El cerebro humano está formado por una compleja red de células nerviosas que utilizan diversas señales para comunicarse entre ellas. La propagación de señales tiene lugar en la sinapsis química en donde el neurotransmisor liberado por la neurona presináptica interacciona con un receptor postsináptico específico. Los canales iónicos activados por ligandos (LGIC) median respuestas rápidas en dichas sinapsis. El rol vital de los mismos es convertir una señal química en un impulso eléctrico. Para generar una respuesta adecuada los LGIC deben ser capaces de activarse en presencia del neurotransmisor y cerrarse en su ausencia. Estos receptores están involucrados en el aprendizaje, la memoria, el movimiento y en enfermedades genéticas, y son blancos de numerosos fármacos. Los receptores pentaméricos Cys-loop son LGIC que intervienen en sinapsis químicas rápidas. La duración, amplitud y frecuencia de una respuesta sináptica es gobernada por la cinética de apertura, cierre y desensibilización del canal. Los mecanismos moleculares de estos procesos no se conocen todavía. Los receptores poseen un dominio extracelular, unidor del neurotransmisor, y una región transmembranal, formadora del poro iónico. Uno de los objetivos de este trabajo de Tesis fue dilucidar el rol funcional de la interfase entre ambos dominios. Con este fin utilizamos receptores homopentaméricos con interfases con secuencias de 7 y 5-HT3A en los diferentes loops que las componen y evaluamos los tiempos de apertura y desensibilización de los receptores formados. Esta estrategia nos permitió determinar la contribución de cada loop y las consecuencias funcionales de la interacción entre ellos. Determinamos que la interacción entre los distintos loops de la interfase permite el acoplamiento de la unión del agonista con la apertura del poro iónico y gobierna la cinética de apertura y desensibilización de los receptores Cys-loop, controlando de esta manera la duración de la respuesta sináptica y el período refractario. Los nematodos parásitos tienen importancia médica y veterinaria ya que afectan la salud del hombre y del animal. Los fármacos antihelmínticos son esenciales para controlar los nematodos parásitos. Los agentes levamisol, pirantel, morantel y oxantel, ejercen su acción actuando sobre los nAChRs de los helmintos. En los últimos años se ha demostrado que la acción de estos fármacos depende del subtipo de receptor nACh. Exploramos las bases estructurales de dichas diferencias estudiando cómo estos agentes activan a los receptores nACh muscular y 7 de mamífero utilizando la técnica electrofisiológica de Patch-clamp. Encontramos que todas estas drogas son agonistas débiles del receptor nACh muscular adulto de mamífero. Por el contrario, pirantel y morantel cambian su comportamiento a agonistas completos y más potentes que la ACh en el receptor 7. Determinamos que la posición 57, localizada en el lado complementario del sitio de unión de agonistas, es responsable de la diferente activación de los receptores nACh muscular y 7 por morantel y pirantel. Esta posición no altera la activación de ACh o de los fármacos oxantel y levamisol. El conocimiento de la activación de los nAChRs por antihelmínticos contribuirá al diseño de terapias más selectivas contra los parásitos y a comprender como éstos desarrollan resistencia a estos fármacos. / The human brain is a vast and complicated network, where billions of nerve cells use signals to communicate with each other. At chemical synapses, neurotransmitters are released from the presynaptic cell. They interact with ligand-gated ion channels (LGIC) at the postsynaptic cell that convert signals from chemical to electrical in less than one millisecond. The channels close as the neurotransmitter dissociates to terminate the synaptic event. These receptors are involved in learning, memory, movement and disease processes, and are targets for clinically relevant drugs. The pentameric Cys-loop receptors are LGIC involved in fast chemical synapsis. Following the neurotransmitter release and binding to Cys-loop receptors, the post-synaptic response is governed by the kinetics of channel activation, deactivation and desensitization. The molecular mechanisms of these processes are still unknown. Cys-loop receptors have an extracellular domain, which contains the agonist binding sites, and a transmembrane domain where the ion pore is located. One of the goals of this Thesis was to determine the functional role of the interfacial region between extracellular and transmembrane domains. We generated homomeric chimeric receptors carrying sequences of 7 or 5-HT3A at the different loops of the interface and evaluated the open channel lifetime and rate of desensitization. This strategy allowed us to determine the functional contribution of each loop and the consecuences of structural mismatching among them. We concluded that the network of loops at the binding-pore interface of homomeric receptors is essential for coupling agonist binding to channel opening and also for dictating the kinetics of gating and desensitization. Thus, this region controls the duration of the refractory period and the synaptic response. Parasitic nematodes are of medical and veterinary importance, affecting human and animal health. Anthelmintic drugs are essential to control nematode parasites. These agents, such as levamisol, pyrantel, morantel and oxantel, exert their action at nAChRs in nerve and muscle of nematodes. In the last years, it has been demonstrated that the actions of these drugs depend on nAChR subtypes. To understand the structural basis of the differential activation of anthelmintics among nAChR subtypes, we studied the activation of mammalian muscle and 7 nAChRs by these agents at the single-channel and macroscopic-current levels. We showed that anthelminitic agents are low efficacious agonists of mammalian muscle AChRs. By contrast, morantel and pyrantel are high-efficacious and more potent agonists than ACh of 7 receptor. Also, we determined that position 57, located at the complementary face of the binding site, is a main determinant of the differential activation of mammalian muscle and 7 nAChRs by morantel and pyrantel. This position is not involved in ACh, oxantel or levamisol activation. These results provide new information for further progress in drug design and help to understand how parasites develop resistance to these drugs.

