NURBS-Based Geometry Parameterization for Aerodynamic Shape Optimization

La motivación de esta tesis es el desarrollo de una herramienta de optimización automática para la mejora del rendimiento de formas aerodinámicas enfocado en la industria aeronáutica. Este trabajo cubre varios aspectos esenciales, desde el empleo de Non-Uniform Rational B-Splines (NURBS), al cálculo de gradientes utilizando la metodología del adjunto continuo, el uso de b-splines volumétricas como parámetros de diseño, el tratamiento de la malla en las intersecciones, y no menos importante, la adaptación de los algoritmos de la dinámica de fluidos computacional (CFD) en arquitecturas hardware de alto paralelismo, como las tarjetas gráficas, para acelerar el proceso de optimización. La metodología adjunta ha posibilitado que los métodos de optimización basados en gradientes sean una alternativa prometedora para la mejora de la eficiencia aerodinámica de los aviones. La formulación del adjunto permite calcular los gradientes de una función de coste, como la resistencia aerodinámica o la sustentación, independientemente del número de variables de diseño, a un coste computacional equivalente a una simulación CFD. Sin embargo, existen problemas prácticos que han imposibilitado su aplicación en la industria, que se pueden resumir en: integrabilidad, rendimiento computacional y robustez de la solución adjunta. Este trabajo aborda estas contrariedades y las analiza en casos prácticos. Como resumen, las contribuciones de esta tesis son: • El uso de NURBS como variables de diseño en un bucle de automático de optimización, aplicado a la mejora del rendimiento aerodinámico de alas en régimen transónico. • El desarrollo de algoritmos de inversión de punto, para calcular las coordenadas paramétricas de las coordenadas espaciales, para ligar los vértices de malla a las NURBS. • El uso y validación de la formulación adjunta para el calculo de los gradientes, a partir de las sensibilidades de la solución adjunta, comparado con diferencias finitas. • Se ofrece una estrategia para utilizar la geometría CAD, en forma de parches NURBS, para tratar las intersecciones, como el ala-fuselaje. • No existen muchas alternativas de librerías NURBS viables. En este trabajo se ha desarrollado una librería, DOMINO NURBS, y se ofrece a la comunidad como código libre y abierto. • También se ha implementado un código CFD en tarjeta gráfica, para realizar una valoración de cómo se puede adaptar un código sobre malla no estructurada a arquitecturas paralelas. • Finalmente, se propone una metodología, basada en la función de Green, como una forma eficiente de paralelizar simulaciones numéricas. Esta tesis ha sido apoyada por las actividades realizadas por el Área de Dinámica da Fluidos del Instituto Nacional de Técnica Aeroespacial (INTA), a través de numerosos proyectos de financiación nacional: DOMINO, SIMUMAT, y CORESFMULAERO. También ha estado en consonancia con las actividades realizadas por el departamento de Métodos y Herramientas de Airbus España y con el grupo