Quantitative single-molecule localization microscopy combined with rule-based modeling reveals ligand-induced TNF-R1 reorganization toward higher-order oligomers

We report on the assembly of tumor necrosis factor receptor 1 (TNF-R1) prior to ligand activation and its ligand-induced reorganization at the cell membrane. We apply single-molecule localization microscopy to obtain quantitative information on receptor cluster sizes and copy numbers. Our data suggest a dimeric pre-assembly of TNF-R1, as well as receptor reorganization toward higher oligomeric states with stable populations comprising three to six TNF-R1. Our experimental results directly serve as input parameters for computational modeling of the ligand-receptor interaction. Simulations corroborate the experimental finding of higher-order oligomeric states. This work is a first demonstration how quantitative, super-resolution and advanced microscopy can be used for systems biology approaches at the single-molecule and single-cell level.

Tridimensional modeling of the cardiac wall

The advance in the graphic computer's techniques and computer's capacity of processing made possible applications like the human anatomic structures modeling, in order to investigate diseases, surgical planning or even provide images for training of Computer Aided Diagnosis (CAD). On this context, this work exhibits an anatomical model of cardiac structures represented in a tridimensional environment. The model was represented with geometrical elements and has anatomical details, as the different tunics that compose the cardiac wall and measures that preserves the characteristics found on real structures. The validation of the anatomical model was made through quantitative comparations with real structures measures, available on specialized literature. The results obtained, evaluated by two specialists, are compatible with real anatomies, respecting the anatomical particularities. This degree of representation will allow the verification of the influence of radiological parameters, morphometric peculiarities and stage of the cardiac diseases on the quality of the images, as well as on the performance of the CAD. © 2010 IEEE.

Computer graphics applied to anatomy: a study of two bio-cad modeling methods on finite element analysis of human edentulous hemi-mandible

Modeling is a step to perform a finite element analysis. Different methods of model construction are reported in literature, as the Bio-CAD modeling. The purpose of this study was to perform a model evaluation and application using two methods of Bio-CAD modeling from human edentulous hemi-mandible on the finite element analysis. From CT scans of dried human skull was reconstructed a stereolithographic model. Two methods of modeling were performed: STL conversion approach (Model 1) associated to STL simplification and reverse engineering approach (Model 2). For finite element analysis was used the action of lateral pterygoid muscle as loading condition to assess total displacement (D), equivalent von-Mises stress (VM) and maximum principal stress (MP). Two models presented differences on the geometry regarding surface number (1834 (model 1); 282 (model 2)). Were observed differences in finite element mesh regarding element number (30428 nodes/16683 elements (model 1); 15801 nodes/8410 elements (model 2). D, VM and MP stress areas presented similar distribution in two models. The values were different regarding maximum and minimum values of D (ranging 0-0.511 mm (model 1) and 0-0.544 mm (model 2), VM stress (6.36E-04-11.4 MPa (model 1) and 2.15E-04-14.7 MPa (model 2) and MP stress (-1.43-9.14 MPa (model 1) and -1.2-11.6 MPa (model 2). From two methods of Bio-CAD modeling, the reverse engineering presented better anatomical representation compared to the STL conversion approach. The models presented differences in the finite element mesh, total displacement and stress distribution.

Mathematical Modeling to Investigate Antiarrhythmic Drug Side Effects: Rate-Dependence Role in Ionic Currents and Action Potentials Shape in the O’Hara Model

Sudden cardiac death due to ventricular arrhythmia is one of the leading causes of mortality in the world. In the last decades, it has proven that anti-arrhythmic drugs, which prolong the refractory period by means of prolongation of the cardiac action potential duration (APD), play a good role in preventing of relevant human arrhythmias. However, it has long been observed that the “class III antiarrhythmic effect” diminish at faster heart rates and that this phenomenon represent a big weakness, since it is the precise situation when arrhythmias are most prone to occur. It is well known that mathematical modeling is a useful tool for investigating cardiac cell behavior. In the last 60 years, a multitude of cardiac models has been created; from the pioneering work of Hodgkin and Huxley (1952), who first described the ionic currents of the squid giant axon quantitatively, mathematical modeling has made great strides. The O’Hara model, that I employed in this research work, is one of the modern computational models of ventricular myocyte, a new generation began in 1991 with ventricular cell model by Noble et al. Successful of these models is that you can generate novel predictions, suggest experiments and provide a quantitative understanding of underlying mechanism. Obviously, the drawback is that they remain simple models, they don’t represent the real system. The overall goal of this research is to give an additional tool, through mathematical modeling, to understand the behavior of the main ionic currents involved during the action potential (AP), especially underlining the differences between slower and faster heart rates. In particular to evaluate the rate-dependence role on the action potential duration, to implement a new method for interpreting ionic currents behavior after a perturbation effect and to verify the validity of the work proposed by Antonio Zaza using an injected current as a perturbing effect.

