Hidrogeología e hidrodinámica del acuífero de los manantiales de Gormaz y su importancia en el caudal base del río Duero, España = Hydrogeology and hydrodynamic of the Gormaz Springs Aquifer and its importance to the base flow of the Duero River, Spain

Se cuantifican las descargas subterráneas de un acuífero a un río que lo atraviesa utilizando correlaciones estadísticas. El río Duero, España, incrementa su caudal base en varios m3/s, al atravesar unos afloramientos carbonatados mesozoicos en un pequeño tramo de su cabecera; esto es de especial importancia en época de estiaje, cuando la mayor parte del caudal base del río procede de manantiales que allí se sitúan. Dichos afloramientos corresponden a uno de los dos acuíferos calcáreos confinados, que se desarrollan en paralelo y están hidráulicamente desconectados por una capa impermeable, que forman el sistema acuífero de los manantiales de Gormaz. Este sistema se encuentra en estado de régimen natural y está apenas explotado. Se define el modelo conceptual de funcionamiento hidrogeológico, considerando el papel hidrogeológico de la falla de Gormaz, situada en la zona de descarga del sistema. Analizando información geológica antecedente y la geofísica exploratoria realizada, se obtuvo un mejor conocimiento de la geometría y los límites de los acuíferos, definiéndose un sistema acuífero con una zona de recarga en el sur, correspondiente a los afloramientos calcáreos, los cuales se confinan hacia el norte bajo el Terciario, hasta intersecar con la falla normal de Gormaz. El salto de falla genera una barrera para las formaciones permeables situadas al extremo norte (margen derecha del río Duero); a su vez, el plano de falla facilita el ascenso del agua subterránea del sistema acuífero en estudio y pone en conexión hidráulica los dos acuíferos. Se estimaron, además, los parámetros hidráulicos de los acuíferos en los alrededores de la falla. La buena correlación entre los niveles piezométricos y las descargas subterráneas al río Duero han permitido la reconstrucción del hidrograma de los manantiales de Gormaz en el periodo 1992-2006. Se calcula así que la contribución subterránea al río Duero es de 135.9 hm3/año, que supone el 18.9% de la aportación total del río. In a short stretch of its headwaters, the base flow of the River Duero increases by several m3/s as it traverses some Mesozoic carbonate outcrops. This is of special importance during the dry season, when the majority of the base flow of the river proceeds from springs in this reach. The outcrops correspond to one of two confined calcareous aquifers that developed in parallel but which are not hydraulically connected because of an impermeable layer. Together, they constitute the aquifer system of the Gormaz Springs. The system is still in its natural regime and is hardly exploited. This study defines the conceptual model of hydrogeological functioning, taking into consideration the role of the Gormaz Fault, which is situated in the discharge zone of the system. Analysis of both antecedent geological information and geophysical explorations has led to a better understanding of the geometry and boundaries of the aquifers, defining an aquifer system with a recharge zone in the south corresponding to in the calcareous outcrops. These calcareous outcrops are confined to the north below Tertiary formations, as far as their intersection with the normal fault of Gormaz. The throw of the fault forms the barrier of the permeable formations situated in the extreme north (right bank of the River Duero). In turn, the fault plane facilitates the upflow of groundwater from the aquifer system and creates hydraulic connection between the two aquifers. In addition, the study estimated the hydraulic parameters of the aquifer around the fault. The close correlation between piezometric levels and the groundwater discharges to the River Duero has enabled the reconstruction of the hydrogram of Gormaz springs over the period 1992-2006. By this means, it is calculated that the groundwater contribution to the River Duero is 135.9 hm3/year, or 18.9% of the total river inflow.