In this dissertation, we consider two important problems pertaining to the analysis of transportation systems. The first of these is an approach-dependent, time-dependent, label-constrained shortest path problem that arises in the context of the Route Planner Module of the Transportation Analysis Simulation System (TRANSIMS), which has been developed by the Los Alamos National Laboratory for the Federal Highway Administration. This is a variant of the shortest path problem defined on a transportation network comprised of a set of nodes and a set of directed arcs such that each arc has an associated label designating a mode of transportation, and an associated travel time function that depends on the time of arrival at the tail node, as well as on the node via which this node was approached. The lattermost feature is a new concept injected into the time-dependent, label-constrained shortest path problem, and is used to model turn-penalties in transportation networks. The time spent at an intersection before entering the next link would depend on whether we travel straight through the intersection, or make a right turn at it, or make a left turn at it. Accordingly, we model this situation by incorporating within each link's travel time function a dependence on the link via which its tail node was approached. We propose two effective algorithms to solve this problem by adapting two efficient existing algorithms to handle time dependency and label constraints: the Partitioned Shortest Path (PSP) algorithm and the Heap-Dijkstra (HP-Dijkstra) algorithm, and present related theoretical complexity results. In addition, we also explore various heuristic methods to curtail the search. We explore an Augmented Ellipsoidal Region Technique (A-ERT) and a Distance-Based A-ERT, along with some variants to curtail the search for an optimal path between a given origin and destination to more promising subsets of the network. This helps speed up computation without sacrificing optimality. We also incorporate an approach-dependent delay estimation function, and in concert with a search tree level-based technique, we derive a total estimated travel time and use this as a key to prioritize node selections or to sort elements in the heap. As soon as we reach the destination node, while it is within some p% of the minimum key value of the heap, we then terminate the search. We name the versions of PSP and HP-Dijkstra that employ this method as Early Terminated PSP (ET-PSP) and Early Terminated Heap-Dijkstra (ETHP-Dijkstra) algorithms. All of these procedures are compared with the original Route Planner Module within TRANSIMS, which is implemented in the Linux operating system, using C++ along with the g++ GNU compiler. Extensive computational testing has been conducted using available data from the Portland, Oregon, and Blacksburg, Virginia, transportation networks to investigate the efficacy of the developed procedures. In particular, we have tested twenty-five different combinations of network curtailment and algorithmic strategies on three test networks: the Blacksburg-light, the Blacksburg-full, and the BigNet network. The results indicate that the Heap-Dijkstra algorithm implementations are much faster than the PSP algorithmic approaches for solving the underlying problem exactly. Furthermore, mong the curtailment schemes, the ETHP-Dijkstra with p=5%, yields the best overall results. This method produces solutions within 0.37-1.91% of optimality, while decreasing CPU effort by 56.68% at an average, as compared with applying the best available exact algorithm. The second part of this dissertation is concerned with the Classification and Regression Tree (CART) algorithm, and its application to the Activity Generation Module of TRANSIMS. The CART algorithm has been popularly used in various contexts by transportation engineers and planners to correlate a set of independent household demographic variables with certain dependent activity or travel time variables. However, the algorithm lacks an automated mechanism for deriving classification trees based on optimizing specified objective functions and handling desired side-constraints that govern the structure of the tree and the statistical and demographic nature of its leaf nodes. Using a novel set partitioning formulation, we propose new tree development, and more importantly, optimal pruning strategies to accommodate the consideration of such objective functions and side-constraints, and establish the theoretical validity of our approach. This general enhancement of the CART algorithm is then applied to the Activity Generator module of TRANSIMS. Related computational results are presented using real data pertaining to the Portland, Oregon, and Blacksburg, Virginia, transportation networks to demonstrate the flexibility and effectiveness of the proposed approach in classifying data, as well as to examine its numerical performance. The results indicate that a variety of objective functions and constraints can be readily accommodated to efficiently control the structural information that is captured by the developed classification tree as desired by the planner or analyst, dependent on the scope of the application at hand. / Ph. D.