Investigación y Tecnología Aeronáutica Europeo (GARTEUR), AG/52. ABSTRACT The motivation of this work is the development of an automatic optimization strategy for large scale shape optimization problems that arise in the aeronautics industry to improve the aerodynamic performance; covering several aspects from the use of Non-Uniform Rational B-Splines (NURBS), the calculation of the gradients with the continuous adjoint formulation, the development of volumetric b-splines parameterization, mesh adaptation and intersection handling, to the adaptation of Computational Fluid Dynamics (CFD) algorithms to take advantage of highly parallel architectures in order to speed up the optimization process. With the development of the adjoint formulation, gradient-based methods for aerodynamic optimization become a promising approach to improve the aerodynamic performance of aircraft designs. The adjoint methodology allows the evaluation the gradients to all design variables of a cost function, such as drag or lift, at the equivalent cost of more or less one CFD simulation. However, some practical problems have been delaying its full implementation to the industry, which can be summarized as: integrability, computer performance, and adjoint robustness. This work tackles some of these issues and analyse them in well-known test cases. As summary, the contributions comprises: • The employment of NURBS as design variables in an automatic optimization loop for the improvement of the aerodynamic performance of aircraft wings in transonic regimen. • The development of point inversion algorithms to calculate the NURBS parametric coordinates from the space coordinates, to link with the computational grid vertex. • The use and validation of the adjoint formulation to calculate the gradients from the surface sensitivities in an automatic optimization loop and evaluate its reliability, compared with finite differences. • This work proposes some algorithms that take advantage of the underlying CAD geometry description, in the form of NURBS patches, to handle intersections and mesh adaptations. • There are not many usable libraries for NURBS available. In this work an open source library DOMINO NURBS has been developed and is offered to the community as free, open source code. • The implementation of a transonic CFD solver from scratch in a graphic card, for an assessment of the implementability of conventional CFD solvers for unstructured grids to highly parallel architectures. • Finally, this research proposes the use of the Green's function as an efficient paralellization scheme of numerical solvers. The presented work has been supported by the activities carried out at the Fluid Dynamics branch of the National Institute for Aerospace Technology (INTA) through national founding research projects: DOMINO, SIMUMAT, and CORESIMULAERO; in line with the activities carried out by the Methods and Tools and Flight Physics department at Airbus and the Group for Aeronautical Research and Technology in Europe (GARTEUR) action group AG/52.