Pietilä: El proyecto de Dipoli

Dipoli es un edificio plurifuncional localizado en el campus de Otaniemi que acoge los servicios generales del alumnado. Tanto encargo como propiedad pertenecía, hasta 2013, a la Asociación de Estudiantes de Helsinki University of Technology TKK (actualmente conocida como Aalto University), cuando se vendió y traspasó a la propia universidad. La tesis estudia este proyecto (1961-66) como uno de los ejemplos más significativos de la obra de los arquitectos Reima (1923-93)y Raili Pietilä (1926-), quienes se unieron tanto personal como profesionalmente el mismo año de la convocatoria del concurso (1961). Debido a la dificultad del encargo por la dimensión y flexibilidad de los espacios requeridos, el primer premio quedó desierto puesto que ninguna propuesta cumplía con todos los requisitos establecidos. El jurado otorgó el segundo premio a su proyecto junto con Osmo Lappo y solicitó posteriormente a ambos un desarrollo más profundo del mismo. Finalmente optaron por construir el edificio planteado por los Pietilä. En él debía desarrollarse un amplio abanico de actividades sociales como reuniones, entretenimiento nocturno, actuaciones, proyecciones de películas, cenas y bailes, así como servir de comedor durante los meses de invierno y espacio destinado a congresos en la época estival. Además, en dicho edificio se pretendía acoger el Sindicato de Estudiantes de la Universidad Tecnológica de Helsinki y se localizaría en el nuevo campus de Otaniemi a escasos kilómetros de la capital, donde Alvar Aalto ya estaba diseñando varios equipamientos universitarios siguiendo el planeamiento general que proyectó en el concurso de 1949. El elemento más característico de este proyecto es la cubierta, una estructura continua formada a partir de un caparazón hueco de hormigón in situ capaz de absorber dos lenguajes diferentes y generar, bajo ella, un espacio singular con multitud de posibilidades funcionales. Su geometría permite dividir el programa en estancias de menor tamaño sin perder ni la identidad ni unidad formal. La manera en que se iluminan los espacios bajo ella se consigue de formas diferentes: si bien la volumetría de líneas cartesianas presenta un sistema de aperturas longitudinales por donde penetra la luz cenital, en la forma más libre aparecen un conjunto de lucernarios de diferente tamaños y posiciones aparentemente aleatorias que introducen la luz natural por el plano del techo de forma más controlada, apoyada por la disposición de las ventanas perimetrales. El juego de espesores de la cubierta ofrece un conjunto de matices que pretenden resolver los tres condicionantes principales del proyecto, la adecuación de los usos en su interior, la compatibilidad de circulaciones de los usuarios y la inserción en el lugar. La percepción de este plano horizontal atraviesa lecturas múltiples, desde su uso primario de cubrición y cuya distancia con el plano del suelo se comprime para tensionar la grieta de luz al tiempo que ofrece nuevas relaciones con el paisaje hasta convertirse en fachada al apoyarse en el suelo y crear un límite físico entre interior y exterior. El objetivo fundamental de la tesis es entender mejor la traza particular de Dipoli desde una visión rigurosa que amplíe el conocimiento del edificio y al mismo tiempo explique el espacio propuesto a través de las diferentes herramientas de proyecto. Para ello se ha elaborado una documentación de la obra que parte de recopilar, seleccionar y redibujar la información existente desde el estado previo a la construcción del objeto terminado. El sentido de volver al Centro de Estudiantes de Otaniemi, supone, además de ayudar a comprender el trabajo de sus autores, entender el proceso de la historia de la arquitectura finlandesa y detectar relaciones con otras obras más lejanas con las que pudiese compartir ciertos valores, facilitando un entendimiento más global de la historia. Esta investigación se inicia desde la hipótesis que la forma final del edificio y su relación con el lugar, para proponer un tipo de arquitectura que confía en la observación sensible del programa, del uso, de las escalas de los espacios, del movimiento de las personas y su relación y anclaje con el lugar. Y en este sentido, el trabajo se desarrolla guiado por estos aspectos que se manifiestan también desde la influencia y comprensión de otros trabajos propios y ajenos. Para detectar las claves de proyecto que les han permitido la construcción espacial y formal de su arquitectura, entendiendo éstas como el conjunto de herramientas y mecanismos que reflexionan sobre una particular composición volumétrica y espacios dinámicos que ofrecen un aspecto exterior expresivo, la tesis se articula sobre dos capítulos principales “Contextos” y “Proyecto y Construcción” donde se quiere estudiar el proyecto en su forma más completa. Esta pareja de apartados aborda la descripción del marco temporal, físico, cultural, personal y profesional de los arquitectos, el análisis y síntesis de la propuesta y, por último, la repercusión del proyecto. Contextos pretende ubicar la obra además de facilitar la comprensión del conjunto de aspectos y condicionantes que determinaron la materialización de Dipoli. Este capítulo se subdivide a su vez en cinco apartados: Contexto Histórico, Físico y Cultural, Personal, Profesional e Incidencia de Dipoli. El Contexto histórico se centra en la descripción pormenorizada del conjunto de situaciones que influyen en el arquitecto cuando se toman decisiones durante el proceso de proyectar. El objetivo es definir los condicionantes que pueden haber afectado directa o indirectamente la obra. El capítulo comienza subrayando los temas de interés comunes para el resto de sus homólogos finlandeses. Principalmente se centra en la década de 1950 como etapa previa a la gestación de Dipoli. También atiende el proceso de evolución de la arquitectura finlandesa desde finales del S.XIX unido a la crisis de identidad nacional que el maestro Alvar Aalto superará por sus obras pero también por su personalidad y supondrá una gran sombra al resto de sus compañeros en el marco nacional e internacional provocando una reacción contraria a sus proyectos y persona entre el resto de arquitectos. Por este motivo, al tiempo que se gestaba el proyecto de Dipoli emergieron un grupo de profesionales que defendían fuertemente las trazas cartesianas del racionalismo como Aulis Blomstedt o Juhani Pallasmaa y que consiguieron abrir una nueva perspectiva intelectual. Por tanto será inevitable que la presencia del maestro nórdico Alvar Aalto aparezca a lo largo de toda la tesis, permitiéndonos un mejor entendimiento de la carga orgánica y humana de sus trabajos desde la perspectiva de los Pietilä. Posteriormente este capítulo desgrana aquellos intereses que dominaban el marco arquitectónico internacional y que pudieron influir en las soluciones planteadas. Dipoli será puesto en relación a diversas arquitecturas contemporáneas que presentan un enfoque diferente al esbozado por el Movimiento Moderno y cuyo marco de referencias guarda algún tipo de relación con los mismos temas de proyecto. Es el caso del grupo Team 10 o determinados ejemplos de arquitectos alemanes como Hugo Häring y Hans Scharoun, incluso puntos en común con el sistema constructivista del vanguardismo soviético. Estas relaciones con otras arquitecturas matizan su carácter singular e incluso se revisa en qué medida esta propuesta amplifica los aspectos que comparten. En cuanto al Contexto físico y cultural, una primera aproximación al ámbito donde el edificio se sitúa nos revela las características generales de un lugar claramente diferente a la ubicación del resto de edificios del campus. A continuación se adentra en el origen del nuevo centro universitario desde el planeamiento urbanístico de Alvar Aalto y revela tanto la forma de disponer las construcciones como las propuestas que el