This dissertation traces Social Security policymaking through most of its post-enactment history in search of ideational processes and schema in path-dependent, path-shaping, and path-breaking modes of institutional persistence and change. The study is grounded in the historical institutionalist literature, specifically the recent debate about the utility of path dependence frameworks in incorporating institutional change, with a particular focus on ideas as stimuli. As a case for tracing path-dependent policy processes, Social Security is overbroad. This breadth requires focusing more narrowly on the interaction between the major coalitions, business/conservative and liberal/labor, on retirement and disability pension (but not health care) issues through the venue of Social Security Advisory Councils. Council is used as a catch-all label for the six-decade succession of (mostly) citizen groups appointed by the secretary of HEW, Senate Finance Committee, and, in one case, the president to deliberate questions of Social Security policy and recommend changes, often enacted into law. A pattern-matching analysis points to a moderate level of path dependence, indicating that the exchange of ideas between coalitions fits the larger consensual pattern of give and take around an existing arrangement. An ideational narrative reveals early negotiations over the emphasis placed on equity versus adequacy, with manifestly ideational exchanges in the 1996 Council's deliberations marking a turning point in the coalitional interaction. A key implication of this research for the application of path dependence frameworks to U.S. political institutions like Social Security is to buttress moderate path dependence arguments, for instance, those advanced by Hacker and Pierson (2002), and to discount the relevance of path-shaping narratives that have been fashioned from European examples (Cox 2004). Yet the research also modifies understanding of path dependence as a self-perpetuating function of increasing returns by identifying an ideational strand that bound both coalitions to social insurance principles. Path-breaking developments apparent in the 1996 Council further implicated new ideas as institutional factors contributing to the loss of historical consensus on Social Security, bolstering the notion of ideational processes as an element of institutional persistence and pressing the argument for further research into ideas as dynamic elements fostering institutional change. / Ph. D.

In this dissertation, we seek to improve and advance the use of the finite-set statistics (FISST) approach to multitarget tracking. We consider a subsea multitarget tracking application that poses several challenges due to factors, such as, clutter/environmental noise, joint target and sensor state dependent measurement uncertainty, target-measurement association ambiguity, and sub-optimal sensor placement. The specific application that we consider is that of an underwater mobile sensor that measures the relative angle (i.e., bearing angle) to sources of acoustic noise in order to track one or more ships (targets) in a noisy environment. However, our contributions are generalizable for a variety of multitarget tracking applications. We build upon existing algorithms and address the problem of improving tracking performance for multiple maneuvering targets by incorporation several target motion models into a FISST tracking algorithm known as the probability hypothesis density filter. Moreover, we develop a novel method for associating measurements to targets using the Bayes factor, which improves tracking performance for FISST methods as well as other approaches to multitarget tracking. Further, we derive a novel formulation of Bayes risk for use with set-valued random variables and develop a real-time planner for sensor motion that avoids local minima that arise in myopic approaches to sensor motion planning. The effectiveness of our contributions are evaluated through a mixture of real-world and simulated data. / Doctor of Philosophy / In this dissertation, we seek to improve the accuracy of multitarget tracking algorithms based on finite-set statistics (FISST). We consider a subsea tracking application where a sensor seeks to estimate the position of nearby ships using measurements of the relative sensor-ship angle. Several challenges arise in our application due to factors such as environmental noise and limited resolution of measurements. Our work advances FISST algorithms by expanding upon existing methods and deriving novel solutions to mitigate challenges. We address the non-trivial question of improving tracking accuracy by planning of future sensor motion. We show that our contributions greatly improve tracking accuracy by evaluating algorithm performance using a mixture of real-world and simulated data.