La silla de la discordia : la pequeña escala como campo de experimentación en la modernidad : Breuer, Mies y Stam

El siglo XIX fue un siglo dedicado a los grandes edificios públicos. Los teatros, las academias, los museos. Sin embargo la arquitectura durante el siglo XX se dedicará al estudio de la casa. Todos los usos y tipologías se verán fuertemente revisados pero el núcleo de todos los esfuerzos y verdadero inicio de la arquitectura moderna será la vivienda. A partir de ella todos los preceptos modernos se irán aplicando a los distintos programas. Nikolaus Pevsner señala a William Morris como el primer arquitecto moderno porque precisamente entendió que un arte verdaderamente social, en consonancia con su tiempo y la sociedad a la que sirve, ha de ocuparse de aquello que preocupe a la gente. Con la nueva situación de la vivienda en el centro de las motivaciones disciplinares el mueble adopta un nuevo protagonismo. En un momento avanzado de su carrera Marcel Breuer observa entre curioso e irónico cómo el mueble moderno había sido promocionado paradójicamente no por los diseñadores de muebles sino por los arquitectos1. La respuesta la da Le Corbusier en una de sus conferencias de 1931 recogida en Precisiones 2 cuando señala la reformulación del mobiliario como el "nudo gordiano" de cuya resolución pendía la renovación de la planta moderna. El Movimiento Moderno se había visto obligado a atacar este tema para poder avanzar en sus propuestas domésticas. El Movimiento Moderno se propuso solucionar los problemas de la vivienda y de una Europa en reconstrucción pero se exigía además ser capaz de aportar una visión propositiva de la vida moderna. No se trataba únicamente de resolver los problemas ya existentes sino que además había la necesidad autoimpuesta de anticipar la domesticidad del futuro. Para ello sus viviendas al completo, mueble e inmueble, debían de presentarse bajo esa nueva imagen. El manifiesto fundacional de la Deustcher Werkbund extendía el radio de acción del nuevo arquitecto desde la construcción de las ciudades a los cojines del sofá. Este mobiliario tenía la compleja misión de condensar sintéticamente todos esos ideales que la modernidad había traído consigo: abstracción, higiene, fascinación maquínica, confianza positivista en la ciencia o la expresión material optimizada. Objetos de la vida moderna, en palabras de Le Corbusier, susceptibles de suscitar un estado de vida moderno. Pocas sillas en la historia del diseño habrán acarreado tanta polémica y tanta disputa por su autoría como la sillas voladas de tubo de acero en sus diferentes versiones. Para entenderlo situémonos en el año 1927 a las puertas de la exposición "Die Wohnung" ("La vivienda") organizada por los maestros de la Bauhaus y dirigida por Mies van der Rohe en la ladera Weissenhof de Stuttgart. Muchos nombres célebres de la arquitectura mostraron en esa ocasión su personal propuesta para la vivienda moderna y los objetos que la habitan. Entre ellos los muebles con tubo de acero fueron una presencia constante en la exposición pero hubo una pieza que destacó sobre todas las demás por su novedad y audacia. La pieza en cuestión era el modelo de silla volada, esto es, sin apoyos posteriores y cuya rigidez estaba conferida al esfuerzo solidario de la estructura continua de tubo de acero y que terminaría por convertirse en el cruce de caminos de tres figuras de la disciplina arquitectónica: Marcel Breuer, Mies van der Rohe y Mart Stam. Cada uno de ellos desarrolló su propio modelo de silla volada en sus versiones MR por parte de Mies, L&C Arnold de Stam y el posterior modelo BR 33 de Marcel Breuer. Los tres, en algún momento de su vida reclamaron de uno u otro modo su autoría como objetos que les pertenecían intelectualmente. Estas sillas se convirtieron en la expresión máxima de uno de los ansiados anhelos de la modernidad, la propia materialidad del acero, en su versión optimizada, era la que había derivado en una forma completamente nueva de un objeto cotidiano y cuyo tipo estaba ya totalmente asumido. Los nuevos materiales y las nuevas formas de hacer habían irrumpido hasta en los utensilios domésticos, y habían sido capaces de reformularlos. El punto de partida para esta investigación es precisamente esa coincidencia de tres figuras de la arquitectura moderna, los tres de formación artesanal, en un mismo modelo de silla y en una misma fecha. Tres arquitectos que se habían encargado de asegurar que el movimiento moderno no reconocía problemas formales sino solamente de construcción, iban a coincidir en el mismo tiempo y lugar, precisamente en una misma forma, como si tal coincidencia hubiera sido producto de una voluntad de época. Sin embargo el interés de este estudio no radica en una indagación sobre la autoría sino sobre cómo un mismo objeto resulta ser propositivo e interesante en campos muy diversos y la forma en que cada uno lo hace suyo incorporándolo a su propia investigación proyectual. La silla, más allá de ser un objeto de diseño exclusivamente, trasciende su propia escala para situarse inmersa en un proceso de búsqueda y exploración a nivel conceptual, formal, constructivo y estructural en la arquitectura cada uno de ellos. En un momento en que el oficio del arquitecto está siendo intensamente redefinido considero especialmente pertinente