maestro había desarrollado con anterioridad a la convocatoria del concurso. Además aquí se destacan aquellos aspectos que propiciaron la elección del solar. Prosigue adentrándose en el programa propuesto por el jurado –entre cuyos miembros se encontraba el propio Aalto- y el análisis de las propuestas presentadas por cada uno de los arquitectos que obtuvieron una mención. Por último, se estudian y definen las obras más relevantes localizadas en el entorno físico del proyecto y que existían con anterioridad, destacando principalmente el trabajo de los Siren (Heikki y Kaija) y Alvar Aalto por los motivos desarrollados en el punto anterior. Prosigue con el Contexto Personal donde se seleccionan de datos biográficos que expliquen, en parte, las circunstancias personales que perfilaron su manera de entender la arquitectura y que consecuentemente influyeron en su camino intelectual hasta llegar a Dipoli. A continuación se indaga en la relación profesional y personal con Raili Paatelainen para establecer en qué medida participaron ambos en la propuesta. Este apartado concluye con el estudio de la etapa docente que profundiza en los temas de proyecto que Pietilä presentaba a los alumnos en sus clases de proyectos. En el proceso de comprensión de la evolución teórica y proyectual de los arquitectos se considera imprescindible la revisión de otros edificios propios que se enmarcan en el Contexto profesional. Éstos forman parte de la etapa de mayor actividad del estudio como son el Pabellón de Finlandia para la Exposición de Bruselas (1956-58), la Iglesia de Kaleva en Tampere (1959-66) y el Pabellón Nórdico para la Bienal de Venecia de 1960. Se completa la visión de estos tres ejemplos previos a Dipoli desde las investigaciones teóricas que realizó de forma paralela y que se difundieron a través de varias exposiciones. Nos centraremos en aquellas tres que fueron más relevantes en la madurez del arquitecto (Morfología y Urbanismo, La Zona y Estudios Modulares) para establecer relaciones entre unos aspectos y otros. En esta sección no se pretende realizar un análisis en profundidad, ni tampoco recoger la mayor parte de la obra de los Pietilä, sino más bien revelar los rasgos más significativos que faciliten el entendimiento de los valores anteriormente mencionados. Por último, Incidencia de Dipoli se refiere a la repercusión del edificio durante su construcción y finalización. Desde esta premisa, recoge el conjunto de críticas publicadas en las revistas de mayor difusión internacional que decidieron mostrar la propuesta además desde el propio interés del proyecto, por tratarse de un arquitecto reconocido internacionalmente gracias a la repercusión que obtuvieron sus proyectos anteriores. Se analiza el contenido de los artículos para establecer diversos encuentros con el capítulo Contextos y con los propios escritos de Pietilä. También se recogen las opiniones de críticos relevantes como Kenneth Frampton, Bruno Zevi o Christian Norberg-Schulz, destacando aquellos aspectos por los que mostraron un interés mayor. También se recoge y valora la opinión de sus homólogos finlandeses y que contradictoriamente se sitúa en el polo opuesto a la del juicio internacional. Se adentra en las situaciones complejas que propició el rechazo del edificio al desvincularse por completo de la corriente racionalista que dominaba el pensamiento crítico finés unido a la búsqueda de nuevas alternativas proyectuales que les distanciase del éxito del maestro Alvar Aalto. Pretende esclarecer tanto la justificación de dichos comentarios negativos como los motivos por los cuales Reima y Raili no obtuvieron encargos durante casi diez años, tras la finalización de Dipoli. Nos referiremos también a la propia opinión de los arquitectos. Para ello, en el apartado Morfología Literal se recoge el texto que Reima Pietilä publicó en el número 9 de la revista Arkkitehti para contrarrestar las numerosas críticas recibidas. Se subraya aquellos aspectos de proyecto que inciden directamente en la percepción y razón de ser de la propuesta. Por último, se manifiesta la valoración crítica de dos personas muy próximas al entorno personal y profesional de los Pietilä: Roger Connah y Malcolm Quantrill. Ambas figuras son las que han adentrado en el trabajo de los arquitectos con mayor profundidad y aportado una visión más completa del contexto arquitectónico de Finlandia en el s.XX. Se han interesado principalmente por el conocimiento morfológico que les ha llevado a la observación de los fenómenos de la naturaleza. Se apunta también la falta de objetividad de sus opiniones originadas en parte por haber colaborado profesionalmente y ser amigo íntimo de la familia respectivamente. El valor de la documentación aportada por ambos reside principalmente en la fiel transmisión de las explicaciones del propio Pietilä. El último capítulo Proyecto y Construcción engloba tanto la descripción exhaustiva del proyecto como el análisis de la obra. Al tiempo que se explica la propuesta, se establecen continuamente relaciones y paralelismos con otras arquitecturas que ayudan a entenderla. Para ello, se establecen tres apartados elementales: “El lugar”, “Programa y geometrías” y “Presencia y materialidad física” y se pretende identificar aquellas herramientas de proyecto en las que confía para la materialización de la obra al tiempo que se profundiza en la evolución de la propuesta. En cuanto a El lugar, se describe de manera pormenorizada el recorrido hasta alcanzar el edificio y cómo la mirada atenta de la naturaleza que lo rodea está continuamente presente en todos los dibujos de la propuesta. Se realiza un estudio tanto de la multiplicidad de accesos como del vacío existente en planta baja que forma parte del espacio público y que atraviesa el edificio diagonalmente. Desde aquí se evaluará los espacios intermedios existentes que matizan los ámbitos donde se desarrolla cada una de las actividades. A continuación se enfoca el estudio de la ventana como elemento relevante en la transición de espacios interiores y exteriores para posteriormente adentrarnos en la importancia de los recorridos en la planta superior y cómo las salas polivalentes se acomodan a estos. Programas y geometrías explica la solución y desarrollo de la propuesta a través de los tanteos de la planta. Detecta simultáneamente aquellos aspectos que aparecen en otros proyectos y que pueden haber influido en el desarrollo de la obra. Una vez que han sido estudiados los dos niveles se introduce la sección para analizar las conexiones entre ambos planos, destacando los tipos de escaleras y accesos que propician la multiplicidad de recorridos y en consecuencia el movimiento de las personas. En el último apartado se identifica la geometría de la estructura a través de la descripción formal de la cubierta y sus apoyos en planta para conocer cómo responde el volumen definitivo a la adecuación de los usos. El carácter del edificio a través del empleo de los materiales y las técnicas de construcción utilizadas se indaga desde la Materialidad física. Este punto de vista esclarece temas de proyecto como la relación multisensorial de Dipoli y el concepto del tiempo relacionado con espacios de carácter dinámico o estático. Una vez se ha realizado un análisis de la obra construida a través de sus recorridos, se plantea un último regreso al exterior para observar la presencia del edificio a través de su tamaño, color y texturas. Este apartado nos mostrará la mirada atenta a la escala del proyecto como vector de dirección que pretende encontrar la inserción adecuada del edificio en el lugar, cerrando el proceso de proyecto. El motivo de desarrollar esta tesis en torno a Dipoli se apoya en su consideración como paradigma de una arquitectura que confía en la observación sensible del programa, uso, las escalas de los espacios, circulaciones y su relación y anclaje con el lugar como argumentos fundamentales de