In the context of path planning, the non-signalized intersections are always a challenging scenario due to the mixture of traffic flow. Most path planning algorithms use the information at the current time instance to generate an optimal path. Because of the dynamics of the non-signalized intersections, iteratively generating a path in a high frequency is necessary, resulting in an enormous waste of computational resources. Rapidly-exploring Random Tree (RRT) as an effective local path planning methodology can determine a feasible path in the static environment. Few improvements are proposed to adopt the RRT to the non-signalized intersections. Gaussian Processes Regression (GPR) is used to predict the other vehicles' future location. The location information in the current and future time instance is used to generate a probability position map. The map not only avoids useless sampling procedures but also increases the speed of generating a path. The optimal steering strategy is deployed to guarantee the trajectory is collision-free in both current and future time frames. Overall, the proposed probabilistic RRT algorithm can select a collision-free path in the non-signalized intersections by combining the GPR, probability position map, and optimal-steering. / Master of Science / Path planning problem is a challenge in the non-signalized intersections. Many path planning algorithms can generate an optimal path in the space domain but not in the time domain. Thus, the algorithms need to run iteratively at a high frequency to ensure the path's optimality in the time domain. By combining prediction and the standard RRT path planning algorithm, the resulting path ensures to be optimal in the space and time domain.

Renewable Portfolio Standards (RPS) have been a staple energy policy in the state of Colorado since 2004. While there has been a steady increase to the RPS percentages over the years, there have been several points where this policy has been significantly contested. This paper explores the political decision making of the two largest electricity producers in the state, Xcel Energy and Tri-State Generation and Transmission Association, to determine at what points that the costs of legislation exceeded the costs of opposition for those two organizations. Using this information, the paper explores the implications these political battles have on characterizing Colorado as a state with renewable path dependency and renewable policy feedback. / Master of Arts / Since 2004, Colorado has enacted several successful laws to increase renewable energy use within the state. However, in recent years these laws have failed to achieve their goals. By analyzing the two largest producers of electricity in the state, Xcel Energy and Tri-State Generation and Transmission Association, this paper tries to answer what parts of the policies were too costly for the organizations to accept. Using this information, this project concludes that the current renewable energy policies are unlikely to be repealed in the future, but there is some evidence to suggest that the rate of renewable energy policy enactment may decrease.

A study of public and private space through human scale architectural elements: Window, Material and Path. The project is an urban infill that is very narrow and long, and incorporates an alley that connects one side of the block to another. The program combines a small restaurant with a home above for the family that owns it. Questions of light and privacy immediately arise, and the thesis begins. A window is typically a two dimensional object that opens for light and air. Window is a dining room overlooking a garden or a large sill to sit on. Window is not only part of the façade but also breaks through it, bringing small private spaces beyond the building boundaries and defining the interior spaces of the home. Window is also a small skylight facing east, scooping in soft morning light to a bedroom. The materials of a building are what it is made of: its cladding, waterproofing, walls and floors. Material makes an emotive space through touch and reflection. Concrete is heavy, rough and protective, Concrete is boundary. Contrastingly, Wood is soft, flexible and changing, Wood is home. An alley is a narrow walkway, an undesirable secondary access point. How can an alley become Path? Path is an invitation to walk and be, Path is not the same from beginning to end. Path belongs to the city, the restaurant, and the pedestrian. Inside + Outside studies what makes these public and private places at the human scale, and how architecture appeals to intuition rather than definition. / Master of Architecture