esta investigación, que en definitiva versa sobre la forma distintiva en que el pensamiento arquitectónico es capaz de proyectarse sobre cualquier disciplina para reformularla. ABSTRACT The nineteenth century was a century dedicated to the great public buildings; theaters, schools or museums. However the architecture in the twentieth century was devoted to the study of housing. All uses and typologies were heavily revised but the focus of all efforts and true beginning of modern architecture was housing. From these beginnings all modern precepts were applied to the various programs. Nikolaus Pevsner points to William Morris as the first modern architect precisely because he understood that a truly social art in line with its time and the society it serves must deal with social concerns at that time. With the new housing situation at the center of disciplinary concerns furniture took on a new prominence. At an advanced stage of his career Marcel Breuer observed partly with curiosity, partly with irony how modern furniture had been promoted not by furniture designers but by architects. The answer is given by Le Corbusier in one of his lectures of 1931 collected in Precisions when he pointed the reformulation of furniture as the "Gordian knot" for the renewal of modern plan resolution. Modernism had been forced to confront this issue in order to advance their domestic approaches. Modernism not only put forward a solution to the problems of housing and a Europe under reconstruction but is also needed to be able to contribute to an exciting vision of modern life. Not only did solve existing problems but also it had the self-imposed necessity of anticipating future domesticity and to do their houses full, movable and immovable, they should be submitted under this new image. The founding manifesto of the Deutsche Werkbund extended the scope of the new architect from building cities to the couch cushions. This furniture had the complex mission of synthetically condensing all the ideals of modernity had brought with it: abstraction, hygiene, mechanization, positivist confidence in science or material expression. Objects of modern life, in words of Le Corbusier, were likely to give rise a state of modern life. Few chairs in design history have resulted in so much controversy and so much dispute over their invention as the various versions of cantilevered tubular steel chairs. To understand this let us place ourselves in 1927 at the gates of the exhibition "Die Wohnung" ("Housing") organized by the teachers of the Bauhaus and directed by Mies van der Rohe in Stuttgart Weissenhoflung. Many famous names in architecture at that time showed their personal proposals for modern housing and the objects that inhabit them. Amongst these objects, the steel tube furniture was a constant presence at the exhibition but there was a piece so audacious that it stood out from all the others. This piece in question was the cantilever model chair, that is, which had no further rear support and whose rigidity was attributed to the solidity of its continues structure of steel tube. This piece would eventually become the crossroads of three very different personalities: Mart Stam, Marcel Breuer and Mies van der Rohe. Each of them developed their own model of cantilevered chair in different versions; The MR model developed by Mies van der Rohe, the L&C by Arnold Stam and a later model BR 33 by Marcel Breuer, and the three, at some point in their lives demanded the authorship of its invention as objects that belonged to them intellectually. These chairs epitomized one of the coveted objects of modernity, steel material in its optimized version, was what had led to a completely new form of an everyday object whose this type was fully adopted on board in design. New materials and production methods had burst into world of household objects, and had been able to reformulate their design. The bold design then became a dark object of controversy. The starting point for this doctoral thesis is the concurrent invention of the same model of chair by three different figures of modern architecture. These three architects, who were responsible for ensuring that the modern movement considered construction rather than form as the main design consideration, were working in the same place and at the same point in time. It was almost as if these three architects were shaped by the culture of the time (Zeitgeist). However the focus of this study lies not in an investigation of responsibility of ownership but in the investigation fo how the same object can turn out to be purposeful and interesting in many different fields and the way in which each researcher makes it his own by developing his own project research. 1927, the year of their meeting, was a initiatory year in the career of our players. The chair, beyond being only a design object transcended its own scale and became immersed in a process of research and development on a conceptual, formal, structural and constructive level in the architectural approach of each of the architects. At a time when the role of the architect is being redefined intensely I consider this research, which ultimately concerns the distinctive way the architectural thought can be projected onto and reformulate any discipline, to be particularly relevant.