proyecto, cuya realidad concreta consigue situar la propuesta en el marco histórico de la arquitectura nórdica e internacional. Además la distancia histórica desde mundo actual respecto a la década de los años 60 del s.XX nos permite entender el contexto cultural donde se inserta Dipoli que continúa nuestra historia reciente de la arquitectura y concibe la obra construida como una extensión de nuestro mundo contemporáneo. Por ello se valora el proyecto desde la mirada hacia atrás que analiza las diferencias entre la realidad construida y las intenciones de partida. Esta revisión dotada de una distancia crítica nos permite adentrarnos en la investigación de manera objetiva. Igualmente presenta una distancia histórica (referida al tiempo transcurrido desde su construcción) y socio-cultural que favorece la atenuación de prejuicios y aspectos morales que puedan desviar una mirada analítica y se alejen de una valoración imparcial. Dipoli, enmarcada en dicho periodo, mantiene la capacidad crítica para ser analizada. ABSTRACT The dissertation defends Dipoli ( 1961-1966 ) as one of the most significant examples of the Reima ( 1923-1993 ) Raili Pietilä (1926 -), who joined both personally and professionally the same year of the project´s competition (1961). Due to the difficulty of the commission by the size and flexibility of the required areas, there was not first prize awarded because none of the submitted proposals met all the requirements. The jury awarded Dipoli with second prize together with a competing scheme by Osmo Lappo. The board subsequently asked for a further development of both proposals and finally selected the one by Pietilä. The completed project allows a wide range of social activities such as meetings, night entertainment, performances, film screenings, dinners and dance to take place while the facility can also serve as a dining hall during winter months and conference center in the summer when necessary. In addition, the building was intended to house the Helsinki University of Technology (now Aalto University) Student Union. The University, at the time being designed by Alvar Aalto following his successful entry to the master plan competition in 1949, was located a few kilometers from the capital on the new campus in Otaniemi. The most characteristic element of the project is its roof which can be described as a continuous form achieved an in-situ concrete cavity structure that can modulate two different geometric languages and generate a singular space under it. The building is, in general terms, an unique shell space with many functional possibilities. Its geometry allows the program to split its functions into smaller sizes without losing the identity or formal unity of the general object. The way in which the spaces are illuminated is solved in two different ways. First, while the Cartesian-line volume presents a series of longitudinal openings into which natural light penetrates, the free-form volume shows a set of skylights in apparently random positions that vary in size and that introduce natural light through the roof in a more controlled manner. In addition the perimeter openings are present that relate directly to the nature that surrounds the building. The adaptable thickness of the roof provides a set of solutions that resolve the three main issues of the project: the adequacy of the functions in the interior areas, the complex capability for user flows and circulation and the manner in which the building is inserted in its context. The perception of the roof´ horizontal plane offers multiple interpretations, from its primary use as a primitive cover whose distance from the ground compresses the void and creates a light tension, to the new relationships with the landscape where by the roof becomes a façade cladding and rests directly on the ground to create a physical boundary between interior and exterior. The main scope of this research is to better understand the particular trace of Dipoli from a rigorous architectural view to deep into the knowledge of the building and, at the same time, to explain the space through a series of project design tools that have been used. For this reason, an accurate documentation has arisen from collecting, selecting and redrawing the existing information from the sketching stage to the built object. A through reanalysis of the Otaniemi Student Center therefore provides not only a more complete understanding of the work of the architects, but also leads to a better comprehension of the history of Finnish architecture, which is related to other cultural relationships and which shares certain architectural values which a more comprehensive understanding of general architectural history. This research starts from the working hypothesis that the final shape of the building and its relationship to its place created a type of architecture that relies on a sensitive observation of the program, the use of varying scales of space, the movement and flow of people and finally the coexistence with the natural context. In this sense, the work is developed based on those aspects that are also reflected in the influence of others architects by understanding both their own and other architects´ work. In order to obtain a personal reading of the project facts that allowed the architects construct Dipoli (understanding the facts as a set of tools and project mechanisms that are able to generate a particular volumetric composition and dynamic spaces that at the same time provide an expressive exterior), the research hinges on two main sections, "Contexts" and "Design and Construction", that study the project from all perspectives. This two parts address the description of temporal , physical , cultural , personal and professional framework, analysis and synthesis of the proposal and finally, the national and international influences on the project. Contexts seek to place the work and to facilitate the understanding of all aspects and conditions that led to the creation of Dipoli. This chapter is subdivided into five sections: Historical Context, Cultural and Physical, Personal, Professional and Dipoli Influences. Historical Context focuses on a detailed description of a set of precedents that influenced the architect when making decisions during design process. The objective is to define the conditions that could directly or indirectly shape the work. This chapter begins by highlighting issues of common interest to the rest its Finnish counterparts. The text is mainly focused on the 1950s as a prelude to Dipoli´s conception. It will also address the process of Finnish architecture from the late nineteenth century as linked to the national identity crisis that the great master Alvar Aalto overcame with both his works and personality, being a great drain on the rest of his colleagues. This aspect caused a reaction against Aalto and his projects. For this reason, at the time that Dipoli came into being a number of professionals who strongly defended the traces of Cartesian Rationalism, including Juhani Pallasmaa and Aulis Blomstedt emerged and brought a new intellectual perspective to the Finnish architecture scene. It is thus inevitable that the presence of Alvar Aalto will be apparent throughout the dissertation to allow a better understanding of the organizational and human character of their work from the Pietiläs´ perspective. Later, this chapter identifies those interests that dominated the international architectural framework that could have influenced Dipoli. The project will be placed in relation to various contemporary architectural works that were created using a different approach to that outlined by the Modern Movement. This is present in the case of Team 10 group and with specific examples of German architects including Hans Scharoun and Hugo Häring, as well as some commonalities with Soviet Constructivism. These