Impact of donor-recipient gender and race mismatching on patient survival in patients with end-stage liver diseases undergoing liver transplantation

Background. End-stage liver disease (ESLD) is an irreversible condition that leads to the imminent complete failure of the liver. Orthotopic liver transplantation (OLT) has been well accepted as the best curative option for patients with ESLD. Despite the progress in liver transplantation, the major limitation nowadays is the discrepancy between donor supply and organ demand. In an effort to alleviate this situation, mismatched donor and recipient gender or race livers are being used. However, the simultaneous impact of donor and recipient gender and race mismatching on patient survival after OLT remains unclear and relatively challenging to surgeons. ^ Objective. To examine the impact of donor and recipient gender and race mismatching on patient survival after OLT using the United Network for Organ Sharing (UNOS) database. ^ Methods. A total of 40,644 recipients who underwent OLT between 2002 and 2011 were included. Kaplan-Meier survival curves and the log-rank tests were used to compare the survival rates among different donor-recipient gender and race combinations. Univariate Cox regression analysis was used to assess the association of donor-recipient gender and race mismatching with patient survival after OLT. Multivariable Cox regression analysis was used to model the simultaneous impact of donor-recipient gender and race mismatching on patient survival after OLT adjusting for a list of other risk factors. Multivariable Cox regression analysis stratifying on recipient hepatitis C virus (HCV) status was also conducted to identify the variables that were differentially associated with patient survival in HCV + and HCV − recipients. ^ Results. In the univariate analysis, compared to male donors to male recipients, female donors to male recipients had a higher risk of patient mortality (HR, 1.122; 95% CI, 1.065–1.183), while in the multivariable analysis, male donors to female recipients experienced an increased mortality rates (adjusted HR, 1.114; 95% CI, 1.048–1.184). Compared to white donors to white recipients, Hispanic donors to black recipients had a higher risk of patient mortality (HR, 1.527; 95% CI, 1.293–1.804) in the univariate analysis, and similar result (adjusted HR, 1.553; 95% CI, 1.314–1.836) was noted in multivariable analysis. After the stratification on recipient HCV status in the multivariable analysis, HCV + mismatched recipients appeared to be at greater risk of mortality than HCV − mismatched recipients. Female donors to female HCV − recipients (adjusted HR, 0.843; 95% CI, 0.769–0.923), and Hispanic HCV + recipients receiving livers from black donors (adjusted HR, 0.758; 95% CI, 0.598–0.960) had a protective effect on patient survival after OLT. ^ Conclusion. Donor-recipient gender and race mismatching adversely affect patient survival after OLT, both independently and after the adjustment for other risk factors. Female recipient HCV status is an important effect modifier in the association between donor-recipient gender combination and patient survival.^

Molecular Mechanisms of Vascular Disease in Patients with Rare Variants in MYH11

Thoracic aortic aneurysms and dissections (TAAD) are the primary disease affecting the thoracic ascending aorta, with an incidence rate of 10.4/100,000. Although about 20% of patients carry a mutation in a single gene that causes their disease, the remaining 80% of patients may also have genetic factors that increase their risk for developing TAAD. Many of the genes that predispose to TAAD encode proteins involved in smooth muscle cell (SMC) contraction and the disease-causing mutations are predicted to disrupt contractile function. SMCs are the predominant cell type in the ascending aortic wall. Mutations in MYH11, encoding the smooth muscle specific myosin heavy chain, are a rare cause of inherited TAAD. However, rare but recurrent non-synonymous variants in MYH11 are present in the general population but do not cause inherited TAAD. The goal of this study was to assess the potential role of these rare variants in vascular diseases. Two distinct variants were selected: the most commonly seen rare variant, MYH11 R247C, and a duplication of the chromosomal region spanning the MYH11 locus at 16p13.1. Genetic analyses indicated that both of these variants were significantly enriched in patients with TAAD compared with controls. A knock-in mouse model of the Myh11 R247C rare variant was generated, and these mice survive and reproduce normally. They have no structural abnormalities of the aorta or signs of aortic disease, but do have decreased aortic contractility. Myh11R247C/R247C mice also have increased proliferative response to vascular injury in vivo and increased proliferation of SMCs in vitro. Myh11R247C/R247C SMCs have decreased contractile gene and protein expression and are dedifferentiated. In fibroblasts, myosin force generation is required for maturation of focal adhesions, and enhancers of RhoA activity replace enhancers of Rac1 activity as maturation occurs. Consistent with these previous findings, focal adhesions are smaller in Myh11R247C/R247C SMCs, and there is decreased RhoA activation. A RhoA activator (CN03) rescues the dedifferentiated phenotype of Myh11R247C/R247C SMCs. Myh11R247C/R247C mice were bred with an existing murine model of aneurysm formation, the Acta2-/- mouse. Over time, mice carrying the R247C allele in conjunction with heterozygous or homozygous loss of Acta2 had significantly increased aortic diameter, and a more rapid accumulation of pathologic markers. These results suggest that the Myh11 R247C rare variant acts as a modifier gene increasing the risk for and severity of TAAD in mice. In patients with 16p13.1 duplications, aortic MYH11 expression is increased, but there is no corresponding increase in smooth muscle myosin heavy chain protein. Using SMCs that overexpress Myh11, we identified alterations in SMC phenotype leading to excessive protein turnover. All contractile proteins, not just myosin, are affected, and the proteins are turned over by autophagic degradation. Surprisingly, these cells are also more contractile compared with wild-type SMCs. The results described in this dissertation firmly establish that rare variants in MYH11 significantly affect the phenotype of SMCs. Further, the data suggests that these rare variants do increase the risk of TAAD via pathways involving altered SMC phenotype and contraction. Therefore, this study validates that these rare genetic variants alter vascular SMCs and provides model systems to explore the contribution of rare variants to disease.