The history of Lincoln University

The Founding of Lincoln Institute -- Period of Development -- The Administrations of Smith, Mitchell, and Clayton -- The Grand Old Man -- The Period from 1989-1898 -- The Period of the Presidents -- Lincoln Institute at the Turn of the century -- The Period of Opposition -- From Institute to University -- A New President with a new Program -- Growth Despite Opposition -- Lincoln University since 1931.

UMA ÁNALISE EXEGÉTICA DA PORÇÃO DE MIQUEIAS 2,1-5: A SITUAÇÃO SOCIOECONÔMICA EM JUDÁ E SUAS IMPLICAÇÕES NA HERANÇA DOS CAMPONESES NA SEFELÁ JUDAÍTA NO SÉCULO VIII A.C.

Esta pesquisa procura examinar, à luz da metodologia exegética, a perícope de Miqueias 2,1-5, a fim de reconstruir o cenário no qual emergiu a dura crítica social do profeta. O texto apresenta, em sua análise literária, características de um dito profético coeso, em estilo poético. Sua estrutura encontra-se dividida em duas unidades (denúncia e castigo), sendo que cada uma das unidades possui outras duas subunidades (genérica e específica). O gênero literário harmoniza-se com um dito profético de julgamento geralmente conhecido como oráculo ai . A análise da dimensão histórica situa o acontecimento fundante em 701 a.C., na Sefelá judaíta. Numa análise investigativa do conteúdo da denúncia norteado pelo modelo teórico do modo de produção tributário, observa-se um conflito entre dois grupos. Nesse conflito, Miqueias faz uma acusação a um grupo de poder em Judá que planeja e executa ações criminosas contra a herança camponesa. O castigo descreve a conspiração e o plano divino contra esse grupo de poder. Javé havia planejado um mal idêntico ao que eles haviam cometido, desonra e privação de suas possessões. Os valores culturais de honra e vergonha subjazem a esse oráculo. Por descumprirem seus deveres junto a Javé e ao povo, os criminosos perderiam todos os seus direitos e, sobretudo, a honra perante a própria comunidade. Com base no modelo teórico do modo de produção tributário, constata-se que, na situação social em Judá no oitavo século, prevalecia um conflito entre campo e cidade. As comunidades aldeãs pagavam tributo à cidade em forma de produtos e serviços. A excessiva arrecadação de tributo e as falhas no sistema de ajuda mútua forçaram os indivíduos e famílias a contrair dívidas, a hipotecar suas terras herdadas dos pais e eventualmente perdê-las. O profeta Miqueias é o porta-voz do protesto da classe campesina que resolve reagir aos desmandos praticados pela elite citadina. Para ele, Javé escuta a queixa dos que estão sendo oprimidos e intervém na história tomando o partido do oprimido.(AU)

UMA ÁNALISE EXEGÉTICA DA PORÇÃO DE MIQUEIAS 2,1-5: A SITUAÇÃO SOCIOECONÔMICA EM JUDÁ E SUAS IMPLICAÇÕES NA HERANÇA DOS CAMPONESES NA SEFELÁ JUDAÍTA NO SÉCULO VIII A.C.

Esta pesquisa procura examinar, à luz da metodologia exegética, a perícope de Miqueias 2,1-5, a fim de reconstruir o cenário no qual emergiu a dura crítica social do profeta. O texto apresenta, em sua análise literária, características de um dito profético coeso, em estilo poético. Sua estrutura encontra-se dividida em duas unidades (denúncia e castigo), sendo que cada uma das unidades possui outras duas subunidades (genérica e específica). O gênero literário harmoniza-se com um dito profético de julgamento geralmente conhecido como oráculo ai . A análise da dimensão histórica situa o acontecimento fundante em 701 a.C., na Sefelá judaíta. Numa análise investigativa do conteúdo da denúncia norteado pelo modelo teórico do modo de produção tributário, observa-se um conflito entre dois grupos. Nesse conflito, Miqueias faz uma acusação a um grupo de poder em Judá que planeja e executa ações criminosas contra a herança camponesa. O castigo descreve a conspiração e o plano divino contra esse grupo de poder. Javé havia planejado um mal idêntico ao que eles haviam cometido, desonra e privação de suas possessões. Os valores culturais de honra e vergonha subjazem a esse oráculo. Por descumprirem seus deveres junto a Javé e ao povo, os criminosos perderiam todos os seus direitos e, sobretudo, a honra perante a própria comunidade. Com base no modelo teórico do modo de produção tributário, constata-se que, na situação social em Judá no oitavo século, prevalecia um conflito entre campo e cidade. As comunidades aldeãs pagavam tributo à cidade em forma de produtos e serviços. A excessiva arrecadação de tributo e as falhas no sistema de ajuda mútua forçaram os indivíduos e famílias a contrair dívidas, a hipotecar suas terras herdadas dos pais e eventualmente perdê-las. O profeta Miqueias é o porta-voz do protesto da classe campesina que resolve reagir aos desmandos praticados pela elite citadina. Para ele, Javé escuta a queixa dos que estão sendo oprimidos e intervém na história tomando o partido do oprimido.(AU)

