A review and a conceptual framework of the key value drivers of mass customisation

The aim of this paper is to conceptualise the key value drivers of mass customisation in order to provide a structured approach to explain the added value that customers attribute to mass customised products. We assume that the added value of mass customisation is ultimately reflected in an increased willingness to pay. Previous studies show diverse results concerning customers' willingness to pay for mass customised products. We contribute to the existing body of research by suggesting and discussing the influence of general product characteristics and factors of the mass customisation approach on the key value drivers of mass customisation. Furthermore, the development of a conceptual framework offers explanations for the dissimilarity in customers' willingness to pay and advances the knowledge about the value increment of mass customised products as perceived by customers.

Differences between innovative and non-innovative microenterprises: internal factors

This exploratory study presents a comparison between two samples of microenterprises. One sample is formed by companies involved in product innovation during the current economic crisis and the other is formed by companies not involved in product innovation during the same period. The comparison analyzes which internal factors, supported by the literature as the influential factors of small business innovation, are significant when explaining the main differences between innovative microenterprise and non-innovative ones. The results suggest that the factors related to the organization and activity of the company are the factors which explain the differences between these two types of firms, rather than those factors related to micro-entrepreneurs own profile.

Cycling habits and other psychological variables affecting commuting by bicycle in city of Madrid

To develop effective cycling policies, decision makers and administrators should know the factors influencing the use of the bicycle for daily mobility. Traditional discrete choice models tend to be based on variables such as time and cost, which do not sufficiently explain the choice of the bicycle as a mode of transportation. Because psychological factors have been identified as particularly influential in the decision to commute by bicycle, this paper examines the perceptions of cycling factors and their influence on commuting by bicycle. Perceptions are measured by attitudes, other psychological variables, and habits. Statistical differences in the variables are established in relation to the choice of commuting mode and bicycle experience (commuter, sport–leisure, no use). Doing so enables the authors to identify the main barriers to commuting by bicycle and to make recommendations for cycling policies. Two underlying structures (factors) of the attitudinal variables are identified: direct benefits and long-term benefits. Three other factors are related to variables of difficulty: physical conditions, external facilities, and individual capacities. The effect of attitudes and other psychological variables on people’s decision to cycle to work–place of study is tested by using a logit model. In the case study of Madrid, Spain, the decision to cycle to work– place of study is heavily influenced by cycling habits (for noncommuting trips). Because bicycle commuting is not common, attitudes and other psychological variables play a less important role in the use of bikes.

