Transcriptional response to cardiac injury in the zebrafish: systematic identification of genes with highly concordant activity across in vivo models

BACKGROUND Zebrafish is a clinically-relevant model of heart regeneration. Unlike mammals, it has a remarkable heart repair capacity after injury, and promises novel translational applications. Amputation and cryoinjury models are key research tools for understanding injury response and regeneration in vivo. An understanding of the transcriptional responses following injury is needed to identify key players of heart tissue repair, as well as potential targets for boosting this property in humans. RESULTS We investigated amputation and cryoinjury in vivo models of heart damage in the zebrafish through unbiased, integrative analyses of independent molecular datasets. To detect genes with potential biological roles, we derived computational prediction models with microarray data from heart amputation experiments. We focused on a top-ranked set of genes highly activated in the early post-injury stage, whose activity was further verified in independent microarray datasets. Next, we performed independent validations of expression responses with qPCR in a cryoinjury model. Across in vivo models, the top candidates showed highly concordant responses at 1 and 3 days post-injury, which highlights the predictive power of our analysis strategies and the possible biological relevance of these genes. Top candidates are significantly involved in cell fate specification and differentiation, and include heart failure markers such as periostin, as well as potential new targets for heart regeneration. For example, ptgis and ca2 were overexpressed, while usp2a, a regulator of the p53 pathway, was down-regulated in our in vivo models. Interestingly, a high activity of ptgis and ca2 has been previously observed in failing hearts from rats and humans. CONCLUSIONS We identified genes with potential critical roles in the response to cardiac damage in the zebrafish. Their transcriptional activities are reproducible in different in vivo models of cardiac injury.

Parameterization of applied general equilibrium models with flexible trade specifications based on the Armington, Krugman, and Melitz models

This paper explains how the Armington-Krugman-Melitz supermodel developed by Dixon and Rimmer can be parameterized, and demonstrates that only two kinds of additional information are required in order to extend a standard trade model to include Melitz-type monopolistic competition and heterogeneous firms. Further, it is shown how specifying too much additional information leads to violations of the model constraints, necessitating adjustment and reconciliation of the data. Once a Melitz-type model is parameterized, a Krugman-type model can also be parameterized using the calibrated values in the Melitz-type model without any additional data. Sample code for the General Algebraic Modeling System (GAMS) has also been prepared to promote the innovative supermodel in the AGE community.

Neutrality in the choice of number of firms or level of fixed costs in calibrating an Armington-Krugman-Melitz encompassing module for applied general equilibrium models

This paper shows how an Armington-Krugman-Melitz encompassing module based on Dixon and Rimmer (2012) can be calibrated, and clarifies the choice of initial levels for two kinds of number of firms, or parameter values for two kinds of fixed costs, that enter a Melitz-type specification can be set freely to any preferred value, just as the cases we derive quantities from given value data assuming some of the initial prices to be unity. In consequence, only one kind of additional information, which is on the shape parameter related to productivity, just is required in order to incorporate Melitz-type monopolistic competition and heterogeneous firms into a standard applied general equilibrium model. To be a Krugman-type, nothing is needed. This enables model builders in applied economics to fully enjoy the featured properties of the theoretical models invented by Krugman (1980) and Melitz (2003) in practical policy simulations at low cost.

Behavioral characteristics of applied general equilibrium models with an Armington-Krugman-Melitz encompassing module

This paper explore how simulation results change with different choice of trade specification, and the strength of preference for traded variety by economic agent differs, utilizing two types of three-region, three-sector AGE model that includes the Armington-Krugman-Melitz Encompassing module based on Dixon and Rimmer (2012). Simulation experiments reveal that: (1) the Melitz-type specification does not always enhance effectiveness of a certain policy change more than the one obtained with the Krugman-type, especially when economic agents' preference for traded variety is not so strong; (2) there are likely to be points where the volumes of effects obtained with the Melitz-type exceed the ones with the Krugman-type; and (3) the preference of the producers, those who are in the sectors that exhibit increasing returns to scale, for traded variety might be the engine of explosive effects as suggested by Fujita, et al. (2000).

