Temporally flat top pulse generation from gain switched semiconductor lasers based on a polarization interferometer with variable transfer function

We propose the use of a polarization based interferometer with variable transfer function for the generation of temporally flat top pulses from gain switched single mode semiconductor lasers. The main advantage of the presented technique is its flexibility in terms of input pulse characteristics, as pulse duration, spectral bandwidth and operating wavelength. Theoretical predictions and experimental demonstrations are presented and the proposed technique is applied to two different semiconductor laser sources emitting in the 1550 nm region. Flat top pulses are successfully obtained with input seed pulses with duration ranging from 40 ps to 100 ps.

Riskmática: Una tecnología educativa desarrollada con Unity

Historically, teachers have always searched for a connection with their students to make education interesting and a vital experience. In the 19th century, pedagogue Johann Heinrich Pestalozzi taught children how to sum using wood blocks. His successors have followed his legacy and today they use a wide variety of media, including board games, in order to reach out to their students. These methods are denominated educational technologies, which are defined as the study and ethical practice of facilitating learning and improving performance by creating, using, and managing appropriate technological processes and resources. With the advent of the information technologies, teachers have at their disposal new media with which they can increase the interest of their students. This technologic revolution is changing the present educational model. The objective of this dissertation is to develop an educational videogame in order to help students learn mathematics. To reach this goal, the videogame has been developed with the game engine Unity as the main tool. Additionally, agile software development methodologies as well as other software engineering techniques have also been used. The result is Riskmatica, an educational videogame based on geographical domination in which knowledge is the best weapon. The players must conquer enemy teritories answering correctly a mathecatical question. Moreover the videogame has the functionality required to configure a new game and input new questions. To conclude, this project has created an educational technology which greatly appeals to students and that can be used by the educators to improve their lessons in mathematics.---RESUMEN---A lo largo de la historia, los educadores siempre han buscado conectar con los alumnos para poder captar su interés y hacer que la educación se convierta en una experiencia vital. El pedagogo Johann Heinrich Pestalozzi conseguía esto en el siglo XIX, enseñando a niños a contar con bloques de madera. Sus sucesores han seguido su legado y hoy en día utilizan variedad de medios con los que motivar a sus alumnos, en algunos casos los juegos de mesa. Estos métodos son denominados tecnologías educativas, que se definen como los estudios y prácticas éticas que facilitan y mejoran la enseñanza, mediante la creación, el uso y el empleo de procesos y recursos tecnológicos. Con el advenimiento de las tecnologías de la información, los educadores tienen a su disposición un nuevo medio con el que llegar al alumnado. Esta revolución tecnológica está cambiando el modelo educativo actual. El objetivo de este proyecto es el de crear un videojuego educativo que ayude a los alumnos a estudiar matemáticas. Para lograrlo se ha utilizado el popular motor de videojuego Unity como herramienta principal. También se han empleado metodologías ágiles de desarrollo además de otras técnicas de ingeniería del software. El resultado es Riskmática, un videojuego educativo de dominación geográfica en el que el arma más eficaz es el conocimiento. Los jugadores deberán conquistar territorios a sus adversarios mediante la respuesta de preguntas de carácter matemático. Además el videojuego cuenta con la funcionalidad necesaria para configurar una partida e introducir nuevas preguntas. Como conlusión, este proyecto ha logrado crear una tecnología educativa muy atractiva para los alumnos con la que los profesores pueden mejorar la enseñanza de las matemáticas.

XRD analysis of InGaN uniform layers grown on Si (111) without any buffer layers and on Sapphire

The International Workshop on Nitride Semiconductors (IWN) is a biennial academic conference in the field of group III nitride research. The IWN and the International Conference on Nitride Semiconductors (ICNS) are held in alternating years and cover similar subject areas.

