the raft-mediated effects of 7-ketocholesterol and the influence of this molecule on the effect of 7-ketocholesterol on the dipole potential are investigated as a potential mechanism for this inhibition. It is hypothesized that α-tocopherols may protect against the deleterious effects of cholesterol oxidation in cell membranes by excluding 7-ketocholesterol from specific microdomains, of which rafts are a subset, acting to preserve their dipole potential and maintain the function of the proteins they support. However, where significant cholesterol oxidation has previously occured the concurrent changes in the microdomain landscape of the membrane is suggested to prevent α-tocopherol succinate from eliciting this protective effect.

The object of this work is to obtain a fundamentalunderstanding of the principal issues concerning the handlingof an aqueous WC-Co powder suspension. The WO3 surface layer on the oxidised tungsten carbidepowder dissolves at pH&gt;3 with the tungsten concentrationincreasing linearly with time. Adding cobalt powder to thetungsten carbide suspension resulted in a significant reductionof the dissolution rate at pH&lt;10. Electrokinetic studiesindicated that the reduced dissolution rate may be related tothe formation of surface complexes; the experiments showed thatCo species in solution adsorb on the oxidised tungsten carbidepowder. The surface forces of oxidised tungsten and cobalt surfaceswere investigated using the atomic force microscope (AFM)colloidal probe technique. The interactions at various ionicstrengths and pH values are well described by DLVO theory. Theadsorption of cobalt ions to tungsten oxide surfaces resultedin an additional non-DLVO force and a reduced absolute value ofthe surface potential. It was shown that the adsorption ofpoly(ethylene imine) (PEI) to the WO3 surfaces induces anelectrosteric repulsion. The properties of spray-dried WC-Co granules were related tothe WC primary particle size, and the poly(ethylene glycol)(PEG) binder and PEI dispersant content in aqueous WC-Cosuspensions. The granule characterisation includes a new methodfor measuring the density of single granules. The increase inthe fracture strength of granules produced from suspensionsthat were stabilised with PEI was related to a more densepacking of the WC-Co particles. The AFM was used to study the friction and adhesion ofsingle spray-dried WC-Co granules containing various amounts ofPEG binder. The adhesion and friction force between two singlegranules (intergranular friction) and between a granule and ahard metal substrate (die-wall friction) have been determinedas a function of relative humidity. The granule-wall frictionincreases with binder content and relative humidity, whereasthe granule-granule friction is essentially independent of therelative humidity and substantially lower than the granule-wallfriction at all PEG contents. Key words:Hard Metal, Cemented Carbide, WC-Co, TungstenCarbide, Cobalt, Oxidation, Dissolution, Surface Complexation,XPS, AFM, Colloidal Probe, Hamaker Constant, Cauchy, WO3,CoOOH, ESCA, Zeta-Potential, Surface Potential, Poly(ethyleneimine), PEI, Suspension, van der Waals, Steric, Spray-Dried,Poly(ethylene glycol), Strength, Density, Friction, Adhesion,Granule, PEG, Pressing, FFM. / <p>QC 20161027</p>