Application of Deadlock Risk Evaluation of Architectural Models

Software architectural evaluation is a key discipline used to identify, at early stages of a real-time system (RTS) development, the problems that may arise during its operation. Typical mechanisms supporting concurrency, such as semaphores, mutexes or monitors, usually lead to concurrency problems in execution time that are difficult to be identified, reproduced and solved. For this reason, it is crucial to understand the root causes of these problems and to provide support to identify and mitigate them at early stages of the system lifecycle. This paper aims to present the results of a research work oriented to the development of the tool called ‘Deadlock Risk Evaluation of Architectural Models’ (DREAM) to assess deadlock risk in architectural models of an RTS. A particular architectural style, Pipelines of Processes in Object-Oriented Architectures–UML (PPOOA) was used to represent platform-independent models of an RTS architecture supported by the PPOOA –Visio tool. We validated the technique presented here by using several case studies related to RTS development and comparing our results with those from other deadlock detection approaches, supported by different tools. Here we present two of these case studies, one related to avionics and the other to planetary exploration robotics. Copyright © 2011 John Wiley & Sons, Ltd.

Artificial Neural Nets with Interaction of Afferents

The aim is to obtain computationally more powerful, neuro physiologically founded, artificial neurons and neural nets. Artificial Neural Nets (ANN) of the Perceptron type evolved from the original proposal by McCulloch an Pitts classical paper [1]. Essentially, they keep the computing structure of a linear machine followed by a non linear operation. The McCulloch-Pitts formal neuron (which was never considered by the author’s to be models of real neurons) consists of the simplest case of a linear computation of the inputs followed by a threshold. Networks of one layer cannot compute anylogical function of the inputs, but only those which are linearly separable. Thus, the simple exclusive OR (contrast detector) function of two inputs requires two layers of formal neurons

Hybrid analysis of nonlinear circuits: DAE models with indices zero and one

We extend in this paper some previous results concerning the differential-algebraic index of hybrid models of electrical and electronic circuits. Specifically, we present a comprehensive index characterization which holds without passivity requirements, in contrast to previous approaches, and which applies to nonlinear circuits composed of uncoupled, one-port devices. The index conditions, which are stated in terms of the forest structure of certain digraph minors, do not depend on the specific tree chosen in the formulation of the hybrid equations. Additionally, we show how to include memristors in hybrid circuit models; in this direction, we extend the index analysis to circuits including active memristors, which have been recently used in the design of nonlinear oscillators and chaotic circuits. We also discuss the extension of these results to circuits with controlled sources, making our framework of interest in the analysis of circuits with transistors, amplifiers, and other multiterminal devices.