O PROTESTANTISMO BRASILEIRO: ENTRE A COLABORAÇÃO E A RESISTÊNCIA NO PERÍODO DA DI-TADURA CIVIL E MILITAR (1964-1974)

Este trabalho analisa um período de crise vivido pelo protestantismo brasileiro (simbolizado aqui pela Igreja Metodista e pela Igreja Presbiteriana do Brasil) durante a época da Ditadura Civil e Militar, focando o olhar mais especificamente no intervalo entre os anos de 1964 e 1974. Influenciadas pelo ambiente político e ideológico da época, essas duas denominações protestantes foram palco de uma disputa entre suas alas conservadoras e progressistas. Como resultado, estabeleceu-se um clima interno de “caça às bruxas”, marcado por atitudes autoritá-rias e de apoio ao regime imposto. Seguindo uma proposta advinda de trabalhos anteriores, a pesquisa procura levantar os fundamentos que embasaram as atitudes das alas conservadoras do protestantismo nesse conflito, um aspecto pouco considerado pela historiografia sobre o tema. A principal suspeita é a de que as posturas conservadoras decorreram do contato do pro-testantismo importado do mundo anglo saxão com a herança cultural patriarcal autoritária e católica presente no Brasil desde seu período fundacional. Essa mescla de elementos teológi-cos importados somada à herança cultural tipicamente brasileira acabou moldando a mentali-dade dos setores conservadores do protestantismo nacional entre o final do século XIX e me-ados do XX, que acabou aflorando quando novos agentes surgiram no cenário religioso duran-te o período do Golpe Civil e Militar.

Investigation of the bottleneck leading to the domestication of maize

Maize (Zea mays ssp. mays) is genetically diverse, yet it is also morphologically distinct from its wild relatives. These two observations are somewhat contradictory: the first observation is consistent with a large historical population size for maize, but the latter observation is consistent with strong, diversity-limiting selection during maize domestication. In this study, we sampled sequence diversity, coupled with simulations of the coalescent process, to study the dynamics of a population bottleneck during the domestication of maize. To do this, we determined the DNA sequence of a 1,400-bp region of the Adh1 locus from 19 individuals representing maize, its presumed progenitor (Z. mays ssp. parviglumis), and a more distant relative (Zea luxurians). The sequence data were used to guide coalescent simulations of population bottlenecks associated with domestication. Our study confirms high genetic diversity in maize—maize contains 75% of the variation found in its progenitor and is more diverse than its wild relative, Z. luxurians—but it also suggests that sequence diversity in maize can be explained by a bottleneck of short duration and very small size. For example, the breadth of genetic diversity in maize is consistent with a founding population of only 20 individuals when the domestication event is 10 generations in length.

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

Linkage disequilibrium analysis can provide high resolution in the mapping of disease genes because it incorporates information on recombinations that have occurred during the entire period from the mutational event to the present. A circumstance particularly favorable for high-resolution mapping is when a single founding mutation segregates in an isolated population. We review here the population structure of Finland in which a small founder population some 100 generations ago has expanded into 5.1 million people today. Among the 30-odd autosomal recessive disorders that are more prevalent in Finland than elsewhere, several appear to have segregated for this entire period in the “panmictic” southern Finnish population. Linkage disequilibrium analysis has allowed precise mapping and determination of genetic distances at the 0.1-cM level in several of these disorders. Estimates of genetic distance have proven accurate, but previous calculations of the confidence intervals were too small because sampling variation was ignored. In the north and east of Finland the population can be viewed as having been “founded” only after 1500. Disease mutations that have undergone such a founding bottleneck only 20 or so generations ago exhibit linkage disequilibrium and haplotype sharing over long genetic distances (5–15 cM). These features have been successfully exploited in the mapping and cloning of many genes. We review the statistical issues of fine mapping by linkage disequilibrium and suggest that improved methodologies may be necessary to map diseases of complex etiology that may have arisen from multiple founding mutations.