Indeterminate QunatiFERON-TB Gold In-Tube assay results in association with procedural specimen collection in children

BACKGROUND. The development of interferon-gamma release assays (IGRA) has introduced powerful tools in diagnosing latent tuberculosis infection (LTBI) and may play a critical role in the future of tuberculosis diagnosis. However, there have been reports of high indeterminate results in young patient populations (0-18 years). This study investigated results of the QunatiFERON-TB Gold In-Tube (QFT-GIT) IGRA in a population of children (0-18 years) at Texas Children's Hospital in association with specimen collection procedures using surrogate variables. ^ METHODS. A retrospective case-control study design was used for this investigation. Cases were defined as having QFT-GIT indeterminate results. Controls were defined as having either positive or negative results (determinates). Patients' admission status, staff performing specimen collection, and specific nurse performing specimen collection were used as surrogates to measure specimen collection procedures. ^ To minimize potential confounding, abstraction of patients' electronic medical records was performed. Abstracted data included patients' medications and evaluation at the time of QFT-GIT specimen collection in addition to their medical history. QFT-GIT related data was also abstracted. Cases and controls were characterized using chi-squared tests or Fisher's exact tests across categorical variables. Continuous variables were analyzed using one-way ANOVA and t-tests for continuous variables. A multivariate model was constructed by backward stepwise removal of statistically significant variables from univariate analysis. ^ RESULTS. Patient data was abstracted from 182 individuals aged 0-18 years from July 2010 to August 2011 at Texas Children's Hospital. 56 cases (indeterminates) and 126 controls (determinates) were enrolled. Cancer was found to be an effect modifier with subsequent stratification resulting in a cancer patient population too small to analyze (n=13). Subsequent analyses excluded these patients. ^ The exclusion of cancer patients resulted in a population of 169 patients with 49 indeterminates (28.99%) and 120 determinates (71.01%), with mean ages of 9.73 (95% CI: 8.03, 11.43) years and 11.66 (95% CI: 10.75, 12.56) years (p = 0.033), respectively. Median age of patients who were indeterminates and determinates were 12.37 and 12.87 years, respectively. Lack of data for our specific nurse surrogate (QFTNurse) resulted in its exclusion from analysis. The final model included only our remaining surrogate variables (QFTStaff and QFTInpatientOutpatient). The staff collecting surrogate (QFTStaff) was found to be modestly associated with indeterminates when nurses collected the specimen (OR = 1.54, 95% CI: 0.51, 4.64, p = 0.439) in the final model. Inpatients were found to have a strong and statistically significant association with indeterminates (OR = 11.65, 95% CI: 3.89, 34.9, p < 0.001) in the final model. ^ CONCLUSION. Inpatient status was used as a surrogate for indication of nurse drawn blood specimens. Nurses have had little to no training regarding shaking of tubes versus phlebotomists regarding QFT-GIT testing procedures. This was also measured by two other surrogates; specifically a medical note stating whether a nurse or phlebotomist collected the specimen (QFTStaff) and the name and title of the specific nurse if collection was performed by a nurse (QFTNurse). Results indicated that inpatient status was a strong and statistically significant factor for indeterminates, however, nurse collected specimens and indeterminate results had no statistically significant association in non-cancer patients. The lack of data denoting the specific nurse performing specimen collection excluded the QFTNurse surrogate in our analysis. ^ Findings suggests training of staff personnel in specimen procedures may have little effect on the number of indeterminates while inpatient status and thus possibly illness severity may be the most important factor for indeterminate results in this population. The lack of congruence between our surrogate measures may imply that our inpatient surrogate gauged illness severity rather than collection procedures as intended. ^ Despite the lack of clear findings, our analysis indicated that more than half of indeterminates were found in specimens drawn by nurses and as such staff training may be explored. Future studies may explore methods in measuring modifiable variables during pre-analytical QFT-GIT procedures that can be discerned and controlled. Identification of such measures may provide insight into ways to lowering indeterminate QFT-GIT rates in children.^