Vibro-acoustic analysis of spacecraft structures with thin air layers

Esta Tesis presenta un estudio sobre el comportamiento vibroacústico de estructuras espaciales que incluyen capas de aire delgadas, así como sobre su modelización numérica. Las capas de aire pueden constituir un elemento fundamental en estos sistemas, como paneles solares plegados, que se consideran el caso de estudio en este trabajo. Para evaluar la influencia de las capas de aire en la respuesta dinámica del sistema se presenta el uso de modelos unidimensionales. La modelización de estos sistemas se estudia para los rangos de baja y alta frecuencia. En el rango de baja frecuencia se propone un conjunto de estrategias de simulación basadas en técnicas numéricas que se utilizan habitualmente en la industria aeroespacial para facilitar la aplicación de los resultados de la Tesis en los modelos numéricos actuales. Los resultados muestran el importante papel de las capas de aire en la respuesta del sistema. El uso de modelos basados en elementos finitos o de contorno para estos elementos proporciona resultados equivalentes aunque la aplicabilidad de estos últimos puede estar condicionada por la geometría del problema. Se estudia asimismo el uso del Análisis Estadístico de la Energía (SEA) para estos elementos. Una de las estrategias de simulación propuestas, que incluye una formulación energética para el aire que rodea a la estructura, se propone como estimador preliminar de la respuesta del sistema y sus frecuencias propias. Para el rango de alta frecuencia, se estudia la influencia de la definición del propio modelo SEA. Se presenta el uso de técnicas de reducción para determinar una matriz de pérdidas SEA reducida para definiciones incompletas del sistema (si algún elemento que interactúa con el resto no se incluye en el modelo). Esta nueva matriz tiene en cuenta la contribución de las subestructuras que no se consideran parte del modelo y que suelen ignorarse en el procedimiento habitual para reducir el tamaño del mismo. Esta matriz permite también analizar sistemas que incluyen algún componente con problemas de accesibilidad para medir su respuesta. Respecto a la determinación de los factores de pérdidas del sistema, se presenta una metodología que permite abordar casos en los que el método usual, el Método de Inyección de Potencia (PIM), no puede usarse. Se presenta un conjunto de métodos basados en la técnicas de optimización y de actualización de modelos para casos en los que no se puede medir la respuesta de todos los elementos del sistema y también para casos en los que no todos los elementos pueden ser excitados, abarcando un conjunto de casos más amplio que el abordable con el PIM. Para ambos rangos de frecuencia se presentan diferentes casos de análisis: modelos numéricos para validar los métodos propuestos y un panel solar plegado como caso experimental que pone de manifiesto la aplicación práctica de los métodos presentados en la Tesis. ABSTRACT This Thesis presents an study on the vibro-acoustic behaviour of spacecraft structures with thin air layers and their numerical modelling. The air layers can play a key role in these systems as solar wings in folded configuration that constitute the study case for this Thesis. A method based on one-dimensional models is presented to assess the influence of the air layers in the dynamic response of the system. The modelling of such systems is studied for low and high frequency ranges. In the low frequency range a set of modelling strategies are proposed based on numerical techniques used in the industry to facilitate the application of the results in the current numerical models. Results show the active role of the air layers in the system response and their great level of influence. The modelling of these elements by means of Finite Elements (FE) and Boundary Elements (BE) provide equivalent results although the applicability of BE models can be conditioned by the geometry of the problem. The use of Statistical Energy Analysis (SEA) for these systems is also presented. Good results on the system response are found for models involving SEA beyond the usual applicability limit. A simulation strategy, involving energetic formulation for the surrounding fluid is proposed as fast preliminary approach for the system response and the coupled eigenfrequencies. For the high frequency range, the influence of the definition of the SEA model is presented. Reduction techniques are used to determine a Reduced SEA Loss Matrix if the system definition is not complete and some elements, which interact with the rest, are not included. This new matrix takes into account the contribution of the subsystems not considered that are neglected in the usual approach for decreasing the size of the model. It also allows the analysis of systems with accessibility restrictions on some element in order to measure its response. Regarding the determination of the loss factors of a system, a methodology is presented for cases in which the usual Power Injection Method (PIM) can not be applied. A set of methods are presented for cases in which not all the subsystem responses can be measured or not all the subsystems can be excited, as solar wings in folded configuration. These methods, based on error minimising and model updating techniques can be used to calculate the system loss factors in a set of cases wider than the PIM’s. For both frequency ranges, different test problems are analysed: Numerical models are studied to validate the methods proposed; an experimental case consisting in an actual solar wing is studied on both frequency ranges to highlight the industrial application of the new methods presented in the Thesis.

Technical evolution of 3d modular construction from the nineteenth century to world war II

3D Modular construction is poorly known and scarcely published in technical literature. In spite of that there are an increasing number of manufacturers offering their products in different countries. This method has largely evolved from early examples such as the American Gold Rush prefabrication in the nineteenth century, the Sears precut homes or Voisin´s prototypes for modular homes, to the end of the first half of the twentieth century. In this period a non negligible number of attempts in 3D modular construction have been carried out, ranging from theoretical proposals to several hundred or thousand units produced. Selected examples of modular architecture will be analyses in order to illustrate its technical evolution, concerning materials, structure, transportation and on site assembly. Success and failure factors of the different systems will be discussed. Conclusions about building criteria shown in them and their applicability in current architecture will be drawn.

A short critical history of the application of genomics to animal breeding

Two scientific schools have been in coexistence from the beginning of genetics, one of them searching for factors of inheritance and the other one applying biometrical models to study the relationships between relatives. With the development of molecular genetics, the possibilities of detecting genes having a noticeable effect in traits augmented. Some genes with large or medium effects were localized in animals, although the most common result was to detect markers linked to these genes, allowing the possibility of assisting selection programs with markers. When a large amount of simple and inexpensive markers were available, the SNPs, new possibilities were opened since they did not need the presence of genes of large or medium effect controlling a trait, because the whole genome was scanned. Using a large amount of SNPs permits having a prediction of the breeding value at birth accurate enough to be used in some cases, like dairy cattle, to halve its generation interval. In other animal breeding programs, the implementation of genomic selection is less clear and the way in which it can be useful should be carefully studied. The need for large populations for associating phenotypic data and markers, plus the need for repeating the process continuously, complicates its application in some cases. The implementation of the information provided by the SNPs in current genetic programs has led to the development of complex statistical tools, joining the efforts of the two schools, factorial and biometrical, that nowadays work closely related.