A family of membrane-embedded metalloproteases involved in regulated proteolysis of membrane-associated transcription factors

We present evidence that the sporulation protein SpoIVFB of Bacillus subtilis is a member of a newly recognized family of metalloproteases that have catalytic centers adjacent to or within the membrane. SpoIVFB is required for converting the membrane-associated precursor protein, pro-σK, to the mature and active transcription factor σK by proteolytic removal of an N-terminal extension of 20 amino acids. SpoIVFB and other family members share the conserved sequence HEXXH, a hallmark of metalloproteases, as well as a second conserved motif NPDG, which is unique to the family. Both motifs, which are expected to form the catalytic center of the protease, overlap hydrophobic segments that are predicted to be separate transmembrane domains. The only other characterized member of this family of membrane-embedded metalloproteases is the mammalian Site-2 protease (S2P), which is required for the intramembrane cleavage of the eukaryotic transcription factor sterol regulatory element binding protein (SREBP). We report that amino acid substitutions in the two conserved motifs of SpoIVFB impair pro-σK processing and σK-directed gene expression during sporulation. These results and those from a similar analysis of S2P support the interpretation that both proteins are founding members of a family of metalloproteases involved in the activation of membrane-associated transcription factors. Thus, the pathways that govern the activation of the prokaryotic transcription factor pro-σK and the mammalian transcription factor SREBP not only are analogous but also use processing enzymes with strikingly homologous features.

MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity

Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1α, -2, -4, -6, and -11, granulocyte/macrophage colony-stimulating factor, interferon γ, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase/signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors.

Sla2p Is Associated with the Yeast Cortical Actin Cytoskeleton via Redundant Localization Signals

Sla2p, also known as End4p and Mop2p, is the founding member of a widely conserved family of actin-binding proteins, a distinguishing feature of which is a C-terminal region homologous to the C terminus of talin. These proteins may function in actin cytoskeleton-mediated plasma membrane remodeling. A human homologue of Sla2p binds to huntingtin, the protein whose mutation results in Huntington’s disease. Here we establish by immunolocalization that Sla2p is a component of the yeast cortical actin cytoskeleton. Deletion analysis showed that Sla2p contains two separable regions, which can mediate association with the cortical actin cytoskeleton, and which can provide Sla2p function. One localization signal is actin based, whereas the other signal is independent of filamentous actin. Biochemical analysis showed that Sla2p exists as a dimer in vivo. Two-hybrid analysis revealed two intramolecular interactions mediated by coiled-coil domains. One of these interactions appears to underlie dimer formation. The other appears to contribute to the regulation of Sla2p distribution between the cytoplasm and plasma membrane. The data presented are used to develop a model for Sla2p regulation and interactions.

Microsatellites provide evidence for Y chromosome diversity among the founders of the New World

Recently, Y chromosome markers have begun to be used to study Native American origins. Available data have been interpreted as indicating that the colonizers of the New World carried a single founder haplotype. However, these early studies have been based on a few, mostly complex polymorphisms of insufficient resolution to determine whether observed diversity stems from admixture or diversity among the colonizers. Because the interpretation of Y chromosomal variation in the New World depends on founding diversity, it is important to develop marker systems with finer resolution. Here we evaluate the hypothesis of a single-founder Y haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind populations. Two of these markers (DYS271, DYS287) are reliable indicators of admixture and detected three non-Amerind chromosomes in our sample. Two other markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to Native Americans. The relatedness of chromosomes defined by these two markers was evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to 394). The microsatellite backgrounds found on the two haplogroups defined by marker DYS199 demonstrate the existence of at least two Amerind founder haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native Americans. The estimated age and distribution of these haplogroups places them among the founders of the New World.