Materialidad poética: arquitectura suiza en el entorno de los Grisones 1992-2004

El entorno alpino de los Grisones ha sido un laboratorio donde experimentar un método arquitectónico procedente de diversas fuentes durante los años 70 en la ETHZ. Este método ha producido durante las últimas tres décadas un discurso teórico propiamente suizo alemán. La tradición continúa siendo un valor cultural para la comunidad alpina de los Grisones, que apuesta por seguir relacionando la arquitectura con su historia y su paisaje. La especificidad de cada entorno suizo alemán es un hecho obvio pero, por encima de sus rasgos característicos, hay un denominador común que les da unidad en silencio: se trata de una idea de la construcción. El fenómeno de los Grisones es territorial en su localización concreta, pero comparte el trasfondo teórico del resto de la arquitectura suizo alemana reciente. La tesis recorre transversalmente las condiciones que han dado lugar a esa trayectoria común hasta la actualidad, en que la arquitectura suizo alemana se halla precisamente en un momento de cambio generacional. La obra de Peter Märkli constituye en esta tesis un paradigma de la voluntad suizo alemana por formar parte de la continuidad cultural de la arquitectura, como una actitud de resistencia compartida frente al mundo globalizado. La tesis se articula a partir de ocho proyectos recientes, realizados por arquitectos suizo alemanes en el entorno del territorio alpino de los Grisones. Estos proyectos condensan la trayectoria arquitectónica suizo alemana durante el siglo XX, así como el fenómeno arquitectónico que ha tenido lugar en el entorno de los Grisones durante las últimas tres décadas. La tesis analiza a través de cada pareja de proyectos los episodios teóricos, artísticos y filosóficos más relevantes que se sintetizan en estas obras, así como sus referentes arquitectónicos y la dimensión trascendente de los materiales en los que la cultura suiza hunde sus raíces: la madera, la piedra y el hormigón. Las vanguardias pictóricas, el Movimiento Moderno y las corrientes humanistas y regionalistas que se fueron sucediendo durante el pasado siglo, configuran el escenario en el que tomó cuerpo la sensibilidad arquitectónica suizo alemana reciente, que emerge a través de la compleja red de relaciones establecidas entre el panorama suizo y el internacional. El mismo bagaje teórico subyace al territorio suizo alemán a nivel general, por lo que asociarlo a través de esta tesis a proyectos realizados en un entorno característico, permite acceder a una realización concreta de ese debate en un entorno tan particular como son los Grisones. La aproximación a los proyectos es de carácter fenomenológico: la experiencia directa de los mismos ha sido el sustrato fundamental del enfoque de la tesis. El trabajo de campo no se limitó a visitar los proyectos que vertebran la tesis, sino que trató de abarcar las obras más relevantes de la producción suizo alemana reciente en los Grisones, con el fin de adquirir cierto grado de sensibilidad perceptiva hacia la singularidad de su identidad territorial. La tesis hace especial hincapié en las obras de Peter Märkli y Peter Zumthor, representantes de los dos extremos del discurso suizo alemán reciente, respecto a la materialidad y al carácter de la secuencia espacial, sistemático o fluido respectivamente, pero que asimismo comparten el clasicismo formalista que subyace al fenómeno suizo alemán. Los dos proyectos que establecen el periodo 1992-2004 explorado por esta investigación constituyen dos hitos fundamentales. El Museo de La Congiunta en Giornico de Peter Märkli se construyó en 1992 y se erige a partir de entonces como un icono arquitectónico de la condensación típicamente suizo alemana de base reductiva. Este paradigma de síntesis conceptual y constructiva comenzó a forjarse en la década de 1930 de la mano del Konkrete Kunst formulado por Max Bill, que es la única manifestación artística genuinamente suiza del siglo XX y que desarrolló pictóricamente los valores de precisión, rigor, racionalismo y abstracción afines a la sensibilidad suizo alemana. En segundo lugar, el proyecto para la rehabilitación de la Villa Garbald y la construcción de la Torre Roccolo en Castasegna llevado a cabo por Miller & Maranta en 2004, supuso la consumación de la Analoge Architektur, que fue la primera corriente arquitectónica propiamente suiza, desarrollada durante la década de 1980 por Miroslav Sik. La Deutscher Tendenza es un periodo de la trayectoria suizo alemana reciente poco conocido, representado por una figura tan relevante como es Peter Zumthor. Las obras que proyectó Zumthor entre 1979 y 1985 forman parte de un periodo en que el arquitecto se encontraba profundamente influido por el neorracionalismo italiano, como ilustra la escuela de Churwalden de 1983. La arquitectura suizo alemana reciente exploró sistemáticamente los sistemas compositivos de las vanguardias pictóricas y del Movimiento Moderno, por encima de su formalismo concreto. La segunda fase de la obra de Zumthor entre 1985 y 1996 se caracteriza por la transfiguración del plano libre del sistema compositivo neoplasticista desarrollado por De Stijl, plano que adquirió grosor hasta convertirse en la caja articuladora de la fluidez de la secuencia espacial. El formalismo de Zumthor en esta fase implica la prioridad del esquema compositivo, compuesto por un perímetro regular en el que se reúnen las cajas que, como las superficies de color de las composiciones de Mondrian, articulan el espacio a su alrededor. La Residencia de Masans de Zumthor de 1993 es un