Relationship among slurry characteristics and gaseous emissions at different types of commercial Spanish pig farms

This study aimed to analyse several factors of variation of slurry composition and to establish prediction equations for potential methane (CH4) and ammonia (NH3) emissions. Seventy-nine feed and slurry samples were collected at two seasons (summer and winter) from commercial pig farms sited at two Spanish regions (Centre and Mediterranean). Nursery, growing-fattening, gestating and lactating facilities were sampled. Feed and slurry composition were determined, and potential CH4 and NH3 emissions measured at laboratory. Feed nutrient contents were used as covariates in the analysis. Near infrared reflectance spectroscopy (NIRS) was evaluated as a predicting tool for slurry composition and potential gaseous emissions. A wide variability was found both in feed and slurry composition. Mediterranean farms had a higher pH (p<0.001) and ash (p=0.02) concentration than those located at the Centre of Spain. Also, type of farm affected ether extract content of the slurry (p=0.02), with highest values obtained for the youngest animal facilities. Results suggested a buffer effect of dietary fibre on slurry pH and a direct relationship (p<0.05) with fibre constituents of manure. Dietary protein content did not affect slurry nitrogen content but decreased (p=0.003) total and volatile solids concentration. Prediction models of potential NH3 emissions (R2=0.89) and CH4 yield (R2=0.61) were obtained from slurry composition. Predictions from NIRS showed a high accuracy for most slurry constituents (R2>0.90) and similar accuracy of prediction of potential NH3 and CH4 emissions (R2=0.84 and 0.68, respectively) to models using slurry characteristics, which can be of interest to estimate emissions from commercial farms and establish mitigation strategies or optimize biogas production.

Functional response of Ulmus minor Mill. to drought, flooding and dutch elm disease