The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase

The transcription factor E2F plays a major role in cell cycle control in mammalian cells. E2F binding sites, which are present in the promoters of a variety of genes required for S phase, shift from a negative to a positive role in transcription at the commitment point, a crucial point in G1 that precedes the G1/S transition. Before the commitment point, E2F activity is repressed by members of the pocket proteins family. This repression is believed to be crucial for the proper control of cell growth. We have previously shown that Rb, the founding member of the pocket proteins family, represses E2F1 activity by recruiting the histone deacetylase HDAC1. Here, we show that the two other members of the pocket proteins family, p107 and p130, also are able to interact physically with HDAC1 in live cells. HDAC1 interacts with p107 and Rb through an “LXCXE”-like motif, similar to that used by viral transforming proteins to bind and inactivate pocket proteins. Indeed, we find that the viral transforming protein E1A competes with HDAC1 for p107 interaction. We also demonstrate that p107 is able to interact simultaneously with HDAC1 and E2F4, suggesting a model in which p107 recruits HDAC1 to repress E2F sites. Indeed, we demonstrate that histone deacetylase activity is involved in the p107- or p130-induced repression of E2F4. Taken together, our data suggest that all members of the E2F family are regulated in early G1 by similar complexes, containing a pocket protein and the histone deacetylase HDAC1.

Identification of two novel transmembrane γ-carboxyglutamic acid proteins expressed broadly in fetal and adult tissues

The proline-rich γ-carboxyglutamic acid (Gla) proteins (PRGPs) 1 and 2 are the founding members of a family of vitamin K-dependent single-pass integral membrane proteins characterized by an extracellular amino terminal domain of approximately 45 amino acids that is rich in Gla. The intracellular carboxyl terminal region of these two proteins contains one or two copies of the sequence PPXY, a motif present in a variety of proteins involved in such diverse cellular functions as signal transduction, cell cycle progression, and protein turnover. In this report, we describe the cloning of the cDNAs for two additional human transmembrane Gla proteins (TMG) of 20–24 kDa named TMG3 and TMG4. These two proteins possess extracellular Gla domains with 13 or 9 potential Gla residues, respectively, followed by membrane-spanning hydrophobic regions and cytoplasmic carboxyl terminal regions that contain PPXY motifs. This emerging family of integral membrane Gla proteins includes proline-rich Gla protein (PRGP) 1, PRGP2, TMG3, and TMG4, all of which are characterized by broad and variable distribution in both fetal and adult tissues. Members of this family can be grouped into two subclasses on the basis of their gene organization and amino acid sequence. These observations suggest novel physiological functions for vitamin K beyond its known role in the biosynthesis of proteins involved in blood coagulation and bone development. The identification and characterization of these proteins may allow a more complete understanding of the teratogenic consequences of exposure in utero to vitamin K antagonists, such as warfarin-based anticoagulants.

The Atomic Bomb Casualty Commission in retrospect

For 50 years, the Atomic Bomb Casualty Commission (ABCC) and its successor, the Radiation Effects Research Foundation (RERF), have conducted epidemiological and genetic studies of the survivors of the atomic bombs and of their children. This research program has provided the primary basis for radiation health standards. Both ABCC (1947–1975) and RERF (1975 to date) have been a joint enterprise of the United States (through the National Academy of Sciences) and of Japan. ABCC began in devastated, occupied Japan. Its mission had to be defined and refined. Early research revealed the urgent need for long term study. In 1946, a Directive of President Truman enjoined the National Research Council of the National Academy of Sciences to develop the program. By 1950, ABCC staff exceeded 1,000, and clinical and genetic studies were underway. Budgetary difficulties and other problems almost forced closure in 1953. In 1955, the Francis Report led to a unified epidemiological study. Much progress was made in the next decade, but changing times required founding of a binational nonprofit organization (RERF) with equal participation by Japan and the United States. New programs have been developed and existing ones have been extended in what is the longest continuing health survey ever undertaken.