Manejo de suelo mediante coberturas vegetales establecidas

El objetivo de esta investigación fue determinar los efectos de las coberturas vegetales en el microclima de la planta de vid. Se compararon cinco coberturas de diferente ciclo vegetativo con respecto al manejo de suelo sin labranza mediante aplicación de herbicidas. El estudio se desarrolló en un viñedo cv. Malbec conducido en espaldera alta, situado en Agrelo, Luján de Cuyo, Mendoza, Argentina. Se determinaron parámetros microclimáticos, temperatura, humedad relativa y radiación a nivel de racimos, temperatura del suelo, cantidad y calidad de la radiación reflejada por la cobertura. También se midió la expresión vegetativa y de uvas y el potencial enológico. Se verificó una significativa disminución de la radiación fotosintéticamente activa (RFA) reflejada por las coberturas con una menor relación “Rojo/Rojo lejano" comparada con el suelo descubierto. Sin embargo, el efecto no se percibió dentro de la canopia debido a que las coberturas permanentes de trébol rojo (Trifolium pratensis) y agropiro alargado (Agropyron elongatum) restringieron el vigor de las cepas, disminuyendo el crecimiento de brotes y el tamaño de hojas, lo cual se tradujo en una mayor recepción directa de la RFA a nivel de racimos. No hubo una significativa variación en cuanto a temperatura máxima, mínima y amplitud térmica a nivel de racimos. No obstante ello, los tratamientos con mayor cobertura de suelo tendieron a reducir levemente la temperatura mínima a nivel de racimos. La humedad relativa en la canopia no fue significativamente afectada. El trébol rojo, el agropiro alargado, la mezcla centeno-cebadilla (Secale cereale-Bromus catharticus) y el sorgo del Sudán (Sorghum sudanensis) redujeron notablemente la amplitud térmica del suelo. El efecto fue determinado principalmente por la disminución de la temperatura máxima. Las coberturas vegetales con alguna dificultad para desarrollarse durante su ciclo vegetativo tuvieron un comportamiento intermedio o uno muy similar al de un suelo descubierto. La introducción de una cobertura permanente con buena invasión del sitio interfilar permitió modificar indirectamente las características microclimáticas de la canopia, a través del control del crecimiento vegetativo y de los rendimientos de la planta de vid, modificando el equilibrio vigor / producción del viñedo, y por lo tanto la composición de las uvas y del vino elaborado.

Geochemical composition of gabbroic rocks from ODP Hole 179-1105A, southwest Indian Ridge