Modeling Calcium Concentration and Biochemical Reactions

Almost all regions of the brain receive one or more neuromodulatory inputs, and disrupting these inputs produces deficits in neuronal function. Neuromodulators act through intracellular second messenger pathways to influence the electrical properties of neurons, integration of synaptic inputs, spatio-temporal firing dynamics of neuronal networks, and, ultimately, systems behavior. Second messengers pathways consist of series of bimolecular reactions, enzymatic reactions, and diffusion. Calcium is the second messenger molecule with the most effectors, and thus is highly regulated by buffers, pumps and intracellular stores. Computational modeling provides an innovative, yet practical method to evaluate the spatial extent, time course and interaction among second messenger pathways, and the interaction of second messengers with neuron electrical properties. These processes occur both in compartments where the number of molecules are large enough to describe reactions deterministically (e.g. cell body), and in compartments where the number of molecules is small enough that reactions occur stochastically (e.g. spines). – In this tutorial, I explain how to develop models of second messenger pathways and calcium dynamics. The first part of the tutorial explains the equations used to model bimolecular reactions, enzyme reactions, calcium release channels, calcium pumps and diffusion. The second part explains some of the GENESIS, Kinetikit and Chemesis objects that implement the appropriate equations. In depth explanation of calcium and second messenger models is provided by reviewing code, both in XPP, Chemesis and Kinetikit, that implements simple models of calcium dynamics and second messenger cascades.

Predictive oncology: a review of multidisciplinary, multiscale in silico modeling linking phenotype, morphology and growth.

Empirical evidence and theoretical studies suggest that the phenotype, i.e., cellular- and molecular-scale dynamics, including proliferation rate and adhesiveness due to microenvironmental factors and gene expression that govern tumor growth and invasiveness, also determine gross tumor-scale morphology. It has been difficult to quantify the relative effect of these links on disease progression and prognosis using conventional clinical and experimental methods and observables. As a result, successful individualized treatment of highly malignant and invasive cancers, such as glioblastoma, via surgical resection and chemotherapy cannot be offered and outcomes are generally poor. What is needed is a deterministic, quantifiable method to enable understanding of the connections between phenotype and tumor morphology. Here, we critically assess advantages and disadvantages of recent computational modeling efforts (e.g., continuum, discrete, and cellular automata models) that have pursued this understanding. Based on this assessment, we review a multiscale, i.e., from the molecular to the gross tumor scale, mathematical and computational "first-principle" approach based on mass conservation and other physical laws, such as employed in reaction-diffusion systems. Model variables describe known characteristics of tumor behavior, and parameters and functional relationships across scales are informed from in vitro, in vivo and ex vivo biology. We review the feasibility of this methodology that, once coupled to tumor imaging and tumor biopsy or cell culture data, should enable prediction of tumor growth and therapy outcome through quantification of the relation between the underlying dynamics and morphological characteristics. In particular, morphologic stability analysis of this mathematical model reveals that tumor cell patterning at the tumor-host interface is regulated by cell proliferation, adhesion and other phenotypic characteristics: histopathology information of tumor boundary can be inputted to the mathematical model and used as a phenotype-diagnostic tool to predict collective and individual tumor cell invasion of surrounding tissue. This approach further provides a means to deterministically test effects of novel and hypothetical therapy strategies on tumor behavior.

Modeling of ore-forming and geoenvironmental systems: Roles of fluid flow and chemical reaction processes

Ore-forming and geoenviromental systems commonly involve coupled fluid flowand chemical reaction processes. The advanced numerical methods and computational modeling have become indispensable tools for simulating such processes in recent years. This enables many hitherto unsolvable geoscience problems to be addressed using numerical methods and computational modeling approaches. For example, computational modeling has been successfully used to solve ore-forming and mine site contamination/remediation problems, in which fluid flow and geochemical processes play important roles in the controlling dynamic mechanisms. The main purpose of this paper is to present a generalized overview of: (1) the various classes and models associated with fluid flow/chemically reacting systems in order to highlight possible opportunities and developments for the future; (2) some more general issues that need attention in the development of computational models and codes for simulating ore-forming and geoenviromental systems; (3) the related progresses achieved on the geochemical modeling over the past 50 years or so; (4) the general methodology for modeling of oreforming and geoenvironmental systems; and (5) the future development directions associated with modeling of ore-forming and geoenviromental systems.