proyecto canónico de este sistema compositivo, que culmina en el esquema radial de las Termas de Vals de 1996. La imagen poética se convirtió en el lenguaje propio del pensamiento de la arquitectura suizo alemana, que permitía una reflexión no verbal, a partir de unos pocos arquetipos fundamentales. Los arquitectos del Ticino buscaron en la Tendenza italiana durante la década de 1970 una alternativa al insostenible modelo territorial que estaba destruyendo su paisaje cultural. Algunos de estos arquitectos comenzaron a dar clase durante esa década en la ETHZ, por lo que transmitieron sus inquietudes al alumnado e introdujeron a Aldo Rossi en la facultad, que era uno de los máximos representantes de la Tendenza. El método analógico de Rossi, basado en la psicología analítica de Carl Jung, fue una influencia fundamental en la ETHZ durante los años 70. Rossi partía de una teoría afín al colectivo intelectual suizo que los arquitectos de la ETHZ pronto comprendieron que debían independizar del contexto italiano, desarrollando su propio método a partir de 1985 con la Analoge Architektur. El valor de la preexistencia de acuerdo a este método incipiente se hallaba en su papel articulador de la continuidad cultural de una comunidad, que Miroslav Sik definió a partir de su concepto de Altneue (literalmente, lo Nuevo-Viejo). La fusión entre lo nuevo y lo viejo era la base de la espontaneidad con la que habían crecido los asentamientos históricamente. Sik consideraba que la continuidad dependía de la comprensión de los patrones preexistentes, con el objeto de mantener su vigencia mediante la incorporación de estrategias contemporáneas, que renovarían su significado sin perder su esencia. La Casa Gugalun en Versam de Zumthor de 1994 supone una aproximación a escala doméstica a este planteamiento. La arquitectura suizo alemana reciente a menudo busca en sus referentes plásticos una manera de explorar ámbitos poco accesibles para la disciplina arquitectónica. El pensamiento arquitectónico basado en la imagen poética se implementa a partir de la tectónica de la construcción, que es el medio para comunicar una idea vertebradora del proyecto de principio a fin. La construcción como medio introduce el concepto clave de la apariencia de la arquitectura, estrechamente relacionado con la filosofía idealista de Friedrich Schiller. La apariencia debe expresar el sentido conceptual de la obra, que los arquitectos suizo alemanes denominan idea, por lo que la construcción no tiene un valor por sí misma, sino en cuanto a la apariencia. La Capilla de Oberrealta de Christian Kerez de 1993 puede ser considerada una obra escultórica en el paisaje, más próxima a las artes plásticas que a la arquitectura. La tensión que surge entre la figura ideal y la pieza sometida a una sutil deformación confiere un carácter dinámico a la composición, que intensifica el efecto perceptivo, de acuerdo a la teoría del pensamiento visual de Rudolph Arnheim. La deformación al servicio de la psicología de la percepción es un fenómeno que caracteriza la arquitectura suizo alemana reciente. El concepto de Forme Forte (forma fuerte) fue introducido por Martin Steinmann para caracterizar el objeto arquitectónico denominado internacionalmente Swiss Box. Este concepto se caracteriza por una predilección por lo monolítico, lo unitario y lo arquetípico. La condición más sustancial de una Forme Forte es, sin embargo, la de configurar un elemento estructurador del entorno. Tanto la base morfológica de una Forme Forte, como su capacidad para estructurar el lugar, se corresponden con los conceptos de arquetipo y monumento de la teoría de Rossi. La tesis explora el sentido de la deformación en la producción suizo alemana reciente, a partir de la Escuela de Paspels de Valerio Olgiati de 1998 y la Torre Roccolo de Villa Garbald de Miller&Maranta de 1998. La teoría tectónica de Gottfried Semper y la razón de la forma de Adolf Loos constituyen el sustrato teórico, que relaciona la actividad existencial de habitar con la materialidad de la arquitectura suizo alemana reciente. La teoría tectónica de Semper fundamenta las revisiones posteriores de los sistemas constructivos tradicionales suizo alemanes. Esta influencia sirvió como base a la vanguardia suiza de la Neues Bauen, que desarrolló un racionalismo funcionalista durante las décadas de 1920 y 1930, que constituye una gramática de base no simbólica. Esta gramática constituye el fundamento de la transición del orden clásico a la materialidad como instrumento compositivo durante la segunda mitad del siglo XX, consolidando el concepto de la base material de la forma. La revisión de la tradición regionalista y racionalista llevada a cabo por la generación de arquitectos suizo alemanes de la década de 1950 y 1960, constituyó una investigación lingüística sustancial. Rudolph Olgiati es la figura determinante de este periodo. La revisión de esta investigación se codificó en clave estructuralista durante los años 70 en la ETHZ, influenciada por la presencia de Roland Barthes como profesor invitado. Esta revisión constituyó la base de la articulación tectónica propiamente suizo alemana todavía vigente, como ilustra expresamente la obra de Burkhalter&Sumi en esta tesis. La obra de Gion Caminada en Vrin entre 1995 y 2002 aporta una intensa investigación sobre el Strickbau, que implementa una y otra vez variaciones sobre un sistema tradicional, ilustrando las infinitas posibilidades que ofrece un lenguaje, paradójicamente limitado por los medios disponibles en un entorno alpino aislado. Para terminar Jürg Conzett es el ingeniero con el