Nonlinear seismic behaviour of concrete arch bridges

Arch bridge structural solution has been known for centuries, in fact the simple nature of arch that require low tension and shear strength was an advantage as the simple materials like stone and brick were the only option back in ancient centuries. By the pass of time especially after industrial revolution, the new materials were adopted in construction of arch bridges to reach longer spans. Nowadays one long span arch bridge is made of steel, concrete or combination of these two as "CFST", as the result of using these high strength materials, very long spans can be achieved. The current record for longest arch belongs to Chaotianmen bridge over Yangtze river in China with 552 meters span made of steel and the longest reinforced concrete type is Wanxian bridge which also cross the Yangtze river through a 420 meters span. Today the designer is no longer limited by span length as long as arch bridge is the most applicable solution among other approaches, i.e. cable stayed and suspended bridges are more reasonable if very long span is desired. Like any super structure, the economical and architectural aspects in construction of a bridge is extremely important, in other words, as a narrower bridge has better appearance, it also require smaller volume of material which make the design more economical. Design of such bridge, beside the high strength materials, requires precise structural analysis approaches capable of integrating the combination of material behaviour and complex geometry of structure and various types of loads which may be applied to bridge during its service life. Depend on the design strategy, analysis may only evaluates the linear elastic behaviour of structure or consider the nonlinear properties as well. Although most of structures in the past were designed to act in their elastic range, the rapid increase in computational capacity allow us to consider different sources of nonlinearities in order to achieve a more realistic evaluations where the dynamic behaviour of bridge is important especially in seismic zones where large movements may occur or structure experience P - _ effect during the earthquake. The above mentioned type of analysis is computationally expensive and very time consuming. In recent years, several methods were proposed in order to resolve this problem. Discussion of recent developments on these methods and their application on long span concrete arch bridges is the main goal of this research. Accordingly available long span concrete arch bridges have been studied to gather the critical information about their geometrical aspects and properties of their materials. Based on concluded information, several concrete arch bridges were designed for further studies. The main span of these bridges range from 100 to 400 meters. The Structural analysis methods implemented in in this study are as following: Elastic Analysis: Direct Response History Analysis (DRHA): This method solves the direct equation of motion over time history of applied acceleration or imposed load in linear elastic range. Modal Response History Analysis (MRHA): Similar to DRHA, this method is also based on time history, but the equation of motion is simplified to single degree of freedom system and calculates the response of each mode independently. Performing this analysis require less time than DRHA. Modal Response Spectrum Analysis (MRSA): As it is obvious from its name, this method calculates the peak response of structure for each mode and combine them using modal combination rules based on the introduced spectra of ground motion. This method is expected to be fastest among Elastic analysis. Inelastic Analysis: Nonlinear Response History Analysis (NL-RHA): The most accurate strategy to address significant nonlinearities in structural dynamics is undoubtedly the nonlinear response history analysis which is similar to DRHA but extended to inelastic range by updating the stiffness matrix for every iteration. This onerous task, clearly increase the computational cost especially for unsymmetrical buildings that requires to be analyzed in a full 3D model for taking the torsional effects in to consideration. Modal Pushover Analysis (MPA): The Modal Pushover Analysis is basically the MRHA but extended to inelastic stage. After all, the MRHA cannot solve the system of dynamics because the resisting force fs(u; u_ ) is unknown for inelastic stage. The solution of MPA for this obstacle is using the previously recorded fs to evaluate system of dynamics. Extended Modal Pushover Analysis (EMPA): Expanded Modal pushover is a one of very recent proposed methods which evaluates response of structure under multi-directional excitation using the modal pushover analysis strategy. In one specific mode,the original pushover neglect the contribution of the directions different than characteristic one, this is reasonable in regular symmetric building but a structure with complex shape like long span arch bridges may go through strong modal coupling. This method intend to consider modal coupling while it take same time of computation as MPA. Coupled Nonlinear Static Pushover Analysis (CNSP): The EMPA includes the contribution of non-characteristic direction to the formal MPA procedure. However the static pushovers in EMPA are performed individually for every mode, accordingly the resulted values from different modes can be combined but this is only valid in elastic phase; as soon as any element in structure starts yielding the neutral axis of that section is no longer fixed for both response during the earthquake, meaning the longitudinal deflection unavoidably affect the transverse one or vice versa. To overcome this drawback, the CNSP suggests executing pushover analysis for governing modes of each direction at the same time. This strategy is estimated to be more accurate than MPA and EMPA, moreover the calculation time is reduced because only one pushover analysis is required. Regardless of the strategy, the accuracy of structural analysis is highly dependent on modelling and numerical integration approaches used in evaluation of each method. Therefore the widely used Finite Element Method is implemented in process of all analysis performed in this research. In order to address the study, chapter 2, starts with gathered information about constructed long span arch bridges, this chapter continuous with geometrical and material definition of new models. Chapter 3 provides the detailed information about structural analysis strategies; furthermore the step by step description of procedure of all methods is available in Appendix A. The document ends with the description of results and conclusion of chapter 4.

Proactive and reactive thermal aware optimization techniques to minimize the environmental impact of data centers