relationships with other architecture qualify its singular character and even extend how this proposal amplifies those shared aspects. Physical and Cultural Context involves the unique site where the building is located which includes different features from the location of other buildings on the campus. IT then progresses into the origin of the new campus from the urban planning of Alvar Aalto and reveals both the setting and proposed constructions that Aalto had developed. This section also highlights the aspects that led to the choice of the site. I go deep into the program proposed by the jury (of whom Aalto was a member) and the analysis of the alternative proposals that received a special commendation. Finally, I study and define the most relevant works located near Dipoli, emphasizing primarily the work of the Sirens (Heikki and Kaija) and Alvar Aalto for the reasons developed in the previous section. I then proceed with the Personal Context, where a series of biographical data are selected to begin to explain the personal circumstances that outlined the Pietilas´ architectural understanding and consequently could have influenced their intellectual approach to design Dipoli. Then the text explores their professional and personal relationship to establish what extent they participated in the proposal. This section concludes with the study of the Reima Pietilä´s teaching period at Oulu that explores the issues he presented to his students there. In the process of understanding the Pietiläs´ theoretical and design evolution, it must be considered essential to study other buildings that are part of their professional context. These projects belong to the most active stage of their office and include the Finnish Pavilion for the World´s Fair in Brussels (1956-1958), Kaleva Church in Tampere (1959-1966) and the Nordic Pavilion at the 1960 Venice Biennale. We will complete the view of Dipoli from previous theoretical investigations performed in parallel that were spread through several exhibitions. We will focus on the three that were most relevant to the evolution of the architect (Morphology and Urbanism, the Zone, and Stick Studies) to establish a series of useful relationships. This section is not intended to be an in-depth analysis nor to collect most of the work of the Pietiläs´; but rather to reveal the most significant features that facilitate an understanding of the above values. Finally, Dipoli´s Impact refers to the influence of the building from many points of view during its construction and after its completion. It collects the reviews published in the world's most relevant magazines which had decided to show the alternate proposals, generally conceived of by internationally-renowned architects. I analyze the content of the articles in order to establish a series of parallels with the chapter Contexts and own writings Pietilä to clarify if main design directions were clear at that time. The views of relevant critics, including Kenneth Frampton, Bruno Zevi and Christian Norberg -Schulz, are also collected here. This episode also collects and assesses the views of these critics´ Finnish counterparts that generally stood at the opposite side of the international debate. It delves into the complex situation that led to the rejection of the building by the rationalists that dominated the Finnish critical thinking while searching for new alternatives to distance themselves from the Alvar Aalto´s success. It aims to clarify both the justification for these negative comments and the reasons why Reima and Raili not obtain a single commission for nearly ten years after the completion of Dipoli. From the critics we will approach the opinion of Reima Pietilä himself. To do this, in the Literal Morphology section we will see how the architect tried to defend his position. Those design tool that directly affected the perception of the proposal are provided through the figures of Roger Connah and Malcolm Quantrill. Finally, a critical –personal and professional- review of these two very close figures will take place. Despite knowing that both delved into the work of architects with greater depth and provided a complete view of the Finnish architectural context in 20th century, they have focused mainly morphological knowledge which has led to the observation of natural phenomena. It also notes the lack of objectivity in their views caused in part by, in the case of Connah, collaborating professionally and in that of Quantrill being a close friend of the Pietilä family. The value of the documentation provided by both resides mainly in the faithful transmission of the Pietiläs´ own explanations. The final chapter covers both Design and Construction and provides a comprehensive project description in order tofaithfully analyse the work. As the proposal is being explained, relationships of its built form are continuously linked to other architectural projects to gain a better understanding of Dipoli itself. To do this we have set three basic sections: "The Place", "Geometries & Function" and "Presence and Materiality. Construction process" that intended to identify those project tools for the realization of the work while deepens the proposal´s evolution. The Place describes how to approach and reach the building in detail and how the view out towards the surrounding natural setting is continuously shown in the proposal´s drawings. We will study both the multiplicity of entrances as well as the corridor downstairs as part of the public space that diagonally goes through the building. Then, the existing voids in the concrete cave for public activities will be evaluated. Lastly, the study will focus on the openings as a significant element in the transition from interior and exterior areas to describe the importance of the circulation on the second floor and how function is able to accommodate through the areas of void. Geometries & Function explains the final solution and the development of the proposal through the floor plan. Simultaneously it detects those aspects that appear in other projects and that may have influenced the development of the work. Once we have analyzed both levels –ground and second floor- section drawings come into the topic to study the connections between the two levels and highlighting the types of hierarchy for the multiple paths to organize the flows of people inside the building. In the last section the structural geometry is identified through the description of the form and how it responds to the final volumetrical settings. The character of the building through the use of materials and construction techniques inquires from Presence and Materiality. This point of view clarifies multisensory project issues as Dipoli relationship to the dynamic or static character or different spaces inside the building. Once the analysis has been made we will step back to a final return to the building´s exterior to analyze the presence of the building through its scale, colour and textures. This section emphasizes the project´s scale and orientation to find the proper insertion of the building in place. In short, this dissertation has been done by the idea that Pietiläs´special abilities were allowed from a sensitive observation of the program, the creation of a variety of special scales, dynamic circulation and the relating relationship with the project´s location as fundamental design tools. From this aspect, Dipoli could be more usefully framed in the historical context of Nordic and international architecture. The dissertation allows us to better understand the cultural context of the 1960s, in which Dipoli was established since it continues our recent architectural history. The final built form is conceived as an extension of our contemporary world. Therefore the project is assessed through the comparison of the architects´ intentions and the final completed project.