User-centric need-driven affect modeling for spoken conversational agents: design and evaluation

It is easy to get frustrated at spoken conversational agents (SCAs), perhaps because they seem to be callous. By and large, the quality of human-computer interaction is affected due to the inability of the SCAs to recognise and adapt to user emotional state. Now with the mass appeal of artificially-mediated communication, there has been an increasing need for SCAs to be socially and emotionally intelligent, that is, to infer and adapt to their human interlocutors’ emotions on the fly, in order to ascertain an affective, empathetic and naturalistic interaction. An enhanced quality of interaction would reduce users’ frustrations and consequently increase their satisfactions. These reasons have motivated the development of SCAs towards including socio-emotional elements, turning them into affective and socially-sensitive interfaces. One barrier to the creation of such interfaces has been the lack of methods for modelling emotions in a task-independent environment. Most emotion models for spoken dialog systems are task-dependent and thus cannot be used “as-is” in different applications. This Thesis focuses on improving this, in which it concerns computational modeling of emotion, personality and their interrelationship for task-independent autonomous SCAs. The generation of emotion is driven by needs, inspired by human’s motivational systems. The work in this Thesis is organised in three stages, each one with its own contribution. The first stage involved defining, integrating and quantifying the psychological-based motivational and emotional models sourced from. Later these were transformed into a computational model by implementing them into software entities. The computational model was then incorporated and put to test with an existing SCA host, a HiFi-control agent. The second stage concerned automatic prediction of affect, which has been the main challenge towards the greater aim of infusing social intelligence into the HiFi agent. In recent years, studies on affect detection from voice have moved on to using realistic, non-acted data, which is subtler. However, it is more challenging to perceive subtler emotions and this is demonstrated in tasks such as labelling and machine prediction. In this stage, we attempted to address part of this challenge by considering the roles of user satisfaction ratings and conversational/dialog features as the respective target and predictors in discriminating contentment and frustration, two types of emotions that are known to be prevalent within spoken human-computer interaction. The final stage concerned the evaluation of the emotional model through the HiFi agent. A series of user studies with 70 subjects were conducted in a real-time environment, each in a different phase and with its own conditions. All the studies involved the comparisons between the baseline non-modified and the modified agent. The findings have gone some way towards enhancing our understanding of the utility of emotion in spoken dialog systems in several ways; first, an SCA should not express its emotions blindly, albeit positive. Rather, it should adapt its emotions to user states. Second, low performance in an SCA may be compensated by the exploitation of emotion. Third, the expression of emotion through the exploitation of prosody could better improve users’ perceptions of an SCA compared to exploiting emotions through just lexical contents. Taken together, these findings not only support the success of the emotional model, but also provide substantial evidences with respect to the benefits of adding emotion in an SCA, especially in mitigating users’ frustrations and ultimately improving their satisfactions. Resumen Es relativamente fácil experimentar cierta frustración al interaccionar con agentes conversacionales (Spoken Conversational Agents, SCA), a menudo porque parecen ser un poco insensibles. En general, la calidad de la interacción persona-agente se ve en cierto modo afectada por la incapacidad de los SCAs para identificar y adaptarse al estado emocional de sus usuarios. Actualmente, y debido al creciente atractivo e interés de dichos agentes, surge la necesidad de hacer de los SCAs unos seres cada vez más sociales y emocionalmente inteligentes, es decir, con capacidad para inferir y adaptarse a las emociones de sus interlocutores humanos sobre la marcha, de modo que la interacción resulte más afectiva, empática y, en definitiva, natural. Una interacción mejorada en este sentido permitiría reducir la posible frustración de los usuarios y, en consecuencia, mejorar el nivel de satisfacción alcanzado por los mismos. Estos argumentos justifican y motivan el desarrollo de nuevos SCAs con capacidades socio-emocionales, dotados de interfaces afectivas y socialmente sensibles. Una de las barreras para la creación de tales interfaces ha sido la falta de métodos de modelado de emociones en entornos independientes de tarea. La mayoría de los modelos emocionales empleados por los sistemas de diálogo hablado actuales son dependientes de tarea y, por tanto, no pueden utilizarse "tal cual" en diferentes dominios o aplicaciones. Esta tesis se centra precisamente en la mejora de este aspecto, la definición de modelos computacionales de las emociones, la personalidad y su interrelación para SCAs autónomos e independientes de tarea. Inspirada en los sistemas motivacionales humanos en el ámbito de la psicología, la tesis propone un modelo de generación/producción de la emoción basado en necesidades. El trabajo realizado en la presente tesis está organizado en tres etapas diferenciadas, cada una con su propia contribución. La primera etapa incluyó la definición, integración y cuantificación de los modelos motivacionales de partida y de los modelos emocionales derivados a partir de éstos. Posteriormente, dichos modelos emocionales fueron plasmados en un modelo computacional mediante su implementación software. Este modelo computacional fue incorporado y probado en un SCA anfitrión ya existente, un agente con capacidad para controlar un equipo HiFi, de alta fidelidad. La segunda etapa se orientó hacia el reconocimiento automático de la emoción, aspecto que ha constituido el principal desafío en relación al objetivo mayor de infundir inteligencia social en el agente HiFi. En los últimos años, los estudios sobre reconocimiento de emociones a partir de la voz han pasado de emplear datos actuados a usar datos reales en los que la presencia u observación de emociones se produce de una manera mucho más sutil. El reconocimiento de emociones bajo estas condiciones resulta mucho más complicado y esta dificultad se pone de manifiesto en tareas tales como el etiquetado y el aprendizaje automático. En esta etapa, se abordó el problema del reconocimiento de las emociones del usuario a partir de características o métricas derivadas del propio diálogo usuario-agente. Gracias a dichas métricas, empleadas como predictores o indicadores del grado o nivel de satisfacción alcanzado por el usuario, fue posible discriminar entre satisfacción y frustración, las dos emociones prevalentes durante la interacción usuario-agente. La etapa final corresponde fundamentalmente a la evaluación del modelo emocional por medio del agente Hifi. Con ese propósito se llevó a cabo una serie de estudios con usuarios reales, 70 sujetos, interaccionando con diferentes versiones del agente Hifi en tiempo real, cada uno en una fase diferente y con sus propias características o capacidades emocionales. En particular, todos los estudios realizados han profundizado en la comparación entre una versión de referencia del agente no dotada de ningún comportamiento o característica emocional, y una versión del agente modificada convenientemente con el modelo emocional propuesto. Los resultados obtenidos nos han permitido comprender y valorar mejor la utilidad de las emociones en los sistemas de diálogo hablado. Dicha utilidad depende de varios aspectos. En primer lugar, un SCA no debe expresar sus emociones a ciegas o arbitrariamente, incluso aunque éstas sean positivas. Más bien, debe adaptar sus emociones a los diferentes estados de los usuarios. En segundo lugar, un funcionamiento relativamente pobre por parte de un SCA podría compensarse, en cierto modo, dotando al SCA de comportamiento y capacidades emocionales. En tercer lugar, aprovechar la prosodia como vehículo para expresar las emociones, de manera complementaria al empleo de mensajes con un contenido emocional específico tanto desde el punto de vista léxico como semántico, ayuda a mejorar la percepción por parte de los usuarios de un SCA. Tomados en conjunto, los resultados alcanzados no sólo confirman el éxito del modelo emocional, sino xv que constituyen además una evidencia decisiva con respecto a los beneficios de incorporar emociones en un SCA, especialmente en cuanto a reducir el nivel de frustración de los usuarios y, en última instancia, mejorar su satisfacción.