que han desarrollado sus proyectos la mayoría de los arquitectos en el entorno de los Grisones, formado durante 8 años con Zumthor y colaborador habitual de Caminada entre otros. Conzett es el referente que relaciona la ingeniería con la arquitectura en el ámbito de esta tesis, imprescindible en el contexto de esta investigación. ABSTRACT The Alpine setting of Grisons has been a laboratory for architectural experimentation with an approach forged in the 1970s from various sources in the Swiss Federal Institute of Technology in Zurich (ETHZ). This method has produced a uniquely German-Swiss theoretical discourse over the past three decades. Tradition continues to be a cultural value for Grisons, a region committed to continue linking its architecture with the region’s history and landscape. The specificity of the German-Swiss environment is obvious, but beyond its characteristic features, there is a common denominator that gives these settings a silent unity: it is an idea of building. The phenomenon of Grisons is geographic in its specific location, but it shares the theoretical basis of the rest of the new German-Swiss architecture. This thesis transversely delves into the conditions that have shaped this common path up to the present, just as German-Swiss architecture is going through a time of generational change. In this thesis, Märkli Peter's work constitutes a paradigm of the German-Swiss will to uphold the cultural and architectural continuity of the region, exemplifying an attitude of shared resistance to the globalized world. The thesis is structured around eight recent projects carried out by German-Swiss architects in the Alpine region of Grisons. These projects represent the trajectory of twentieth century German-Swiss architectural history, as well as the architectural phenomenon that has taken place in the environs of Grisons over the past three decades. Through these projects the thesis analyzes the most relevant theoretical, artistic and philosophical references that are synthesized in the works, as well as their architectural references and the transcendental dimension of the materials in which Swiss culture is rooted: wood, stone and concrete. The artistic avant-garde, together with Modernism and the humanistic and regional movements that occurred during the last century, set the stage for present-day German-Swiss architectural sensitivity, which emerges from a complex web of relationships established between the Swiss and international panorama. This same theoretical background and experience underlies all of the German-Swiss territory in general, so associating it through this thesis to a particular context allows the description of a specific embodiment of this debate, within the unique environment of Grisons. The methodological approach to analyzing the projects was phenomenological: direct experience is the main substrate underpinning the focus of the thesis. Field work was not limited to visiting the projects featured in the thesis, but rather encompassed the most important works of recent German-Swiss construction in the Grisons in order to gain some degree of perceptual sensitivity to the uniqueness of its territorial identity. The present paper puts special emphasis on the works of Peter Märkli and Peter Zumthor, who share the formal classicist perspective of the German-Swiss context but stand on opposite sides of the philosophical spectrum with regard to the notion of materiality and the nature of space, which they conceive as systematic or fluid, respectively. The two projects that establish the boundaries of the time period 1992–2004 explored by this research represent two key milestones. The Museum La Congiunta in Giornico, by Peter Märkli, was built in 1992 and quickly established itself as an architectural icon of German-Swiss reductionism. This paradigm of conceptual and constructive synthesis began to take shape in the 1930s under the banner of Konkrete Kunst (Concrete Art), led by Max Bill. The only genuinely Swiss artistic movement of the twentieth century, Konkrete Kunst was characterized by the artistic values of precision, rigor, rationalism and abstraction, sentiments that were very close to the German-Swiss tradition. Secondly, the project for the rehabilitation of Villa Garbald and the construction of the Roccolo Tower in Castasegna, conducted by Miller&Maranta in 2004, represented the consummation of the Analoge Architektur, which was the first truly Swiss architectural movement, spearheaded in the 1980s by Miroslav Sik. The Deutscher Tendenza is a little-known period of recent German-Swiss history, represented by the important figure of Peter Zumthor. The projects that Zumthor led between 1979 and 1985 are part of a period when Italian Neo-Rationalism exercised a profound influence on the architect, as illustrated by the Churwalden School, circa 1983. Recent German-Swiss architecture systematically explored the compositional systems of the artistic avant-garde and Modernism, beyond its specific formal aspects. The second phase of Zumthor's work, between 1985 and 1996, is characterized by the transfiguration of the free plane, neoplastic compositional system developed by De Stijl, a plane that thickened until it became the box articulating fluidity from the spatial sequence. Zumthor's formalism in this phase prioritizes the compositional scheme, consisting of a regular perimeter in which the boxes that -like Mondrian’s colored surfaces- arrange the space around it. Zumthor’s Masans Residence, circa 1993, is a canonical project of this compositional system, which