Ulmus minor es una especie arbórea originaria de Europa cuyas poblaciones han sido diezmadas por el hongo patógeno causante de la enfermedad de la grafiosis. La conservación de los olmos exige plantearse su propagación a través de plantaciones y conocer mejor su ecología y biología. Ulmus minor es un árbol de ribera, pero frecuentemente se encuentra alejado del cauce de arroyos y ríos, donde la capa freática sufre fuertes oscilaciones. Por ello, nuestra hipótesis general es que esta especie es moderadamente resistente tanto a la inundación como a la sequía. El principal objetivo de esta tesis doctoral es entender desde un punto de vista funcional la respuesta de U. minor a la inundación, la sequía y la infección por O. novo-ulmi; los factores que posiblemente más influyen en la distribución actual de U. minor. Con este objetivo se persigue dar continuidad a los esfuerzos de conservación de esta especie que desde hace años se dedican en varios centros de investigación a nivel mundial, ya que, entender mejor los mecanismos que contribuyen a la resistencia de U. minor ante la inoculación con O. novo-ulmi y factores de estrés abiótico ayudará en la selección y propagación de genotipos resistentes a la grafiosis. Se han planteado tres experimentos en este sentido. Primero, se ha comparado la tolerancia de brinzales de U. minor y U. laevis – otro olmo ibérico – a una inmersión controlada con el fin de evaluar su tolerancia a la inundación y comprender los mecanismos de aclimatación. Segundo, se ha comparado la tolerancia de brinzales de U. minor y Quercus ilex – una especie típica de ambientes Mediterránea secos – a la falta de agua en el suelo con el fin de evaluar el grado de tolerancia y los mecanismos de aclimatación a la sequía. El hecho de comparar dos especies contrastadas responde al interés en entender mejor cuales son los procesos que conducen a la muerte de una planta en condiciones de sequía – asunto sobre el que hay una interesante discusión desde hace algunos años. En tercer lugar, con el fin de entender mejor la resistencia de algunos genotipos de U. minor a la grafiosis, se han estudiado las diferencias fisiológicas y químicas constitutivas e inducidas por O. novo-ulmi entre clones de U. minor seleccionados a priori por su variable grado de resistencia a esta enfermedad. En el primer experimento se observó que los brinzales de U. minor sobrevivieron 60 días inmersos en una piscina con agua no estancada hasta una altura de 2-3 cm por encima del cuello de la raíz. A los 60 días, los brinzales de U. laevis se sacaron de la piscina y, a lo largo de las siguientes semanas, fueron capaces de recuperar las funciones fisiológicas que habían sido alteradas anteriormente. La conductividad hidráulica de las raíces y la tasa de asimilación de CO2 neta disminuyeron en ambas especies. Por el contrario, la tasa de respiración de hojas, tallos y raíces aumentó en las primeras semanas de la inundación, posiblemente en relación al aumento de energía necesario para desarrollar mecanismos de aclimatación a la inundación, como la hipertrofia de las lenticelas que se observó en ambas especies. Por ello, el desequilibrio del balance de carbono de la planta podría ser un factor relevante en la mortalidad de las plantas ante inundaciones prolongadas. Las plantas de U. minor (cultivadas en envases de 16 litros a media sombra) sobrevivieron por un prolongado periodo de tiempo en verano sin riego; la mitad de las plantas murieron tras 90 días sin riego. El cierre de los estomas y la pérdida de hojas contribuyeron a ralentizar las pérdidas de agua y tolerar la sequía en U. minor. Las obvias diferencias en tolerancia a la sequía con respecto a Q. ilex se reflejaron en la distinta capacidad para ralentizar la aparición del estrés hídrico tras dejar de regar y para transportar agua en condiciones de elevada tensión en el xilema. Más relevante es que las plantas con evidentes síntomas de decaimiento previo a su muerte exhibieron pérdidas de conductividad hidráulica en las raíces del 80% en ambas especies, mientras que las reservas de carbohidratos apenas variaron y lo hicieron de forma desigual en ambas especies. Árboles de U. minor de 5 y 6 años de edad (plantados en eras con riego mantenido) exhibieron una respuesta a la inoculación con O. novo-ulmi consistente con ensayos previos de resistencia. La conductividad hidráulica del tallo, el potencial hídrico foliar y la tasa de asimilación de CO2 neta disminuyeron significativamente en relación a árboles inoculados con agua, pero solo en los clones susceptibles. Este hecho enlaza con el perfil químico “más defensivo” de los clones resistentes, es decir, con los mayores niveles de suberina, ácidos grasos y compuestos fenólicos en estos clones que en los susceptibles. Ello podría restringir la propagación del hongo en el árbol y preservar el comportamiento fisiológico de los clones resistentes al inocularlos con el patógeno. Los datos indican una respuesta fisiológica común de U. minor a la inundación, la sequía y la infección por O. novo-ulmi: pérdida de conductividad hidráulica, estrés hídrico y pérdida de ganancia neta de carbono. Pese a ello, U. minor desarrolla varios mecanismos que le confieren una capacidad moderada para vivir en suelos temporalmente anegados o secos. Por otro lado, el perfil químico es un factor relevante en la resistencia de ciertos genotipos a la