Post-­‐occupancy monitoring of two flats in Madrid: development and assessment of a mixed methods methodology

Recent research has shown large differences between the expected and the actual energy consumption in buildings. The differences have been attributed partially, to the assumptions made during the design phase of buildings when simulation methods are employed. More accurate occupancy profiles on building operation could help to carry out more precise building performance calculations. This study focuses on the post-occupancy evaluation of two apartments, one renovated and one non renovated, in Madrid within the same building complex. The aim of this paper is to present an application of the mixed-methods methodology (Creswell, 2007) to assess thermal comfort and occupancy practices used in the case studies, and to discuss the shortcomings and opportunities associated with it. The mixed-methods methodology offers strategies for integrating qualitative and quantitative methods to investigate complex phenomena. This approach is expected to contribute to the growing knowledge of occupants’ behaviour and building performance by explaining the differences observed between energy consumption and thermal comfort in relation to people’s saving and comfort practices and the related experiences, preferences and values.

Automated detection and classification of brain injury lesions on structural magnetic resonance imaging

El daño cerebral adquirido (DCA) es un problema social y sanitario grave, de magnitud creciente y de una gran complejidad diagnóstica y terapéutica. Su elevada incidencia, junto con el aumento de la supervivencia de los pacientes, una vez superada la fase aguda, lo convierten también en un problema de alta prevalencia. En concreto, según la Organización Mundial de la Salud (OMS) el DCA estará entre las 10 causas más comunes de discapacidad en el año 2020. La neurorrehabilitación permite mejorar el déficit tanto cognitivo como funcional y aumentar la autonomía de las personas con DCA. Con la incorporación de nuevas soluciones tecnológicas al proceso de neurorrehabilitación se pretende alcanzar un nuevo paradigma donde se puedan diseñar tratamientos que sean intensivos, personalizados, monitorizados y basados en la evidencia. Ya que son estas cuatro características las que aseguran que los tratamientos son eficaces. A diferencia de la mayor parte de las disciplinas médicas, no existen asociaciones de síntomas y signos de la alteración cognitiva que faciliten la orientación terapéutica. Actualmente, los tratamientos de neurorrehabilitación se diseñan en base a los resultados obtenidos en una batería de evaluación neuropsicológica que evalúa el nivel de afectación de cada una de las funciones cognitivas (memoria, atención, funciones ejecutivas, etc.). La línea de investigación en la que se enmarca este trabajo de investigación pretende diseñar y desarrollar un perfil cognitivo basado no sólo en el resultado obtenido en esa batería de test, sino también en información teórica que engloba tanto estructuras anatómicas como relaciones funcionales e información anatómica obtenida de los estudios de imagen. De esta forma, el perfil cognitivo utilizado para diseñar los tratamientos integra información personalizada y basada en la evidencia. Las técnicas de neuroimagen representan una herramienta fundamental en la identificación de lesiones para la generación de estos perfiles cognitivos. La aproximación clásica utilizada en la identificación de lesiones consiste en delinear manualmente regiones anatómicas cerebrales. Esta aproximación presenta diversos problemas relacionados con inconsistencias de criterio entre distintos clínicos, reproducibilidad y tiempo. Por tanto, la automatización de este procedimiento es fundamental para asegurar una extracción objetiva de información. La delineación automática de regiones anatómicas se realiza mediante el registro tanto contra atlas como contra otros estudios de imagen de distintos sujetos. Sin embargo, los cambios patológicos asociados al DCA están siempre asociados a anormalidades de intensidad y/o cambios en la localización de las estructuras. Este hecho provoca que los algoritmos de registro tradicionales basados en intensidad no funcionen correctamente y requieran la intervención del clínico para seleccionar ciertos puntos (que en esta tesis hemos denominado puntos singulares). Además estos algoritmos tampoco permiten que se produzcan deformaciones grandes deslocalizadas. Hecho que también puede ocurrir ante la presencia de lesiones provocadas por un accidente cerebrovascular (ACV) o un traumatismo craneoencefálico (TCE). Esta tesis se centra en el diseño, desarrollo e implementación de una metodología para la detección automática de estructuras lesionadas que integra algoritmos cuyo objetivo principal es generar resultados que puedan ser reproducibles y objetivos. Esta metodología se divide en cuatro etapas: pre-procesado, identificación de puntos singulares, registro y detección de lesiones. Los trabajos y resultados alcanzados en esta tesis son los siguientes: Pre-procesado. En esta primera etapa el objetivo es homogeneizar todos los datos de entrada con el objetivo de poder extraer conclusiones válidas de los resultados obtenidos. Esta etapa, por tanto, tiene un gran impacto en los resultados finales. Se compone de tres operaciones: eliminación del cráneo, normalización en intensidad y normalización espacial. Identificación de puntos singulares. El objetivo de esta etapa es automatizar la identificación de puntos anatómicos (puntos singulares). Esta etapa equivale a la identificación manual de puntos anatómicos por parte del clínico, permitiendo: identificar un mayor número de puntos lo que se traduce en mayor información; eliminar el factor asociado a la variabilidad inter-sujeto, por tanto, los resultados son reproducibles y objetivos; y elimina el tiempo invertido en el marcado manual de puntos. Este trabajo de investigación propone un algoritmo de identificación de puntos singulares (descriptor) basado en una solución multi-detector y que contiene información multi-paramétrica: espacial y asociada a la intensidad. Este algoritmo ha sido contrastado con otros algoritmos similares encontrados en el estado del arte. Registro. En esta etapa se pretenden poner en concordancia espacial dos estudios de imagen de sujetos/pacientes distintos. El algoritmo propuesto en este trabajo de investigación está basado en descriptores y su principal objetivo es el cálculo de un campo vectorial que permita introducir deformaciones deslocalizadas en la imagen (en distintas regiones de la imagen) y tan grandes como indique el vector de deformación asociado. El algoritmo propuesto ha sido comparado con otros algoritmos de registro utilizados en aplicaciones de neuroimagen que se utilizan con estudios de sujetos control. Los resultados obtenidos son prometedores y representan un nuevo contexto para la identificación automática de estructuras. Identificación de lesiones. En esta última etapa se identifican aquellas estructuras cuyas características asociadas a la localización espacial y al área o volumen han sido modificadas con respecto a una situación de normalidad. Para ello se realiza un estudio estadístico del atlas que se vaya a utilizar y se establecen los parámetros estadísticos de normalidad asociados a la localización y al área. En función de las estructuras delineadas en el atlas, se podrán identificar más o menos estructuras anatómicas, siendo nuestra metodología independiente del atlas seleccionado. En general, esta tesis doctoral corrobora las hipótesis de investigación postuladas relativas a la identificación automática de lesiones utilizando estudios de imagen médica estructural, concretamente estudios de resonancia magnética. Basándose en estos cimientos, se han abrir nuevos campos de investigación que contribuyan a la mejora en la detección de lesiones. ABSTRACT Brain injury constitutes a serious social and health problem of increasing magnitude and of great diagnostic and therapeutic complexity. Its high incidence and survival rate, after the initial critical phases, makes it a prevalent problem that needs to be addressed. In particular, according to the World Health Organization (WHO), brain injury will be among the 10 most common causes of disability by 2020. Neurorehabilitation improves both cognitive and functional deficits and increases the autonomy of brain injury patients. The incorporation of new technologies to the neurorehabilitation tries to reach a new paradigm focused on designing intensive, personalized, monitored and evidence-based treatments. Since these four characteristics ensure the effectivity of treatments. Contrary to most medical disciplines, it is not possible to link symptoms and cognitive disorder syndromes, to assist the therapist. Currently, neurorehabilitation treatments are planned considering the results obtained from a neuropsychological assessment battery, which evaluates the functional impairment of each cognitive function (memory, attention, executive functions, etc.). The research line, on which this PhD falls under, aims to design and develop a cognitive profile based not only on the results obtained in the assessment battery, but also on theoretical information that includes both anatomical structures and functional relationships and anatomical information obtained from medical imaging studies, such as magnetic resonance. Therefore, the cognitive profile used to design these treatments integrates information personalized and evidence-based. Neuroimaging techniques represent an essential tool to identify lesions and generate this type of cognitive dysfunctional profiles. Manual delineation of brain anatomical regions is the classical approach to identify brain anatomical regions. Manual approaches present several problems related to inconsistencies across different clinicians, time and repeatability. Automated delineation is done by registering brains to one another or to a template. However, when imaging studies contain lesions, there are several intensity abnormalities and location alterations that reduce the performance of most of the registration algorithms based on intensity parameters. Thus, specialists may have to manually interact with imaging studies to select landmarks (called singular points in this PhD) or identify regions of interest. These two solutions have the same inconvenient than manual approaches, mentioned before. Moreover, these registration algorithms do not allow large and distributed deformations. This type of deformations may also appear when a stroke or a traumatic brain injury (TBI) occur. This PhD is focused on the design, development and implementation of a new methodology to automatically identify lesions in anatomical structures. This methodology integrates algorithms whose main objective is to generate objective and reproducible results. It is divided into four stages: pre-processing, singular points identification, registration and lesion detection. Pre-processing stage. In this first stage, the aim is to standardize all input data in order to be able to draw valid conclusions from the results. Therefore, this stage has a direct impact on the final results. It consists of three steps: skull-stripping, spatial and intensity normalization. Singular points identification. This stage aims to automatize the identification of anatomical points (singular points). It involves the manual identification of anatomical points by the clinician. This automatic identification allows to identify a greater number of points which results in more information; to remove the factor associated to inter-subject variability and thus, the results are reproducible and objective; and to eliminate the time spent on manual marking. This PhD proposed an algorithm to automatically identify singular points (descriptor) based on a multi-detector approach. This algorithm contains multi-parametric (spatial and intensity) information. This algorithm has been compared with other similar algorithms found on the state of the art. Registration. The goal of this stage is to put in spatial correspondence two imaging studies of different subjects/patients. The algorithm proposed in this PhD is based on descriptors. Its main objective is to compute a vector field to introduce distributed deformations (changes in different imaging regions), as large as the deformation vector indicates. The proposed algorithm has been compared with other registration algorithms used on different neuroimaging applications which are used with control subjects. The obtained results are promising and they represent a new context for the automatic identification of anatomical structures. Lesion identification. This final stage aims to identify those anatomical structures whose characteristics associated to spatial location and area or volume has been modified with respect to a normal state. A statistical study of the atlas to be used is performed to establish which are the statistical parameters associated to the normal state. The anatomical structures that may be identified depend on the selected anatomical structures identified on the atlas. The proposed methodology is independent from the selected atlas. Overall, this PhD corroborates the investigated research hypotheses regarding the automatic identification of lesions based on structural medical imaging studies (resonance magnetic studies). Based on these foundations, new research fields to improve the automatic identification of lesions in brain injury can be proposed.