culminates in the radial pattern of the Therme Vals, circa 1996. The poetic image became the appropriate language of thought for German-Swiss architecture, which invited a nonverbal reflection inspired by a few fundamental archetypes. The architects of Ticino sought, through the Italian Tendenza of the 1970s, an alternative to the unsustainable territorial model that was destroying their cultural landscape. Some of these architects began to teach during that decade at ETHZ, and naturally they transmitted their unease to their students. These architects also introduced Aldo Rossi, one of the leading representatives of the Tendenza, to the school. Rossi’s analogue method, based on the analytical psychology of Carl Jung, was a major influence on the ETHZ during the 1970s. Rossi’s theoretical grounding was very much in tune with Swiss intellectualism, and it did not take long for architects from ETHZ to realize that they should break away from the Italian context, developing their own method from 1985 on with the Analoge Architektur. The value of the pre-existing conformity of this emerging method, stemmed from its role in facilitating the cultural continuity of a community, which Miroslav Sik defined in his concept of Altneue (literally, Old-new). This fusion of old and new was the basis for the spontaneity with which settlements had historically grown. Sik considered that continuity depended on understanding the existing patterns and sustaining their relevance through the incorporation of contemporary strategies, which would renew their meaning without losing their essence. Zumthor’s Gugalun House in Versam, circa 1994, is a domestic-scale approach to this philosophy. Modern German-Swiss architecture often looks to its references in visual art for a way to explore areas that are normally inaccessible to the architectural discipline. Architectural thinking based on the poetic image is achieved through a building’s tectonics, which communicate the core idea of a project from start to finish. The understanding of construction as a medium introduces the key concept of the appearance in architecture, closely related to the idealistic philosophy of Friedrich Schiller. The appearance should express the conceptual meaning of the work, which German-Swiss architects call the idea, so that the building does not have value in and of itself, but only in terms of its appearance. The Oberrealta Chapel by Christian Kerez, circa 1993, can be considered a sculpture in the landscape, closer to the visual arts than to architecture. The tension that arises between the ideal figure and the piece subjected to a subtle deformation confers a dynamic character onto the composition, intensifying the perceptual effect, according to Rudolf Arnheim’s theory of visual thought. The deformation in the service of the psychology of perception is a phenomenon that characterizes recent German-Swiss architecture. Martin Steinmann introduced the Forme Forte (Strong Form) concept to describe the architectural object known internationally as the Swiss Box. This concept is characterized by a predilection for all things monolithic, unitary and archetypal. The most substantial condition of a Forme Forte, however, is the configuration of a structuring element in the environment. Both the morphological basis of a Forme Forte and its ability to frame the place, correspond to the concepts of archetype and monument put forward by Rossi’s theory. The present thesis explores the sense of deformation in recent German-Swiss production, based on the School of Paspels by Valerio Olgiati, circa 1998 and the Roccolo Tower in Villa Garbald, by Miller&Maranta, circa 1998. Gottfried Semper’s tectonic theory and Adolf Loos’s reason for form constitute the theoretical foundation that links the existential activity of dwelling to the materiality of recent German-Swiss architecture. Semper’s tectonic theory laid the foundation for subsequent revisions of the German-Swiss traditional building systems. This influence was the basis for the Swiss avant-garde of Neues Bauen, which developed a functional rationalism during the 1920s and 30s that served as a non-symbolic grammatical foundation for the transition from classical order to materiality as a compositional tool. During the second half of the twentieth century, this architectural grammar helped consolidate the concept of the material base of the form. The revision of the regionalist and rationalist tradition, carried out by the generation of German-Swiss architects of the 1950s and 60s, constituted a substantial linguistic investigation. Rudolph Olgiati is the key figure of this period. The research was codified in terms of structuralism in the 1970s in ETHZ and influenced by the presence of Roland Barthes as a visiting professor. This revision was the basis of the uniquely German-Swiss tectonic design still in use today, as specifically illustrated by the work of Burkhalter & Sumi in this thesis. Gion Caminada's work in Vrin between 1995 and 2002 offers an extensive study on the Strickbau, which implements variations on a traditional system again and again, illustrating the endless possibilities of a language that paradoxically seems limited by the available resources in a remote Alpine setting. Finally, Jürg Conzett is the engineer with whom most architects in the Grisons region have developed their projects. Trained under Zumthor for 8 years, and a regular collaborator of Caminada, among others, Conzett is the reference point linking engineering with architecture in this thesis, essential in the context of this research.