We study an informative path planning problem where the goal is to minimize the time required to learn a spatial field. Specifically, our goal is to ensure that the mean square error between the learned and actual fields is below a predefined value. We study three versions of the problem. In the placement version, the objective is to minimize the number of measurement locations. In the mobile robot version, we seek to minimize the total time required to visit and collect measurements from the measurement locations. A multi-robot version is studied as well where the objective is to minimize the time required by the last robot to return back to a common starting location called depot. By exploiting the properties of Gaussian Process regression, we present constant-factor approximation algorithms that ensure the required guarantees. In addition to the theoretical results, we also compare the empirical performance using a real-world dataset with other baseline strategies. / M. S. / We solve the problem of measuring a physical phenomenon accurately using a team of robots in minimum time. Examples of such phenomena include the amount of nitrogen present in the soil within a farm and concentration of harmful chemicals in a water body etc. Knowing accurately the extent of such quantities is important for a variety of economic and environmental reasons. For example, knowing the content of various nutrients in the soil within a farm can help the farmers to improve the yield and reduce the application of fertilizers, the concentration of certain chemicals inside a water body may affect the marine life in various ways. In this thesis, we present several algorithms which can help robots to be deployed efficiently to quantify such phenomena accurately. Traditionally, robots had to be teleoperated. The algorithms proposed in this thesis enable robots to work more autonomously.

This thesis presents a grid-based indoor radiolocation technique based on a Spatially Coherent Path Loss Model (SCPL). SCPL is a path loss model which characterizes the radio wave propagation in an environment by solely using Received Signal Strength (RSS) fingerprints. The propagation of the radio waves is characterized by uniformly dividing the environment into grid cells, followed by the estimation of the propagation parameters for each grid cell individually. By using SCPL and RSS fingerprints acquired at an unknown location, the distance between an agent and all the access point in an indoor environment can be determined. A least-squares based trilateration is then used as the global fix of location the agent in the environment. The result of the trilateration is then represented in a probability distribution function over the grid cells induced by SCPL. Since the proposed technique is able to locally model the propagation accounting for attenuation of non-uniform environmental irregularities, the characterization of the path loss in the indoor environment and radiolocation technique might yield improved results. The efficacy of the proposed technique was investigated with an experiment comparing SCPL and an indoor radiolocation technique based on a conventional path loss model. / Master of Science / This thesis presents a technique uses radio waves to localize an agent in an indoor environment. By characterizing the difference between transmitted and received power of the radio waves, the agent can determine how far it is away from the transmitting antennas, i.e. access points, placed in the environment. Since the power difference mainly results from obstructions in the environment, the attenuation profile of the environment carries a significant importance in radiolocation techniques. The proposed technique, called Spatially Coherent Path Loss Model (SCPL), characterizes the radio wave propagation, i.e. the attenuation, separately for different regions of the environment, unlike the conventional techniques employing global attenuation profiles. The localization environment is represented with grid-cell structure and the parameters of SCPL model describing the extent of the attenuation of the environment are estimated individually. After creating an attenuation profile of the environment, the agent localizes itself in the localization environment by using SCPL with signal powers received from the access points. This scheme of attenuation profiling constitutes the main contribution of the proposed technique. The efficacy and validity of the proposed technique was investigated with an experiment comparing SCPL and an indoor radiolocation technique based on a conventional path loss model.

H2O and CO2 concentrations of the glass phase in melt inclusions (MI) are commonly used both as a barometer and to track magma degassing behavior during ascent due to the strong pressure dependence of H2O and CO2 solubilities in silicate melts. A requirement for this method to be valid is that the glass phase in the MI must represent the composition of the melt that was originally trapped. However, melt inclusions commonly contain a vapor bubble that formed after trapping. Such bubbles may contain CO2 that was originally dissolved in the melt. In this study, we determined the contribution of CO2 in the vapor bubble to the overall CO2 content of MI based on quantitative Raman analysis of the vapor bubbles in MI from the 1959 Kilauea Iki, 1960 Kapoho, 1974 Fuego volcano, and 1977 Seguam Island eruptions. The bubbles contain up to 90% or more of the total CO2 in some MI. Reconstructing the original CO2 content by adding the CO2 in the bubble back into the melt results in an increase in CO2 concentration by as much an order of magnitude (1000s of ppm), corresponding to trapping pressures that are significantly greater (by 1 to >3 kbars) than one would predict based on analysis of the volatiles in the glass alone. Many MI also showed the presence of a carbonate mineral phase; failure to include its contained CO2 when reconstructing the CO2 content of the originally trapped melt may introduce significant errors in the calculated volatile budget. / Master of Science