Oxide-free olivine gabbro and gabbro, and oxide olivine gabbro and gabbro make up the bulk of the gabbroic suite recovered from Ocean Drilling Program (ODP) Leg 179 Hole 1105A, which lies 1.2 km away from Hole 735B on the eastern transverse ridge of the Atlantis II Fracture Zone, Southwest Indian Ridge. The rocks recovered during Leg 179 show striking similarities to rocks recovered from the uppermost 500 m of Hole 735B during ODP Leg 118. The rocks of the Atlantis platform were likely unroofed as part of the footwall block of a large detachment fault on the inside corner of the intersection of the Southwest Indian Ridge and the Atlantis II Transform at ~11.5 Ma. We analyzed the lithologic, geochemical, and structural stratigraphy of the section. Downhole lithologic variation allowed division of the core into 141 lithologic intervals and 4 main units subdivided on the basis of predominance of oxide gabbroic vs. oxide-free gabbroic rocks. Detailed analyses of whole-rock chemistry, mineral chemistry, microstructure, and modes of 147 samples are presented and clearly show that the gabbroic rocks are of cumulate origin. These studies also indicate that geochemistry results correlate well with downhole magnetic susceptibility and Formation MicroScanner (FMS) resistivity measurements and images. FMS images show rocks with a well-layered structure and significant numbers of mappable layer contacts or compositional contrasts. Downhole cryptic mineral and whole-rock chemical variations depict both "normal" and inverse fine-scale variations on a scale of 10 m to <2 m with significant compositional variation over a short distance within the 143-m section sampled. A Mg# shift in whole-rock or Fo contents of olivine of as much as 20-30 units over a few meters of section is not atypical of the extreme variation in downhole plots. The products of the earliest stages of basaltic differentiation are not represented by any cumulates, as the maximum Fo content was Fo78. Similarly, the extent of fractionation represented by the gabbroic rocks and scarce granophyres in the section is much greater than that represented in the Atlantis II basalts. The abundance of oxide gabbros is similar to that in Hole 735B, Unit IV, which is tentatively correlated as a similar unit or facies with the oxide gabbroic units of Hole 1105A. Oxide phases are generally present in the most fractionated gabbroic rocks and lacking in more primitive gabbroic rocks, and there is a definite progression of oxide abundance as, for example, the Mg# of clinopyroxene falls below 73-75. Coprecipitation of oxide at such early Mg#s cannot be modeled by perfect fractional crystallization. In situ boundary layer fractionation may offer a more plausible explanation for the complex juxtaposition of oxide- and nonoxide-bearing more primitive gabbroic rocks. The geochemical signal may, in part, be disrupted by the presence of mylonitic shear zones, which strike east-west and dip both to the south and north, but predominantly to the south away from the northern rift valley where they formed. Downhole deformation textures indicate increasing average strain and crystal-plastic deformation in units that contain oxides. Oxide-rich zones may represent zones of rheologic weakness in the cumulate section along which mylonitic and foliated gabbroic shear zones nucleate in the solid state at high temperature, or the oxide may be a symptom of former melt-rich zones and hypersolidus flow, as predicted during study of Hole 735B.

Influence of different organoclays on the curing, morphology, and dynamic mechanical properties of an epoxy adhesive

The thermal, mechanical, and adhesive properties of nanoclay-modified adhesives were investigated. Two organically modified montmorillonites: Cloisite 93A (C93A) and Nanomer I.30E (I.30E) were used as reinforcement of an epoxy adhesive. C93A and I.30E are modified with tertiary and primary alkyl ammonium cations, respectively. The aim was to study the influence of the organoclays on the curing, and on the mechanical and adhesive properties of the nanocomposites. A specific goal was to compare their behavior with that of Cloisite30B/epoxy and Cloisite15A/ epoxy nanocomposites that we have previously studied. Both C30B and C15A are modified with quaternary alkyl ammonium cations. Differential scanning calorimetry results showed that the clays accelerate the curing reaction, an effect that is related to the chemical structure of the ammonium cations. The three Cloisite/nanocomposites showed intercalated clay structures,the interlayer distance was independent of the clay content. The I.30E/epoxy nanocomposites presented exfoliated structure due to the catalytic effect of the organic modifier. Clay-epoxy nanocompo-sites showed lower glass transition temperature (Tg) and higher values of storage modulus than neat epoxy thermoset, with no significant differences between exfoliated or intercalated nanocom-posites. The shear strength of aluminum joints using clay/epoxy adhesives was lower than with the neat epoxy adhesive. The wáter aging was less damaging for joints with I.30E/epoxy adhesive.

Thermoplastic Polymer Nanocomposites Based on Inorganic Fullerene-like Nanoparticles and Inorganic Nanotubes

Using inorganic fullerene-like (IF) nanoparticles and inorganic nanotubes (INT) in organic-inorganic hybrid composite, materials provide the potential for improving thermal, mechanical, and tribological properties of conventional composites. The processing of such high-performance hybrid thermoplastic polymer nanocomposites is achieved via melt-blending without the aid of any modifier or compatibilizing agent. The incorporation of small quantities (0.1-4 wt.%) of IF/INTs (tungsten disulfide, IF-WS2 or molybdenum disulfide, MoS2) generates notable performance enhancements through reinforcement effects and excellent lubricating ability in comparison with promising carbon nanotubes or other inorganic nanoscale fillers. It was shown that these IF/INT nanocomposites can provide an effective balance between performance, cost effectiveness, and processability, which is of significant importance for extending the practical applications of diverse hierarchical thermoplastic-based composites.