Precursor B cells for autoantibody production in genomically Fas-intact autoimmune disease are not subject to Fas-mediated immune elimination

The Fas/Fas ligand (FasL) system participates in regulation of the immune system through the apoptotic process. However, the extent to which abnormalities in this system are involved in the loss of self-tolerance and development of autoimmune disease not associated with Fas/FasL mutations remains unknown. The present study addresses this issue in Fas/FasL-intact, systemic lupus erythematosus (SLE)-prone (NZB × NZW) (NZB/W) F1 mice. While splenic B cells from 2-month-old mice before overt SLE expressed Fas poorly, in vitro stimulation with an agonistic anti-CD40 mAb up-regulated their Fas expression, thus revealing the existence of two populations: one was Fashigh and highly susceptible to anti-Fas mAb-induced apoptosis, and the other was Faslow and apoptosis-resistant. The Faslow cells were included in the CD5+ B cell subpopulation and contained most of the cells that produced IgM anti-DNA antibodies. The isotype of anti-DNA antibodies switches from IgM to IgG in NZB/W F1 mice at ages beginning at about 6 months. These IgG anti-DNA antibodies were produced almost exclusively by a subpopulation of splenic B cells that spontaneously expressed low levels of Fas in vivo and were apoptosis-resistant. The findings indicate that precursor B cells for autoantibody production and presumably autoantibody-secreting cells in these mice are relatively resistant to Fas-mediated apoptosis, a finding supporting the concept that abnormalities of Fas-mediated apoptotic process are involved in the development of autoreactive B cells in Fas/FasL-intact autoimmune disease.

Evidence for two nonidentical drug-interaction sites in the human P-glycoprotein

Human P-glycoprotein (Pgp) confers multidrug resistance to cancer cells by ATP-dependent extrusion of a great many structurally dissimilar hydrophobic compounds. The manner in which Pgp recognizes these different substrates is unknown. The protein shows internal homology between its N- and C-terminal halves, each comprised of six putative transmembrane helices and a consensus ATP binding/utilization site. Photoactive derivatives of certain Pgp substrates specifically label two regions, one on each half of the protein. In this study, using [125I]iodoarylazidoprazosin ([125I]IAAP), a photoactive analog of prazosin, we have demonstrated the presence of two nonidentical drug-interaction sites within Pgp. Taking advantage of a highly susceptible trypsin cleavage site in the linker region of Pgp, we characterized the [125I]IAAP binding to the N- and C-terminal halves. cis(Z)-Flupentixol, a modulator of Pgp function, preferentially increased the affinity of [125I]IAAP for the C-terminal half of the protein (C-site) by reducing the Kd from 20 to 6 nM without changing the labeling or affinity (Kd = 42–46 nM) of the N-terminal half (N-site). Also, the concentration of vinblastine (Pgp substrate) and cyclosporin A (Pgp modulator) required for 50% inhibition of [125I]IAAP binding to the C-site was increased 5- to 6-fold by cis(Z)-flupentixol without any effect on the N-site. In addition, [125I]IAAP binding to the N-site was less susceptible than to C-site to inhibition by vanadate which blocks ATP hydrolysis and drug transport. These data demonstrate the presence of at least two nonidentical substrate interaction sites in Pgp.

Distinct Molecular Events during Secretory Granule Biogenesis Revealed by Sensitivities to Brefeldin A

The biogenesis of peptide hormone secretory granules involves a series of sorting, modification, and trafficking steps that initiate in the trans-Golgi and trans-Golgi network (TGN). To investigate their temporal order and interrelationships, we have developed a pulse–chase protocol that follows the synthesis and packaging of a sulfated hormone, pro-opiomelanocortin (POMC). In AtT-20 cells, sulfate is incorporated into POMC predominantly on N-linked endoglycosidase H-resistant oligosaccharides. Subcellular fractionation and pharmacological studies confirm that this sulfation occurs at the trans-Golgi/TGN. Subsequent to sulfation, POMC undergoes a number of molecular events before final storage in dense-core granules. The first step involves the transfer of POMC from the sulfation compartment to a processing compartment (immature secretory granules, ISGs): Inhibiting export of pulse-labeled POMC by brefeldin A (BFA) or a 20°C block prevents its proteolytic conversion to mature adrenocorticotropic hormone. Proteolytic cleavage products were found in vesicular fractions corresponding to ISGs, suggesting that the processing machinery is not appreciably activated until POMC exits the sulfation compartment. A large portion of the labeled hormone is secreted from ISGs as incompletely processed intermediates. This unregulated secretory process occurs only during a limited time window: Granules that have matured for 2 to 3 h exhibit very little unregulated release, as evidenced by the efficient storage of the 15-kDa N-terminal fragment that is generated by a relatively late cleavage event within the maturing granule. The second step of granule biogenesis thus involves two maturation events: proteolytic activation of POMC in ISGs and a transition of the organelle from a state of high unregulated release to one that favors intracellular storage. By using BFA, we show that the two processes occurring in ISGs may be uncoupled: although the unregulated secretion from ISGs is impaired by BFA, proteolytic processing of POMC within this organelle proceeds unaffected. The finding that BFA impairs constitutive secretion from both the TGN and ISGs also suggests that these secretory processes may be related in mechanism. Finally, our data indicate that the unusually high levels of unregulated secretion often associated with endocrine tumors may result, at least in part, from inefficient storage of secretory products at the level of ISGs.

Saccharomyces Genome Database provides tools to survey gene expression and functional analysis data

Upon the completion of the Saccharomyces cerevisiae genomic sequence in 1996 [Goffeau,A. et al. (1997) Nature, 387, 5], several creative and ambitious projects have been initiated to explore the functions of gene products or gene expression on a genome-wide scale. To help researchers take advantage of these projects, the Saccharomyces Genome Database (SGD) has created two new tools, Function Junction and Expression Connection. Together, the tools form a central resource for querying multiple large-scale analysis projects for data about individual genes. Function Junction provides information from diverse projects that shed light on the role a gene product plays in the cell, while Expression Connection delivers information produced by the ever-increasing number of microarray projects. WWW access to SGD is available at genome-www.stanford.edu/Saccharomyces/.

Nanohedra: Using symmetry to design self assembling protein cages, layers, crystals, and filaments

A general strategy is described for designing proteins that self assemble into large symmetrical nanomaterials, including molecular cages, filaments, layers, and porous materials. In this strategy, one molecule of protein A, which naturally forms a self-assembling oligomer, An, is fused rigidly to one molecule of protein B, which forms another self-assembling oligomer, Bm. The result is a fusion protein, A-B, which self assembles with other identical copies of itself into a designed nanohedral particle or material, (A-B)p. The strategy is demonstrated through the design, production, and characterization of two fusion proteins: a 49-kDa protein designed to assemble into a cage approximately 15 nm across, and a 44-kDa protein designed to assemble into long filaments approximately 4 nm wide. The strategy opens a way to create a wide variety of potentially useful protein-based materials, some of which share similar features with natural biological assemblies.