The unity of the organism; or, The organismal conception of life, by William Emerson Ritter ...

1

Libya’s new unity government faces the mother of all rebuilding jobs

Publisher PDF

Compression, gain, and nonlinear distortion in an active cochlear model with subpartitions

The propagation of inhomogeneous, weakly nonlinear waves is considered in a cochlear model having two degrees of freedom that represent the transverse motions of the tectorial and basilar membranes within the organ of Corti. It is assumed that nonlinearity arises from the saturation of outer hair cell active force generation. I use multiple scale asymptotics and treat nonlinearity as a correction to a linear hydroelastic wave. The resulting theory is used to explain experimentally observed features of the response of the cochlear partition to a pure tone, including: the amplification of the response in a healthy cochlea vs a dead one; the less than linear growth rate of the response to increasing sound pressure level; and the amount of distortion to be expected at high and low frequencies at basal and apical locations, respectively. I also show that the outer hair cell nonlinearity generates retrograde waves.

Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas

Genomic imprinting is a reversible condition that causes parental-specific silencing of maternally or paternally inherited genes. Analysis of DNA and RNA from 52 human hepatocarcinoma samples revealed abnormal imprinting of genes located at chromosome 11p15 in 51% of 37 informative samples. The most frequently detected abnormality was gain of imprinting, which led to loss of expression of genes present on the maternal chromosome. As compared with matched normal liver tissue, hepatocellular carcinomas showed extinction or significant reduction of expression of one of the alleles of the CDKN1C, SLC22A1L, and IGF2 genes. Loss of maternal-specific methylation at the KvDMR1 locus in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues. These results point to the role of epigenetic mechanisms leading to loss of expression of imprinted genes at chromosome region 11p15 in human tumors.

Corticotropin-releasing factor-binding protein ligand inhibitor blunts excessive weight gain in genetically obese Zucker rats and rats during nicotine withdrawal