Los Centros de Datos se encuentran actualmente en cualquier sector de la economía mundial. Están compuestos por miles de servidores, dando servicio a los usuarios de forma global, las 24 horas del día y los 365 días del año. Durante los últimos años, las aplicaciones del ámbito de la e-Ciencia, como la e-Salud o las Ciudades Inteligentes han experimentado un desarrollo muy significativo. La necesidad de manejar de forma eficiente las necesidades de cómputo de aplicaciones de nueva generación, junto con la creciente demanda de recursos en aplicaciones tradicionales, han facilitado el rápido crecimiento y la proliferación de los Centros de Datos. El principal inconveniente de este aumento de capacidad ha sido el rápido y dramático incremento del consumo energético de estas infraestructuras. En 2010, la factura eléctrica de los Centros de Datos representaba el 1.3% del consumo eléctrico mundial. Sólo en el año 2012, el consumo de potencia de los Centros de Datos creció un 63%, alcanzando los 38GW. En 2013 se estimó un crecimiento de otro 17%, hasta llegar a los 43GW. Además, los Centros de Datos son responsables de más del 2% del total de emisiones de dióxido de carbono a la atmósfera. Esta tesis doctoral se enfrenta al problema energético proponiendo técnicas proactivas y reactivas conscientes de la temperatura y de la energía, que contribuyen a tener Centros de Datos más eficientes. Este trabajo desarrolla modelos de energía y utiliza el conocimiento sobre la demanda energética de la carga de trabajo a ejecutar y de los recursos de computación y refrigeración del Centro de Datos para optimizar el consumo. Además, los Centros de Datos son considerados como un elemento crucial dentro del marco de la aplicación ejecutada, optimizando no sólo el consumo del Centro de Datos sino el consumo energético global de la aplicación. Los principales componentes del consumo en los Centros de Datos son la potencia de computación utilizada por los equipos de IT, y la refrigeración necesaria para mantener los servidores dentro de un rango de temperatura de trabajo que asegure su correcto funcionamiento. Debido a la relación cúbica entre la velocidad de los ventiladores y el consumo de los mismos, las soluciones basadas en el sobre-aprovisionamiento de aire frío al servidor generalmente tienen como resultado ineficiencias energéticas. Por otro lado, temperaturas más elevadas en el procesador llevan a un consumo de fugas mayor, debido a la relación exponencial del consumo de fugas con la temperatura. Además, las características de la carga de trabajo y las políticas de asignación de recursos tienen un impacto importante en los balances entre corriente de fugas y consumo de refrigeración. La primera gran contribución de este trabajo es el desarrollo de modelos de potencia y temperatura que permiten describes estos balances entre corriente de fugas y refrigeración; así como la propuesta de estrategias para minimizar el consumo del servidor por medio de la asignación conjunta de refrigeración y carga desde una perspectiva multivariable. Cuando escalamos a nivel del Centro de Datos, observamos un comportamiento similar en términos del balance entre corrientes de fugas y refrigeración. Conforme aumenta la temperatura de la sala, mejora la eficiencia de la refrigeración. Sin embargo, este incremente de la temperatura de sala provoca un aumento en la temperatura de la CPU y, por tanto, también del consumo de fugas. Además, la dinámica de la sala tiene un comportamiento muy desigual, no equilibrado, debido a la asignación de carga y a la heterogeneidad en el equipamiento de IT. La segunda contribución de esta tesis es la propuesta de técnicas de asigación conscientes de la temperatura y heterogeneidad que permiten optimizar conjuntamente la asignación de tareas y refrigeración a los servidores. Estas estrategias necesitan estar respaldadas por modelos flexibles, que puedan trabajar en tiempo real, para describir el sistema desde un nivel de abstracción alto. Dentro del ámbito de las aplicaciones de nueva generación, las decisiones tomadas en el nivel de aplicación pueden tener un impacto dramático en el consumo energético de niveles de abstracción menores, como por ejemplo, en el Centro de Datos. Es importante considerar las relaciones entre todos los agentes computacionales implicados en el problema, de forma que puedan cooperar para conseguir el objetivo común de reducir el coste energético global del sistema. La tercera contribución de esta tesis es el desarrollo de optimizaciones energéticas para la aplicación global por medio de la evaluación de los costes de ejecutar parte del procesado necesario en otros niveles de abstracción, que van desde los nodos hasta el Centro de Datos, por medio de técnicas de balanceo de carga. Como resumen, el trabajo presentado en esta tesis lleva a cabo contribuciones en el modelado y optimización consciente del consumo por fugas y la refrigeración de servidores; el modelado de los Centros de Datos y el desarrollo de políticas de asignación conscientes de la heterogeneidad; y desarrolla mecanismos para la optimización energética de aplicaciones de nueva generación desde varios niveles de abstracción. ABSTRACT Data centers are easily found in every sector of the worldwide economy. They consist of tens of thousands of servers, serving millions of users globally and 24-7. In the last years, e-Science applications such e-Health or Smart Cities have experienced a significant development. The need to deal efficiently with the computational needs of next-generation applications together with the increasing demand for higher resources in traditional applications has facilitated the rapid proliferation and growing of data centers. A drawback to this capacity growth has been the rapid increase of the energy consumption of these facilities. In 2010, data center electricity represented 1.3% of all the electricity use in the world. In year 2012 alone, global data center power demand grew 63% to 38GW. A further rise of 17% to 43GW was estimated in 2013. Moreover, data centers are responsible for more than 2% of total carbon dioxide emissions. This PhD Thesis addresses the energy challenge by proposing proactive and reactive thermal and energy-aware optimization techniques that contribute to place data centers on a more scalable curve. This work develops energy models and uses the knowledge about the energy demand of the workload to be executed and the computational and cooling resources available at data center to optimize energy consumption. Moreover, data centers are considered as a crucial element within their application framework, optimizing not only the energy consumption of the facility, but the global energy consumption of the application. The main contributors to the energy consumption in a data center are the computing power drawn by IT equipment and the cooling power needed to keep the servers within a certain temperature range that ensures safe operation. Because of the cubic relation of fan power with fan speed, solutions based on over-provisioning cold air into the server usually lead to inefficiencies. On the other hand, higher chip temperatures lead to higher leakage power because of the exponential dependence of leakage on temperature. Moreover, workload characteristics as well as allocation policies also have an important impact on the leakage-cooling tradeoffs. The first key contribution of this work is the development of power and temperature models that accurately describe the leakage-cooling tradeoffs at the server level, and the proposal of strategies to minimize server energy via joint cooling and workload management from a multivariate perspective. When scaling to the data center level, a similar behavior in terms of leakage-temperature tradeoffs can be observed. As room temperature raises, the efficiency of data room cooling units improves. However, as we increase room temperature, CPU temperature raises and so does leakage power. Moreover, the thermal dynamics of a data room exhibit unbalanced patterns due to both the workload allocation and the heterogeneity of computing equipment. The second main contribution is the proposal of thermal- and heterogeneity-aware workload management techniques that jointly optimize the allocation of computation and cooling to servers. These strategies need to be backed up by flexible room level models, able to work on runtime, that describe the system from a high level perspective. Within the framework of next-generation applications, decisions taken at this scope can have a dramatical impact on the energy consumption of lower abstraction levels, i.e. the data center facility. It is important to consider the relationships between all the computational agents involved in the problem, so that they can cooperate to achieve the common goal of reducing energy in the overall system. The third main contribution is the energy optimization of the overall application by evaluating the energy costs of performing part of the processing in any of the different abstraction layers, from the node to the data center, via workload management and off-loading techniques. In summary, the work presented in this PhD Thesis, makes contributions on leakage and cooling aware server modeling and optimization, data center thermal modeling and heterogeneityaware data center resource allocation, and develops mechanisms for the energy optimization for next-generation applications from a multi-layer perspective.