Extending the expressiveness of fuzzy logic languages

En el trabajo que aquí presentamos se incluye la base teórica (sintaxis y semántica) y una implementación de un framework para codificar el razonamiento de la representación difusa o borrosa del mundo (tal y como nosotros, seres humanos, entendemos éste). El interés en la realización de éste trabajo parte de dos fuentes: eliminar la complejidad existente cuando se realiza una implementación con un lenguaje de programación de los llamados de propósito general y proporcionar una herramienta lo suficientemente inteligente para dar respuestas de forma constructiva a consultas difusas o borrosas. El framework, RFuzzy, permite codificar reglas y consultas en una sintaxis muy cercana al lenguaje natural usado por los seres humanos para expresar sus pensamientos, pero es bastante más que eso. Permite representar conceptos muy interesantes, como fuzzificaciones (funciones usadas para convertir conceptos no difusos en difusos), valores por defecto (que se usan para devolver resultados un poco menos válidos que los que devolveríamos si tuviésemos la información necesaria para calcular los más válidos), similaridad entre atributos (característica que utilizamos para buscar aquellos individuos en la base de datos con una característica similar a la buscada), sinónimos o antónimos y, además, nos permite extender el numero de conectivas y modificadores (incluyendo modificadores de negación) que podemos usar en las reglas y consultas. La personalización de la definición de conceptos difusos (muy útil para lidiar con el carácter subjetivo de los conceptos borrosos, donde nos encontramos con que cualificar a alguien de “alto” depende de la altura de la persona que cualifica) es otra de las facilidades incluida. Además, RFuzzy implementa la semántica multi-adjunta. El interés en esta reside en que introduce la posibilidad de obtener la credibilidad de una regla a partir de un conjunto de datos y una regla dada y no solo el grado de satisfacción de una regla a partir de el universo modelado en nuestro programa. De esa forma podemos obtener automáticamente la credibilidad de una regla para una determinada situación. Aún cuando la contribución teórica de la tesis es interesante en si misma, especialmente la inclusión del modificador de negacion, sus multiples usos practicos lo son también. Entre los diferentes usos que se han dado al framework destacamos el reconocimiento de emociones, el control de robots, el control granular en computacion paralela/distribuída y las busquedas difusas o borrosas en bases de datos. ABSTRACT In this work we provide a theoretical basis (syntax and semantics) and a practical implementation of a framework for encoding the reasoning and the fuzzy representation of the world (as human beings understand it). The interest for this work comes from two sources: removing the existing complexity when doing it with a general purpose programming language (one developed without focusing in providing special constructions for representing fuzzy information) and providing a tool intelligent enough to answer, in a constructive way, expressive queries over conventional data. The framework, RFuzzy, allows to encode rules and queries in a syntax very close to the natural language used by human beings to express their thoughts, but it is more than that. It allows to encode very interesting concepts, as fuzzifications (functions to easily fuzzify crisp concepts), default values (used for providing results less adequate but still valid when the information needed to provide results is missing), similarity between attributes (used to search for individuals with a characteristic similar to the one we are looking for), synonyms or antonyms and it allows to extend the number of connectives and modifiers (even negation) we can use in the rules. The personalization of the definition of fuzzy concepts (very useful for dealing with the subjective character of fuzziness, in which a concept like tall depends on the height of the person performing the query) is another of the facilities included. Besides, RFuzzy implements the multi-adjoint semantics. The interest in them is that in addition to obtaining the grade of satisfaction of a consequent from a rule, its credibility and the grade of satisfaction of the antecedents we can determine from a set of data how much credibility we must assign to a rule to model the behaviour of the set of data. So, we can determine automatically the credibility of a rule for a particular situation. Although the theoretical contribution is interesting by itself, specially the inclusion of the negation modifier, the practical usage of it is equally important. Between the different uses given to the framework we highlight emotion recognition, robocup control, granularity control in parallel/distributed computing and flexible searches in databases.