Large scale multiphysics modeling of neurites

Situado en el límite entre Ingeniería, Informática y Biología, la mecánica computacional de las neuronas aparece como un nuevo campo interdisciplinar que potencialmente puede ser capaz de abordar problemas clínicos desde una perspectiva diferente. Este campo es multiescala por naturaleza, yendo desde la nanoescala (como, por ejemplo, los dímeros de tubulina) a la macroescala (como, por ejemplo, el tejido cerebral), y tiene como objetivo abordar problemas que son complejos, y algunas veces imposibles, de estudiar con medios experimentales. La modelización computacional ha sido ampliamente empleada en aplicaciones Neurocientíficas tan diversas como el crecimiento neuronal o la propagación de los potenciales de acción compuestos. Sin embargo, en la mayoría de los enfoques de modelización hechos hasta ahora, la interacción entre la célula y el medio/estímulo que la rodea ha sido muy poco explorada. A pesar de la tremenda importancia de esa relación en algunos desafíos médicos—como, por ejemplo, lesiones traumáticas en el cerebro, cáncer, la enfermedad del Alzheimer—un puente que relacione las propiedades electrofisiológicas-químicas y mecánicas desde la escala molecular al nivel celular todavía no existe. Con ese objetivo, esta investigación propone un marco computacional multiescala particularizado para dos escenarios respresentativos: el crecimiento del axón y el acomplamiento electrofisiológicomecánico de las neuritas. En el primer caso, se explora la relación entre los constituyentes moleculares del axón durante su crecimiento y sus propiedades mecánicas resultantes, mientras que en el último, un estímulo mecánico provoca deficiencias funcionales a nivel celular como consecuencia de sus alteraciones electrofisiológicas-químicas. La modelización computacional empleada en este trabajo es el método de las diferencias finitas, y es implementada en un nuevo programa llamado Neurite. Aunque el método de los elementos finitos es también explorado en parte de esta investigación, el método de las diferencias finitas tiene la flexibilidad y versatilidad necesaria para implementar mode los biológicos, así como la simplicidad matemática para extenderlos a simulaciones a gran escala con un coste computacional bajo. Centrándose primero en el efecto de las propiedades electrofisiológicas-químicas sobre las propiedades mecánicas, una versión adaptada de Neurite es desarrollada para simular la polimerización de los microtúbulos en el crecimiento del axón y proporcionar las propiedades mecánicas como función de la ocupación de los microtúbulos. Después de calibrar el modelo de crecimiento del axón frente a resultados experimentales disponibles en la literatura, las características mecánicas pueden ser evaluadas durante la simulación. Las propiedades mecánicas del axón muestran variaciones dramáticas en la punta de éste, donde el cono de crecimiento soporta las señales químicas y mecánicas. Bansándose en el conocimiento ganado con el modelo de diferencias finitas, y con el objetivo de ir de 1D a 3D, este esquema preliminar pero de una naturaleza innovadora allana el camino a futuros estudios con el método de los elementos finitos. Centrándose finalmente en el efecto de las propiedades mecánicas sobre las propiedades electrofisiológicas- químicas, Neurite es empleado para relacionar las cargas mecánicas macroscópicas con las deformaciones y velocidades de deformación a escala microscópica, y simular la propagación de la señal eléctrica en las neuritas bajo carga mecánica. Las simulaciones fueron calibradas con resultados experimentales publicados en la literatura, proporcionando, por tanto, un modelo capaz de predecir las alteraciones de las funciones electrofisiológicas neuronales bajo cargas externas dañinas, y uniendo lesiones mecánicas con las correspondientes deficiencias funcionales. Para abordar simulaciones a gran escala, aunque otras arquitecturas avanzadas basadas en muchos núcleos integrados (MICs) fueron consideradas, los solvers explícito e implícito se implementaron en unidades de procesamiento central (CPU) y unidades de procesamiento gráfico (GPUs). Estudios de escalabilidad fueron llevados acabo para ambas implementaciones mostrando resultados prometedores para casos de simulaciones extremadamente grandes con GPUs. Esta tesis abre la vía para futuros modelos mecánicos con el objetivo de unir las propiedades electrofisiológicas-químicas con las propiedades mecánicas. El objetivo