Asymptotic and computational analysis of mistuning effects on the dynamics of bladed disks

Es bien conocido que las pequeñas imperfecciones existentes en los álabes de un rótor de turbomaquinaria (conocidas como “mistuning”) pueden causar un aumento considerable de la amplitud de vibración de la respuesta forzada y, por el contrario, tienen típicamente un efecto beneficioso en el flameo del rótor. Para entender estos efectos se pueden llevar a cabo estudios numéricos del problema aeroelástico completo. Sin embargo, el cálculo de “mistuning” usando modelos de alta resolución es una tarea difícil de realizar, ya que los modelos necesarios para describir de manera precisa el componente de turbomáquina (por ejemplo rotor) tienen, necesariamente, un número muy elevado de grados de libertad, y, además, es necesario hacer un estudio estadístico para poder explorar apropiadamente las distribuciones posibles de “mistuning”, que tienen una naturaleza aleatoria. Diferentes modelos de orden reducido han sido desarrollados en los últimos años para superar este inconveniente. Uno de estos modelos, llamado “Asymptotic Mistuning Model (AMM)”, se deriva de la formulación completa usando técnicas de perturbaciones que se basan en que el “mistuning” es pequeño. El AMM retiene sólo los modos relevantes para describir el efecto del mistuning, y permite identificar los mecanismos clave involucrados en la amplificación de la respuesta forzada y en la estabilización del flameo. En este trabajo, el AMM se usa para estudiar el efecto del “mistuning” de la estructura y de la amortiguación sobre la amplitud de la respuesta forzada. Los resultados obtenidos son validados usando modelos simplificados del rotor y también otros de alta definición. Además, en el marco del proyecto europeo FP7 "Flutter-Free Turbomachinery Blades (FUTURE)", el AMM se aplica para diseñar distribuciones de “mistuning” intencional: (i) una que anula y (ii) otra que reduce a la mitad la amplitud del flameo de un rotor inestable; y las distribuciones obtenidas se validan experimentalmente. Por último, la capacidad de AMM para predecir el comportamiento de flameo de rotores con “mistuning” se comprueba usando resultados de CFD detallados. Abstract It is well known that the small imperfections of the individual blades in a turbomachinery rotor (known as “mistuning”) can cause a substantial increase of the forced response vibration amplitude, and it also typically results in an improvement of the flutter vibration characteristics of the rotor. The understanding of these phenomena can be attempted just by performing numerical simulations of the complete aeroelastic problem. However, the computation of mistuning cases using high fidelity models is a formidable task, because a detailed model of the whole rotor has to be considered, and a statistical study has to be carried out in order to properly explore the effect of the random mistuning distributions. Many reduced order models have been developed in recent years to overcome this barrier. One of these models, called the Asymptotic Mistuning Model (AMM), is systematically derived from the complete bladed disk formulation using a consistent perturbative procedure that exploits the smallness of mistuning to simplify the problem. The AMM retains only the essential system modes that are involved in the mistuning effect, and it allows to identify the key mechanisms of the amplification of the forced response amplitude and the flutter stabilization. In this work, AMM methodolgy is used to study the effect of structural and damping mistuning on the forced response vibration amplitude. The obtained results are verified using a one degree of freedom model of a rotor, and also high fidelity models of the complete rotor. The AMM is also applied, in the frame of the European FP7 project “Flutter-Free Turbomachinery Blades (FUTURE)”, to design two intentional mistuning patterns: (i) one to complete stabilize an unstable rotor, and (ii) other to approximately reduce by half its flutter amplitude. The designed patterns are validated experimentally. Finally, the ability of AMM to predict the flutter behavior of mistuned rotors is checked against numerical, high fidelity CFD results.