The dual role of ultraspiracle, the Drosophila retinoid X receptor, in the ecdysone response

The Drosophila homolog of the retinoid X receptor, ultraspiracle (USP), heterodimerizes with the ecdysone receptor (EcR) to form a functional complex that mediates the effects of the steroid molting hormone ecdysone by activating and repressing expression of ecdysone response genes. As with other retinoid X receptor heterodimers, EcR/USP affects gene transcription in a ligand-modulated manner. We used in vivo, cell culture, and biochemical approaches to analyze the functions of two usp alleles, usp3 and usp4, which encode stable proteins with defective DNA-binding domains. We observed that USP is able to activate as well as repress the Z1 isoform of the ecdysone-responsive broad complex (BrC-Z1). Activation of BrC-Z1 as well as EcR, itself an ecdysone response gene, can be mediated by both the USP3 and USP4 mutant proteins. USP3 and USP4 also activate an ecdysone-responsive element, hsp27EcRE, in cultured cells. These results differ from the protein null allele, usp2, which is unable to mediate activation [Schubiger, M. & Truman, J. W. (2000) Development 127, 1151–1159]. BrC-Z1 repression is compromised in all three usp alleles, suggesting that repression involves the association of USP with DNA. Our results distinguish two mechanisms by which USP modulates the properties of EcR: one that involves the USP DNA-binding domain and one that can be achieved solely through the ligand-binding domain. These newly revealed properties of USP might implicate similar properties for retinoid X receptor.

Medial prefrontal cortex and self-referential mental activity: Relation to a default mode of brain function

Medial prefrontal cortex (MPFC) is among those brain regions having the highest baseline metabolic activity at rest and one that exhibits decreases from this baseline across a wide variety of goal-directed behaviors in functional imaging studies. This high metabolic rate and this behavior suggest the existence of an organized mode of default brain function, elements of which may be either attenuated or enhanced. Extant data suggest that these MPFC regions may contribute to the neural instantiation of aspects of the multifaceted “self.” We explore this important concept by targeting and manipulating elements of MPFC default state activity. In this functional magnetic resonance imaging (fMRI) study, subjects made two judgments, one self-referential, the other not, in response to affectively normed pictures: pleasant vs. unpleasant (an internally cued condition, ICC) and indoors vs. outdoors (an externally cued condition, ECC). The ICC was preferentially associated with activity increases along the dorsal MPFC. These increases were accompanied by decreases in both active task conditions in ventral MPFC. These results support the view that dorsal and ventral MPFC are differentially influenced by attentiondemanding tasks and explicitly self-referential tasks. The presence of self-referential mental activity appears to be associated with increases from the baseline in dorsal MPFC. Reductions in ventral MPFC occurred consistent with the fact that attention-demanding tasks attenuate emotional processing. We posit that both self-referential mental activity and emotional processing represent elements of the default state as represented by activity in MPFC. We suggest that a useful way to explore the neurobiology of the self is to explore the nature of default state activity.

Specific transcellular binding between membrane proteins crucial to Alzheimer disease.

Molecular genetic studies of families suffering from genetic forms of early onset Alzheimer disease (AD) have identified three genes and their protein products as being crucially involved in the etiology of AD. The three proteins are all integral membrane proteins. One of them is beta-APP, the precursor of the beta-amyloid found in the characteristic neuritic plaques present in the brains of AD patients. The other two, S182 and STM2, are homologous in amino acid sequence to one another but are unrelated to beta-APP. It is shown here, using cultured cells transfected for each of these proteins, that beta-APP binds specifically and transcellularly to either S182 or STM2. We propose that this transcellular binding may not only be important in normal neuronal physiology and development but may be directly involved in the process of formation of beta-amyloid from beta-APP.

Host range restrictions of oncogenes: myc genes transform avian but not mammalian cells and mht/raf genes transform mammalian but not avian cells.

The host range of retroviral oncogenes is naturally limited by the host range of the retroviral vector. The question of whether the transforming host range of retroviral oncogenes is also restricted by the host species has not been directly addressed. Here we have tested in avian and murine host species the transforming host range of two retroviral onc genes, myc of avian carcinoma viruses MH2 and MC29 and mht/raf of avian carcinoma virus MH2 and murine sarcoma virus MSV 3611. Virus vector-mediated host restriction was bypassed by recombining viral oncogenes with retroviral vectors that can readily infect the host to be tested. It was found that, despite high expression, transforming function of retroviral myc genes is restricted to avian cells, and that of retroviral mht/raf genes is restricted to murine cells. Since retroviral oncogenes encode the same proteins as certain cellular genes, termed protooncogenes, our data must also be relevant to the oncogene hypothesis of cancer. According to this hypothesis, cancer is caused by mutation of protooncogenes. Because protooncogenes are conserved in evolution and are presumed to have conserved functions, the oncogene hypothesis assumes no host range restriction of transforming function. For example, mutated human proto-myc is postulated to cause Burkitt lymphoma, because avian retroviruses with myc genes cause cancer in birds. But there is no evidence that known mutated protooncogenes can transform human cells. The findings reported here indicate that host range restriction appears to be one of the reasons (in addition to insufficient transcriptional activation) why known, mutated protooncogenes lack transforming function in human cells.

Selective attention to stimulus location modulates the steady-state visual evoked potential.

Steady-state visual evoked potentials (SSVEPs) were recorded from the scalp of human subjects who were cued to attend to a rapid sequence of alphanumeric characters presented to one visual half-field while ignoring a concurrent sequence of characters in the opposite half-field. These two-character sequences were each superimposed upon a small square background that was flickered at a rate of 8.6 Hz in one half-field and 12 Hz in the other half-field. The amplitude of the frequency-coded SSVEP elicited by either of the task-irrelevant flickering backgrounds was significantly enlarged when attention was focused upon the character sequence at the same location. This amplitude enhancement with attention was most prominent over occipital-temporal scalp areas of the right cerebral hemisphere regardless of the visual field of stimulation. These findings indicate that the SSVEP reflects an enhancement of neural responses to all stimuli that fall within the "spotlight" of spatial attention, whether or not the stimuli are task-relevant. Recordings of the SSVEP provide a new approach for studying the neural mechanisms and functional properties of selective attention to multi-element visual displays.

Two different but related mechanisms are used in plants for the repair of genomic double-strand breaks by homologous recombination.

Genomic double-strand breaks (DSBs) are key intermediates in recombination reactions of living organisms. We studied the repair of genomic DSBs by homologous sequences in plants. Tobacco plants containing a site for the highly specific restriction enzyme I-Sce I were cotransformed with Agrobacterium strains carrying sequences homologous to the transgene locus and, separately, containing the gene coding for the enzyme. We show that the induction of a DSB can increase the frequency of homologous recombination at a specific locus by up to two orders of magnitude. Analysis of the recombination products demonstrates that a DSB can be repaired via homologous recombination by at least two different but related pathways. In the major pathway, homologies on both sides of the DSB are used, analogous to the conservative DSB repair model originally proposed for meiotic recombination in yeast. Homologous recombination of the minor pathway is restricted to one side of the DSB as described by the nonconservative one-sided invasion model. The sequence of the recombination partners was absolutely conserved in two cases, whereas in a third case, a deletion of 14 bp had occurred, probably due to DNA polymerase slippage during the copy process. The induction of DSB breaks to enhance homologous recombination can be applied for a variety of approaches of plant genome manipulation.