general es mejorar el conocimiento de las comunidades médicas y de bioingeniería sobre la mecánica de las neuronas y las deficiencias funcionales que aparecen de los daños producidos por traumatismos mecánicos, como lesiones traumáticas en el cerebro, o enfermedades neurodegenerativas como la enfermedad del Alzheimer. ABSTRACT Sitting at the interface between Engineering, Computer Science and Biology, Computational Neuron Mechanics appears as a new interdisciplinary field potentially able to tackle clinical problems from a new perspective. This field is multiscale by nature, ranging from the nanoscale (e.g., tubulin dimers) to the macroscale (e.g., brain tissue), and aims at tackling problems that are complex, and sometime impossible, to study through experimental means. Computational modeling has been widely used in different Neuroscience applications as diverse as neuronal growth or compound action potential propagation. However, in the majority of the modeling approaches done in this field to date, the interactions between the cell and its surrounding media/stimulus have been rarely explored. Despite of the tremendous importance of such relationship in several medical challenges—e.g., traumatic brain injury (TBI), cancer, Alzheimer’s disease (AD)—a bridge between electrophysiological-chemical and mechanical properties of neurons from the molecular scale to the cell level is still lacking. To this end, this research proposes a multiscale computational framework particularized for two representative scenarios: axon growth and electrophysiological-mechanical coupling of neurites. In the former case, the relation between the molecular constituents of the axon during its growth and its resulting mechanical properties is explored, whereas in the latter, a mechanical stimulus provokes functional deficits at cell level as a consequence of its electrophysiological-chemical alterations. The computational modeling approach chosen in this work is the finite difference method (FDM), and was implemented in a new program called Neurite. Although the finite element method (FEM) is also explored as part of this research, the FDM provides the necessary flexibility and versatility to implement biological models, as well as the mathematical simplicity to extend them to large scale simulations with a low computational cost. Focusing first on the effect of electrophysiological-chemical properties on the mechanical proper ties, an adaptation of Neurite was developed to simulate microtubule polymerization in axonal growth and provide the axon mechanical properties as a function of microtubule occupancy. After calibrating the axon growth model against experimental results available in the literature, the mechanical characteristics can be tracked during the simulation. The axon mechanical properties show dramatic variations at the tip of the axon, where the growth cone supports the chemical and mechanical signaling. Based on the knowledge gained from the FDM scheme, and in order to go from 1D to 3D, this preliminary yet novel scheme paves the road for future studies with FEM. Focusing then on the effect of mechanical properties on the electrophysiological-chemical properties, Neurite was used to relate macroscopic mechanical loading to microscopic strains and strain rates, and simulate the electrical signal propagation along neurites under mechanical loading. The simulations were calibrated against experimental results published in the literature, thus providing a model able to predict the alteration of neuronal electrophysiological function under external damaging load, and linking mechanical injuries to subsequent acute functional deficits. To undertake large scale simulations, although other state-of-the-art architectures based on many integrated cores (MICs) were considered, the explicit and implicit solvers were implemented for central processing units (CPUs) and graphics processing units (GPUs). Scalability studies were done for both implementations showing promising results for extremely large scale simulations with GPUs. This thesis opens the avenue for future mechanical modeling approaches aimed at linking electrophysiological- chemical properties to mechanical properties. Its overarching goal is to enhance the bioengineering and medical communities knowledge on neuronal mechanics and functional deficits arising from damages produced by direct mechanical insults, such as TBI, or neurodegenerative evolving illness, such as AD.