Automated wordlength optimization framework for multi-source statistical interval-based analysis of nonlinear systems with control-flow structures

El uso de aritmética de punto fijo es una opción de diseño muy extendida en sistemas con fuertes restricciones de área, consumo o rendimiento. Para producir implementaciones donde los costes se minimicen sin impactar negativamente en la precisión de los resultados debemos llevar a cabo una asignación cuidadosa de anchuras de palabra. Encontrar la combinación óptima de anchuras de palabra en coma fija para un sistema dado es un problema combinatorio NP-hard al que los diseñadores dedican entre el 25 y el 50 % del ciclo de diseño. Las plataformas hardware reconfigurables, como son las FPGAs, también se benefician de las ventajas que ofrece la aritmética de coma fija, ya que éstas compensan las frecuencias de reloj más bajas y el uso más ineficiente del hardware que hacen estas plataformas respecto a los ASICs. A medida que las FPGAs se popularizan para su uso en computación científica los diseños aumentan de tamaño y complejidad hasta llegar al punto en que no pueden ser manejados eficientemente por las técnicas actuales de modelado de señal y ruido de cuantificación y de optimización de anchura de palabra. En esta Tesis Doctoral exploramos distintos aspectos del problema de la cuantificación y presentamos nuevas metodologías para cada uno de ellos: Las técnicas basadas en extensiones de intervalos han permitido obtener modelos de propagación de señal y ruido de cuantificación muy precisos en sistemas con operaciones no lineales. Nosotros llevamos esta aproximación un paso más allá introduciendo elementos de Multi-Element Generalized Polynomial Chaos (ME-gPC) y combinándolos con una técnica moderna basada en Modified Affine Arithmetic (MAA) estadístico para así modelar sistemas que contienen estructuras de control de flujo. Nuestra metodología genera los distintos caminos de ejecución automáticamente, determina las regiones del dominio de entrada que ejercitarán cada uno de ellos y extrae los momentos estadísticos del sistema a partir de dichas soluciones parciales. Utilizamos esta técnica para estimar tanto el rango dinámico como el ruido de redondeo en sistemas con las ya mencionadas estructuras de control de flujo y mostramos la precisión de nuestra aproximación, que en determinados casos de uso con operadores no lineales llega a tener tan solo una desviación del 0.04% con respecto a los valores de referencia obtenidos mediante simulación. Un inconveniente conocido de las técnicas basadas en extensiones de intervalos es la explosión combinacional de términos a medida que el tamaño de los sistemas a estudiar crece, lo cual conlleva problemas de escalabilidad. Para afrontar este problema presen tamos una técnica de inyección de ruidos agrupados que hace grupos con las señales del sistema, introduce las fuentes de ruido para cada uno de los grupos por separado y finalmente combina los resultados de cada uno de ellos. De esta forma, el número de fuentes de ruido queda controlado en cada momento y, debido a ello, la explosión combinatoria se minimiza. También presentamos un algoritmo de particionado multi-vía destinado a minimizar la desviación de los resultados a causa de la pérdida de correlación entre términos de ruido con el objetivo de mantener los resultados tan precisos como sea posible. La presente Tesis Doctoral también aborda el desarrollo de metodologías de optimización de anchura de palabra basadas en simulaciones de Monte-Cario que se ejecuten en tiempos razonables. Para ello presentamos dos nuevas técnicas que exploran la reducción del tiempo de ejecución desde distintos ángulos: En primer lugar, el método interpolativo aplica un interpolador sencillo pero preciso para estimar la sensibilidad de cada señal, y que es usado después durante la etapa de optimización. En segundo lugar, el método incremental gira en torno al hecho de que, aunque es estrictamente necesario mantener un intervalo de confianza dado para los resultados finales de nuestra búsqueda, podemos emplear niveles de confianza más relajados, lo cual deriva en un menor número de pruebas por simulación, en las etapas iniciales de la búsqueda, cuando todavía estamos lejos de las soluciones optimizadas. Mediante estas dos aproximaciones demostramos que podemos acelerar el tiempo de ejecución de los algoritmos clásicos de búsqueda voraz en factores de hasta x240 para problemas de tamaño pequeño/mediano. Finalmente, este libro presenta HOPLITE, una infraestructura de cuantificación automatizada, flexible y modular que incluye la implementación de las técnicas anteriores y se proporciona de forma pública. Su objetivo es ofrecer a desabolladores e investigadores un entorno común para prototipar y verificar nuevas metodologías de cuantificación de forma sencilla. Describimos el flujo de trabajo, justificamos las