Elevation of the neuropeptide corticotropin-releasing factor (CRF) in the brain is associated with a reduction of food intake and body weight gain in normal and obese animals. A protein that binds CRF and the related peptide, urocortin, with high affinity, CRF-binding protein (CRF-BP), may play a role in energy homeostasis by inactivating members of this peptide family in ingestive and metabolic regulatory brain regions. Intracerebroventricular administration in rats of the high-affinity CRF-BP ligand inhibitor, rat/human CRF (6-33), which dissociates CRF or urocortin from CRF-BP and increases endogenous brain levels of “free” CRF or urocortin significantly blunted exaggerated weight gain in Zucker obese subjects and in animals withdrawn from chronic nicotine. Chronic administration of CRF suppressed weight gain nonselectively by 60% in both Zucker obese and lean control rats, whereas CRF-BP ligand inhibitor treatment significantly reduced weight gain in obese subjects, without altering weight gain in lean control subjects. Nicotine abstinent subjects, but not nicotine-naive controls, experienced a 35% appetite suppression and a 25% weight gain reduction following acute and chronic administration, respectively, of CRF-BP ligand inhibitor. In marked contrast to the effects of a CRF-receptor agonist, the CRF-BP ligand inhibitor did not stimulate adrenocorticotropic hormone secretion or elevate heart rate and blood pressure. These results provide support for the hypothesis that the CRF-BP may function within the brain to limit selected actions of CRF and/or urocortin. Furthermore, CRF-BP may represent a novel and functionally selective target for the symptomatic treatment of excessive weight gain associated with obesity of multiple etiology.

A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes

Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial–mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients.

Gain- and loss-of-function of Rhp51, a Rad51 homolog in fission yeast, reveals dissimilarities in chromosome integrity

Rad51 is crucial not only in homologous recombination and recombinational repair but also in normal cellular growth. To address the role of Rad51 in normal cell growth we investigated morphological changes of cells after overexpression of wild-type and a dominant negative form of Rad51 in fission yeast. Rhp51, a Rad51 homolog in Schizosaccharomyces pombe, has a highly conserved ATP-binding motif. Rhp51 K155A, which has a single substitution in this motif, failed to rescue hypersensitivity of a rhp51Δ mutant to methyl methanesulfonate (MMS) and UV, whereas it binds normally to Rhp51 and Rad22, a Rad52 homolog. Two distinct cellular phenotypes were observed when Rhp51 or Rhp51 K155A was overexpressed in normal cells. Overexpression of Rhp51 caused lethality in the absence of DNA-damaging agents, with acquisition of a cell cycle mutant phenotype and accumulation of a 1C DNA population. On the other hand, overexpression of Rhp51 K155A led to a delay in G2 with decondensed nuclei, which resembled the phenotype of rhp51Δ. The latter also exhibited MMS and UV sensitivity, indicating that Rhp51 K155A has a dominant negative effect. These results suggest an association between DNA replication and Rad51 function.

Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity

Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. However, although CNTF mimics the ability of leptin to cause fat loss in mice that are obese because of genetic deficiency of leptin (ob/ob mice), CNTF is also effective in diet-induced obesity models that are more representative of human obesity, and which are resistant to leptin. This discordance again raised the possibility that CNTF might be acting via nonleptin pathways, perhaps more analogous to those activated by cachectic cytokines. Arguing strongly against this possibility, we now show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently than the prototypical cachectic cytokine, IL-1. Further analyses of hypothalamic signaling reveals that CNTF can suppress food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation; thus, unlike forced dieting, cessation of CNTF treatment does not result in binge overeating and immediate rebound weight gain.

Src, a molecular switch governing gain control of synaptic transmission mediated by N-methyl-d-aspartate receptors

The N-methyl-d-aspartate (NMDA) receptor is a principal subtype of glutamate receptor mediating fast excitatory transmission at synapses in the dorsal horn of the spinal cord and other regions of the central nervous system. NMDA receptors are crucial for the lasting enhancement of synaptic transmission that occurs both physiologically and in pathological conditions such as chronic pain. Over the past several years, evidence has accumulated indicating that the activity of NMDA receptors is regulated by the protein tyrosine kinase, Src. Recently it has been discovered that, by means of up-regulating NMDA receptor function, activation of Src mediates the induction of the lasting enhancement of excitatory transmission known as long-term potentiation in the CA1 region of the hippocampus. Also, Src has been found to amplify the up-regulation of NMDA receptor function that is produced by raising the intracellular concentration of sodium. Sodium concentration increases in neuronal dendrites during high levels of firing activity, which is precisely when Src becomes activated. Therefore, we propose that the boost in NMDA receptor function produced by the coincidence of activating Src and raising intracellular sodium may be important in physiological and pathophysiological enhancement of excitatory transmission in the dorsal horn of the spinal cord and elsewhere in the central nervous system.

Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function.

The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.