Forces from highly focused laser beams: Modeling, measurement and application to refractive index measurements

The optical forces in optical tweezers can be robustly modeled over a broad range of parameters using generalsed Lorenz–Mie theory. We describe the procedure, and show how the combination of experimental measurement of properties of the trap coupled with computational modeling, can allow unknown parameters of the particle—in this case, the refractive index—to be determined.

A New Method for Modeling Free Surface Flows and Fluid-structure Interaction with Ocean Applications

The computational modeling of ocean waves and ocean-faring devices poses numerous challenges. Among these are the need to stably and accurately represent both the fluid-fluid interface between water and air as well as the fluid-structure interfaces arising between solid devices and one or more fluids. As techniques are developed to stably and accurately balance the interactions between fluid and structural solvers at these boundaries, a similarly pressing challenge is the development of algorithms that are massively scalable and capable of performing large-scale three-dimensional simulations on reasonable time scales. This dissertation introduces two separate methods for approaching this problem, with the first focusing on the development of sophisticated fluid-fluid interface representations and the second focusing primarily on scalability and extensibility to higher-order methods.

We begin by introducing the narrow-band gradient-augmented level set method (GALSM) for incompressible multiphase Navier-Stokes flow. This is the first use of the high-order GALSM for a fluid flow application, and its reliability and accuracy in modeling ocean environments is tested extensively. The method demonstrates numerous advantages over the traditional level set method, among these a heightened conservation of fluid volume and the representation of subgrid structures.