decisiones de diseño tomadas, explicamos su API pública y hacemos una demostración paso a paso de su funcionamiento. Además mostramos, a través de un ejemplo sencillo, la forma en que conectar nuevas extensiones a la herramienta con las interfaces ya existentes para poder así expandir y mejorar las capacidades de HOPLITE. ABSTRACT Using fixed-point arithmetic is one of the most common design choices for systems where area, power or throughput are heavily constrained. In order to produce implementations where the cost is minimized without negatively impacting the accuracy of the results, a careful assignment of word-lengths is required. The problem of finding the optimal combination of fixed-point word-lengths for a given system is a combinatorial NP-hard problem to which developers devote between 25 and 50% of the design-cycle time. Reconfigurable hardware platforms such as FPGAs also benefit of the advantages of fixed-point arithmetic, as it compensates for the slower clock frequencies and less efficient area utilization of the hardware platform with respect to ASICs. As FPGAs become commonly used for scientific computation, designs constantly grow larger and more complex, up to the point where they cannot be handled efficiently by current signal and quantization noise modelling and word-length optimization methodologies. In this Ph.D. Thesis we explore different aspects of the quantization problem and we present new methodologies for each of them: The techniques based on extensions of intervals have allowed to obtain accurate models of the signal and quantization noise propagation in systems with non-linear operations. We take this approach a step further by introducing elements of MultiElement Generalized Polynomial Chaos (ME-gPC) and combining them with an stateof- the-art Statistical Modified Affine Arithmetic (MAA) based methodology in order to model systems that contain control-flow structures. Our methodology produces the different execution paths automatically, determines the regions of the input domain that will exercise them, and extracts the system statistical moments from the partial results. We use this technique to estimate both the dynamic range and the round-off noise in systems with the aforementioned control-flow structures. We show the good accuracy of our approach, which in some case studies with non-linear operators shows a 0.04 % deviation respect to the simulation-based reference values. A known drawback of the techniques based on extensions of intervals is the combinatorial explosion of terms as the size of the targeted systems grows, which leads to scalability problems. To address this issue we present a clustered noise injection technique that groups the signals in the system, introduces the noise terms in each group independently and then combines the results at the end. In this way, the number of noise sources in the system at a given time is controlled and, because of this, the combinato rial explosion is minimized. We also present a multi-way partitioning algorithm aimed at minimizing the deviation of the results due to the loss of correlation between noise terms, in order to keep the results as accurate as possible. This Ph.D. Thesis also covers the development of methodologies for word-length optimization based on Monte-Carlo simulations in reasonable times. We do so by presenting two novel techniques that explore the reduction of the execution times approaching the problem in two different ways: First, the interpolative method applies a simple but precise interpolator to estimate the sensitivity of each signal, which is later used to guide the optimization effort. Second, the incremental method revolves on the fact that, although we strictly need to guarantee a certain confidence level in the simulations for the final results of the optimization process, we can do it with more relaxed levels, which in turn implies using a considerably smaller amount of samples, in the initial stages of the process, when we are still far from the optimized solution. Through these two approaches we demonstrate that the execution time of classical greedy techniques can be accelerated by factors of up to ×240 for small/medium sized problems. Finally, this book introduces HOPLITE, an automated, flexible and modular framework for quantization that includes the implementation of the previous techniques and is provided for public access. The aim is to offer a common ground for developers and researches for prototyping and verifying new techniques for system modelling and word-length optimization easily. We describe its work flow, justifying the taken design decisions, explain its public API and we do a step-by-step demonstration of its execution. We also show, through an example, the way new extensions to the flow should be connected to the existing interfaces in order to expand and improve the capabilities of HOPLITE.