grafiosis. Futuros estudios deberían examinar como este perfil químico y la resistencia a la grafiosis se ven alteradas por el estrés abiótico. ABSTRACT Ulmus minor is a native European elm species whose populations have been decimated by the Dutch elm disease (DED). An active conservation of this species requires large-scale plantations and a better understanding of its biology and ecology. U. minor generally grows close to water channels. However, of the Iberian riparian tree species, U. minor is the one that spread farther away from rivers and streams. For these reasons, we hypothesize that this species is moderately tolerant to both flooding and drought stresses. The main aim of the present PhD thesis is to better understand the functional response of U. minor to the abiotic stresses – flooding and drought – and the biotic stress – DED – that can be most influential on its distribution. The overarching goal is to aid in the conservation of this emblematic species through a better understanding of the mechanisms that contribute to resistance to abiotic and biotic stresses; an information that can help in the selection of resistant genotypes and their expansion in large-scale plantations. To this end, three experiments were set up. First, we compared the tolerance to experimental immersion between seedlings of U. minor and U. laevis – another European riparian elm species – in order to assess their degree of tolerance and understand the mechanisms of acclimation to this stress. Second, we investigated the tolerance to drought of U. minor seedlings in comparison with Quercus ilex (an oak species typical of dry Mediterranean habitats). Besides assessing and understanding U. minor tolerance to drought at the seedling stage, the aim was to shed light into the functional alterations that trigger drought-induced plant mortality – a matter of controversy in the last years. Third, we studied constitutive and induced physiological and biochemical differences among clones of variable DED resistance, before and following inoculation with Ophiostoma novo-ulmi. The goal is to shed light into the factors of DED resistance that is evident in some genotypes of U. minor, but not others. Potted seedlings of U. minor survived for 60 days immersed in a pool with running water to approximately 2-3 cm above the stem collar. By this time, U. minor seedlings died, whereas U. laevis seedlings moved out of the pool were able to recover most physiological functions that had been altered by flooding. For example, root hydraulic conductivity and leaf photosynthetic CO2 uptake decreased in both species; while respiration initially increased with flooding in leaves, stems and roots possibly to respond to energy demands associated to mechanisms of acclimation to soil oxygen deficiency; as example, a remarkable hypertrophy of lenticels was soon observed in flooded seedlings of both species. Therefore, the inability to maintain a positive carbon balance somehow compromises seedling survival under flooding, earlier in U. minor than U. laevis, partly explaining their differential habitats. Potted seedlings of U. minor survived for a remarkable long time without irrigation – half of plants dying only after 90 days of no irrigation in conditions of high vapour pressure deficit typical of summer. Some mechanisms that contributed to tolerate drought were leaf shedding and stomata closure, which reduced water loss and the risk of xylem cavitation. Obviously, U. minor was less tolerant to drought than Q. ilex, differences in drought tolerance resulting mostly from the distinct capacity to postpone water stress and conduct water under high xylem tension among species. More relevant was that plants of both species exhibited similar symptoms of root hydraulic failure (i.e. approximately 80% loss of hydraulic conductivity), but a slight and variable depletion of non-structural carbohydrate reserves preceding dieback. Five- and six-year-old trees of U. minor (planted in the field with supplementary watering) belonging to clones of contrasted susceptibility to DED exhibited a different physiological response to inoculation with O. novo-ulmi. Stem hydraulic conductivity, leaf water potential and photosynthetic CO2 uptake decreased significantly relative to control trees inoculated with water only in DED susceptible clones. This is consistent with the “more defensive” chemical profile observed in resistant clones, i.e. with higher levels of saturated hydrocarbons (suberin and fatty acids) and phenolic compounds than in susceptible clones. These compounds could restrict the spread of O. novo-ulmi and contribute to preserving the near-normal physiological function of resistant trees when exposed to the pathogen. These results evidence common physiological responses of U. minor to flooding, drought and pathogen infection leading to xylem water disruption, leaf water stress and reduced net carbon gain. Still, seedlings of U. minor develop various mechanisms of acclimation to abiotic stresses that can play a role in surviving moderate periods of flood and drought. The chemical profile appears to be an important factor for the resistance of some genotypes of U. minor to DED. How abiotic stresses such as flooding and drought affect the capacity of resistant U. minor clones to face O. novo-ulmi is a key question that must be contemplated in future research.