Next, we present a finite-volume algorithm for solving the incompressible Euler equations in two and three dimensions in the presence of a flow-driven free surface and a dynamic rigid body. In this development, the chief concerns are efficiency, scalability, and extensibility (to higher-order and truly conservative methods). These priorities informed a number of important choices: The air phase is substituted by a pressure boundary condition in order to greatly reduce the size of the computational domain, a cut-cell finite-volume approach is chosen in order to minimize fluid volume loss and open the door to higher-order methods, and adaptive mesh refinement (AMR) is employed to focus computational effort and make large-scale 3D simulations possible. This algorithm is shown to produce robust and accurate results that are well-suited for the study of ocean waves and the development of wave energy conversion (WEC) devices.

Modern Computational Chemistry Methods for Prediction of Ground- and Excited-State Properties in Open-Shell Systems

The main goal of the research presented in this work is to provide some important insights about computational modeling of open-shell species. Such projects are: the investigation of the size-extensivity error in Equation-of-Motion Coupled Cluster methods, the analysis of the Long-Range corrected scheme in predicting UV-Vis spectra of Cu(II) complexes with the 4-imidazole acetate and its ethylated derivative, and the exploration of the importance of choosing a proper basis set for the description of systems such as the lithium monoxide anion. The most significant findings of this research are: (i) The contribution of the left operator to the size-extensivity error of the CR-EOMCC(2,3) approach, (ii) The cause of d-d shifts when varying the range-separation parameter and the amount of the exact exchange arising from the imbalanced treatment of localized vs. delocalized orbitals via the "tuned" CAM-B3LYP* functional, (iii) The proper acidity trend of the first-row hydrides and their lithiated analogs that may be reversed if the basis sets are not correctly selected.

A NATURALISTIC COMPUTATIONAL MODEL OF HUMAN BEHAVIOR IN NAVIGATION AND SEARCH TASKS

Planning, navigation, and search are fundamental human cognitive abilities central to spatial problem solving in search and rescue, law enforcement, and military operations. Despite a wealth of literature concerning naturalistic spatial problem solving in animals, literature on naturalistic spatial problem solving in humans is comparatively lacking and generally conducted by separate camps among which there is little crosstalk. Addressing this deficiency will allow us to predict spatial decision making in operational environments, and understand the factors leading to those decisions. The present dissertation is comprised of two related efforts, (1) a set of empirical research studies intended to identify characteristics of planning, execution, and memory in naturalistic spatial problem solving tasks, and (2) a computational modeling effort to develop a model of naturalistic spatial problem solving. The results of the behavioral studies indicate that problem space hierarchical representations are linear in shape, and that human solutions are produced according to multiple optimization criteria. The Mixed Criteria Model presented in this dissertation accounts for global and local human performance in a traditional and naturalistic Traveling Salesman Problem. The results of the empirical and modeling efforts hold implications for basic and applied science in domains such as problem solving, operations research, human-computer interaction, and artificial intelligence.

Computational Analysis Based on Parametric Models of Historic Masonry Vaulted Structures Strengthened by Fiber-Reinforced Composite Materials

Historic vaulted masonry structures often need strengthening interventions that can effectively improve their structural performance, especially during seismic events, and at the same time respect the existing setting and the modern conservation requirements. In this context, the use of innovative materials such as fiber-reinforced composite materials has been shown as an effective solution that can satisfy both aspects. This work aims to provide insight into the computational modeling of a full-scale masonry vault strengthened by fiber-reinforced composite materials and analyze the influence of the arrangement of the reinforcement on the efficiency of the intervention. At first, a parametric model of a cross vault focusing on a realistic representation of its micro-geometry is proposed. Then numerical modeling, simulating the pushover analyses, of several barrel vaults reinforced with different reinforcement configurations is performed. Finally, the results are collected and discussed in terms of force-displacement curves obtained for each proposed configuration.

Finite element analysis of concrete cracking at early age

The study of the early age concrete properties is becoming more important, as the thermal effects and the shrinkage, even in the first hours, could generate cracks, increasing the permeability of the structure and being able to induce problems of durability and functionality in the same ones. The detailed study of the stresses development during the construction process can be decisive to keep low the cracking levels. In this work a computational model, based on the finite element method, was implemented to simulate the early age concrete behavior and, specially, the evaluation of the cracking risk. The finite element analysis encloses the computational modeling of the following phenomena: chemical, thermal, moisture diffusion and mechanical which occur at the first days after the concrete cast. The developed software results were compared with experimental values found in the literature, demonstrating an excellent approach for all the implemented analysis.