Checkpoints in the progression of autoimmune disease: lessons from diabetes models.

In the last few years, data from experiments employing transgenic models of autoimmune disease have strengthened a particular concept of autoimmunity: disease results not so much from cracks in tolerance induction systems, leading to the generation of anti-self repertoire, as from the breakdown of secondary systems that keep these cells in check. T cells with anti-self specificities are readily found in disease-free individuals but ignore target tissues. This is also the case in some transgenic models, in spite of overwhelming numbers of autoreactive cells. In other instances, local infiltration and inflammation result, but they are well tolerated for long periods of time and do not terminally destroy target tissue. We review the possible molecular and cellular mechanisms that underlie these situations, with a particular emphasis on the destruction of pancreatic beta cells in transgenic models of insulin-dependent disease.

Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models.

Most models of tumorigenesis assume that the tumor grows by increased cell division. In these models, it is generally supposed that daughter cells behave as do their parents, and cell numbers have clear potential for exponential growth. We have constructed simple mathematical models of tumorigenesis through failure of programmed cell death (PCD) or differentiation. These models do not assume that descendant cells behave as their parents do. The models predict that exponential growth in cell numbers does sometimes occur, usually when stem cells fail to die or differentiate. At other times, exponential growth does not occur: instead, the number of cells in the population reaches a new, higher equilibrium. This behavior is predicted when fully differentiated cells fail to undergo PCD. When cells of intermediate differentiation fail to die or to differentiate further, the values of growth parameters determine whether growth is exponential or leads to a new equilibrium. The predictions of the model are sensitive to small differences in growth parameters. Failure of PCD and differentiation, leading to a new equilibrium number of cells, may explain many aspects of tumor behavior--for example, early premalignant lesions such as cervical intraepithelial neoplasia, the fact that some tumors very rarely become malignant, the observation of plateaux in the growth of some solid tumors, and, finally, long lag phases of growth until mutations arise that eventually result in exponential growth.

The CuA center of cytochrome-c oxidase: electronic structure and spectra of models compared to the properties of CuA domains.

The electronic structure and spectrum of several models of the binuclear metal site in soluble CuA domains of cytochrome-c oxidase have been calculated by the use of an extended version of the complete neglect of differential overlap/spectroscopic method. The experimental spectra have two strong transitions of nearly equal intensity around 500 nm and a near-IR transition close to 800 nm. The model that best reproduces these features consists of a dimer of two blue (type 1) copper centers, in which each Cu atom replaces the missing imidazole on the other Cu atom. Thus, both Cu atoms have one cysteine sulfur atom and one imidazole nitrogen atom as ligands, and there are no bridging ligands but a direct Cu-Cu bond. According to the calculations, the two strong bands in the visible region originate from exciton coupling of the dipoles of the two copper monomers, and the near-IR band is a charge-transfer transition between the two Cu atoms. The known amino acid sequence has been used to construct a molecular model of the CuA site by the use of a template and energy minimization. In this model, the two ligand cysteine residues are in one turn of an alpha-helix, whereas one ligand histidine is in a loop following this helix and the other one is in a beta-strand.

The evolution of mass tourism destinations: new approaches beyond deterministic models in Benidorm (Spain)

Although deterministic models of the evolution of mass tourism coastal resorts predict an almost inevitable decline over time, theoretical frameworks of the evolution and restructuring policies of mature destinations should be revised to reflect the complex and dynamic way in which these destinations evolve and interact with the tourism market and global socio-economic environment. The present study examines Benidorm because its urban and tourism model and large-scale tourism supply and demand make it one of the most unique destinations on the Mediterranean coast. The investigation reveals the need to adopt theories and models that are not purely deterministic. The dialectic interplay between external factors and the internal factors inherent in this destination simultaneously reveals a complex and diverse stage of maturity and the ability of destinations to create their own future.