Analysis of quality of experience in 3D video systems

Esta tesis presenta un estudio exhaustivo sobre la evaluación de la calidad de experiencia (QoE, del inglés Quality of Experience) percibida por los usuarios de sistemas de vídeo 3D, analizando el impacto de los efectos introducidos por todos los elementos de la cadena de procesamiento de vídeo 3D. Por lo tanto, se presentan varias pruebas de evaluación subjetiva específicamente diseñadas para evaluar los sistemas considerados, teniendo en cuenta todos los factores perceptuales relacionados con la experiencia visual tridimensional, tales como la percepción de profundidad y la molestia visual. Concretamente, se describe un test subjetivo basado en la evaluación de degradaciones típicas que pueden aparecer en el proceso de creación de contenidos de vídeo 3D, por ejemplo debidas a calibraciones incorrectas de las cámaras o a algoritmos de procesamiento de la señal de vídeo (p. ej., conversión de 2D a 3D). Además, se presenta el proceso de generación de una base de datos de vídeos estereoscópicos de alta calidad, disponible gratuitamente para la comunidad investigadora y que ha sido utilizada ampliamente en diferentes trabajos relacionados con vídeo 3D. Asimismo, se presenta otro estudio subjetivo, realizado entre varios laboratorios, con el que se analiza el impacto de degradaciones causadas por la codificación de vídeo, así como diversos formatos de representación de vídeo 3D. Igualmente, se describen tres pruebas subjetivas centradas en el estudio de posibles efectos causados por la transmisión de vídeo 3D a través de redes de televisión sobre IP (IPTV, del inglés Internet Protocol Television) y de sistemas de streaming adaptativo de vídeo. Para estos casos, se ha propuesto una innovadora metodología de evaluación subjetiva de calidad vídeo, denominada Content-Immersive Evaluation of Transmission Impairments (CIETI), diseñada específicamente para evaluar eventos de transmisión simulando condiciones realistas de visualización de vídeo en ámbitos domésticos, con el fin de obtener conclusiones más representativas sobre la experiencia visual de los usuarios finales. Finalmente, se exponen dos experimentos subjetivos comparando varias tecnologías actuales de televisores 3D disponibles en el mercado de consumo y evaluando factores perceptuales de sistemas Super Multiview Video (SMV), previstos a ser la tecnología futura de televisores 3D de consumo, gracias a una prometedora visualización de contenido 3D sin necesidad de gafas específicas. El trabajo presentado en esta tesis ha permitido entender los factores perceptuales y técnicos relacionados con el procesamiento y visualización de contenidos de vídeo 3D, que pueden ser de utilidad en el desarrollo de nuevas tecnologías y técnicas de evaluación de la QoE, tanto metodologías subjetivas como métricas objetivas. ABSTRACT This thesis presents a comprehensive study of the evaluation of the Quality of Experience (QoE) perceived by the users of 3D video systems, analyzing the impact of effects introduced by all the elements of the 3D video processing chain. Therefore, various subjective assessment tests are presented, particularly designed to evaluate the systems under consideration, and taking into account all the perceptual factors related to the 3D visual experience, such as depth perception and visual discomfort. In particular, a subjective test is presented, based on evaluating typical degradations that may appear during the content creation, for instance due to incorrect camera calibration or video processing algorithms (e.g., 2D to 3D conversion). Moreover, the process of generation of a high-quality dataset of 3D stereoscopic videos is described, which is freely available for the research community, and has been already widely used in different works related with 3D video. In addition, another inter-laboratory subjective study is presented analyzing the impact of coding impairments and representation formats of stereoscopic video. Also, three subjective tests are presented studying the effects of transmission events that take place in Internet Protocol Television (IPTV) networks and adaptive streaming scenarios for 3D video. For these cases, a novel subjective evaluation methodology, called Content-Immersive Evaluation of Transmission Impairments (CIETI), was proposed, which was especially designed to evaluate transmission events simulating realistic home-viewing conditions, to obtain more representative conclusions about the visual experience of the end users. Finally, two subjective experiments are exposed comparing various current 3D displays available in the consumer market, and evaluating perceptual factors of Super Multiview Video (SMV) systems, expected to be the future technology for consumer 3D displays thanks to a promising visualization of 3D content without specific glasses. The work presented in this thesis has allowed to understand perceptual and technical factors related to the processing and visualization of 3D video content, which may be useful in the development of new technologies and approaches for QoE evaluation, both subjective methodologies and objective metrics.

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.

Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene

Activation by growth factors of the Ras-dependent signaling cascade results in the induction of p90 ribosomal S6 kinases (p90rsk). These are translocated into the nucleus upon phosphorylation by mitogen-activated protein kinases, with which p90rsk are physically associated in the cytoplasm. In humans there are three isoforms of the p90rsk family, Rsk-1, Rsk-2, and Rsk-3, which are products of distinct genes. Although these isoforms are structurally very similar, little is known about their functional specificity. Recently, mutations in the Rsk-2 gene have been associated with the Coffin–Lowry syndrome (CLS). We have studied a fibroblast cell line established from a CLS patient that bears a nonfunctional Rsk-2. Here we document that in CLS fibroblasts there is a drastic attenuation in the induced Ser-133 phosphorylation of transcription factor CREB (cAMP response element-binding protein) in response to epidermal growth factor stimulation. The effect is specific, since response to serum, cAMP, and UV light is unaltered. Furthermore, epidermal growth factor-induced expression of c-fos is severely impaired in CLS fibroblasts despite normal phosphorylation of serum response factor and Elk-1. Finally, coexpression of Rsk-2 in transfected cells results in the activation of the c-fos promoter via the cAMP-responsive element. Thus, we establish a link in the transduction of a specific growth factor signal to changes in gene expression via the phosphorylation of CREB by Rsk-2.

Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis

This report shows that loss of heterozygosity at the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) locus occurred in 5/8 (63%) dysplastic liver lesions and 11/18 (61%) hepatocellular carcinomas (HCCs) associated with the high risk factors of hepatitis virus infection and liver cirrhosis. Mutations in the remaining allele were detected in 6/11 (55%) HCCs, including deletions in a polydeoxyguanosine region known to be a target of microsatellite instability. M6P/IGF2R allele loss was also found in cirrhotic tissue of clonal origin adjacent to these dysplastic lesions and HCCs, demonstrating that M6P/IGF2R inactivation occurs early in liver carcinogenesis. In conclusion, HCCs frequently develop from clonal expansions of phenotypically normal, M6P/IGF2R-mutated hepatocytes, providing further support for the idea that M6P/IGF2R functions as a liver tumor-suppressor gene.

Smad8 mediates the signaling of the receptor serine kinase

Smad proteins are critical intracellular mediators of signaling by growth and differentiation factors of the transforming growth factor β superfamily. We have isolated a member of the Smad family, Smad8, from a rat brain cDNA library and biochemically and functionally characterized its ability to transduce signals from serine kinase receptors. In Xenopus embryo, Smad8 is able to transcriptionally activate a subset of mesoderm target genes similar to those induced by the receptor serine kinase, activin receptor-like kinase (ALK)-2. Smad8 can be specifically phosphorylated by a constitutively active ALK-2 but not the related receptor serine kinase, ALK-4. In response to signaling from ALK-2, Smad8 associates with a common regulatory molecule, Smad4, and this association leads to a synergistic effect on gene transcription. Furthermore, Smad8 is able to rescue the expression of mesoderm genes blocked by truncated ALK-2 in the embryo. These results indicate that Smad8 can function as a downstream signaling mediator of ALK-2.

Pontin52, an interaction partner of β-catenin, binds to the TATA box binding protein

β-catenin, the vertebrate homolog of the Drosophila Armadillo protein, has been shown to have dual cellular functions, as a component of both the cadherin-catenin cell adhesion complex and the Wnt signaling pathway. At Wnt signaling, β-catenin becomes stabilized in the cytoplasm and subsequently available for interaction with transcription factors of the lymphocyte enhancer factor-1/T-cell factor family, resulting in a nuclear localization of β-catenin. Although β-catenin does not bind DNA directly, its carboxyl- and amino-terminal regions exhibit a transactivating activity still not well understood molecularly. Here we report the identification of an interaction partner of β-catenin, a nuclear protein designated Pontin52. Pontin52 binds β-catenin in the region of Armadillo repeats 2–5 and, more importantly, also binds the TATA box binding protein. We provide evidence for an in vivo multiprotein complex composed of Pontin52, β-catenin, and lymphocyte enhancer factor-1/T-cell factor. Our results suggest involvement of Pontin52 in the nuclear function of β-catenin.

Determination of the binding sites of the proton transfer inhibitors Cd2+ and Zn2+ in bacterial reaction centers

The reaction center (RC) from Rhodobacter sphaeroides couples light-driven electron transfer to protonation of a bound quinone acceptor molecule, QB, within the RC. The binding of Cd2+ or Zn2+ has been previously shown to inhibit the rate of reduction and protonation of QB. We report here on the metal binding site, determined by x-ray diffraction at 2.5-Å resolution, obtained from RC crystals that were soaked in the presence of the metal. The structures were refined to R factors of 23% and 24% for the Cd2+ and Zn2+ complexes, respectively. Both metals bind to the same location, coordinating to Asp-H124, His-H126, and His-H128. The rate of electron transfer from QA− to QB was measured in the Cd2+-soaked crystal and found to be the same as in solution in the presence of Cd2+. In addition to the changes in the kinetics, a structural effect of Cd2+ on Glu-H173 was observed. This residue was well resolved in the x-ray structure—i.e., ordered—with Cd2+ bound to the RC, in contrast to its disordered state in the absence of Cd2+, which suggests that the mobility of Glu-H173 plays an important role in the rate of reduction of QB. The position of the Cd2+ and Zn2+ localizes the proton entry into the RC near Asp-H124, His-H126, and His-H128. Based on the location of the metal, likely pathways of proton transfer from the aqueous surface to QB⨪ are proposed.