Pulsiones del espacio : Oteiza y la aproximación a la arquitectura como vacío activo

Este trabajo se centra en el estudio de las investigaciones de Jorge Oteiza en torno a la funcionalidad estética del espacio, en especial, en la actividad artística que desarrolló en el año 1958, un año decisivo en la vida del escultor en el que dio por finalizado su proceso de experimentación sobre la naturaleza espacial de la estatua. En este desenlace tuvo un papel fundamental la relación funcional que planteó, a la hora de retomar su trabajo después de su triunfo en la IV Bienal de São Paulo de 1957, entre la escultura y la arquitectura. La primera, entendida como organismo puramente espacial, debía de responder a las condiciones de su mundo circundante, el espacio arquitectónico. Su función: acondicionarlo estéticamente para satisfacer las necesidades espirituales del habitante. Siguiendo el canon estético que para la escultura acababa de anunciar en Brasil, la desocupación espacial (la liberación de la energía espacial de la estatua, el rompimiento de la neutralidad del espacio libre) no se trataba de embellecer superficialmente la arquitectura sino de activar su vacío interior. Oteiza, que siempre estuvo muy interesado por la arquitectura y que había colaborado con anterioridad en numerosas ocasiones con los mejores arquitectos del país, fue durante este año cuando profundizó de manera más sistemática (teórica y prácticamente) sobre la relación arte-arquitectura. De hecho, él mismo nombraba como el último trabajo de su línea de experimentación en escultura a su propuesta para el concurso del Monumento a José Batlle en Montevideo, que junto al arquitecto Roberto Puig acabaron a finales de año. En el proyecto se planteaba a escala urbana, y como ejemplo concreto, el modelo teórico de integración arquitectura + (arte=0) que había elaborado los meses anteriores, la integración vacía. En el texto explicativo que acompañaba al proyecto (un texto que desbordaba los límites de una memoria al uso) demandaba la necesidad de la toma de conciencia estética del espacio, como acto de libertad individual, y declaraba el fin del rol de espectador del hombre frente a la obra de arte, reclamando su participación activa en la misma. Para él, la noción del espacio estético no era una condición innata en el hombre, se descubría, se aprendía, evolucionaba y se olvidaba (una vez convertido en hábito). Frente a la ceguera de la sensibilidad espacial del hombre, proponía la educación de la percepción espacial, condicionar emocionalmente la reflexión espontánea ante el juego espacial de las formas en la naturaleza y el espectáculo natural de la ciudad. Aprender a leer el lenguaje emocional del espacio, a pensar visualmente. La obra de arte era así un catalizador espiritual del contorno del mundo, modificador de la vida espacial circundante que corregía hábitos visuales y condicionaba estímulos y reflejos. Desde una resonancia afectiva con la definición psicológica del término (como energía psíquica profunda que invita o incita a pasar a la acción), a diferencia del instinto, la pulsión (siendo la fuente de toda conducta espontánea) es susceptible de ser modificada por la experiencia, por la educación, por la cultura, por el deseo. Es desde esta aproximación en términos de energía desde la que se propone la noción pulsiones del espacio como fórmula (reversible) entre la energía espacial liberada en el proceso de desocupación definido por Oteiza y caracterizadora de la obra como vacío activo (en escultura, en arquitectura), y la energía psíquica profunda que invita o incita a la toma de posesión del espacio (la voluntad espacial absoluta con la que Oteiza definía su modelo de arte=0, cero como expresión formal). Si el hombre modifica su entorno al mismo tiempo que es condicionado por él, es indispensable una conciencia estética del espacio que le enseñe, de entre todas las posibilidades que este le ofrece, qué es lo que necesita (qué es lo que le falta), para tomar posesión de él, para un efectivo ser o existir en el espacio. Es desde esta caracterización como energía por lo que las pulsiones del espacio se sitúan entre el hombre y su entorno (construido) y permiten la transformación entre energía espacial y energía psíquica; entre su hábitat y sus hábitos. Por estas mismas fechas, Oteiza definía una casa como un conjunto articulado de vacíos activos, como una obra de plástica pura que no es arte sino en función del habitante. Es este habitante, educado en la toma de conciencia estética del espacio, el que participando activamente en la interpretación de los espacios previstos por el arquitecto, sintiendo y movido por las pulsiones del espacio, hará uso adecuado de la arquitectura; pasando de un arte como objeto a un arte como comportamiento, transformará su habitar en un arte, el arte de habitar. ABSTRACT This work focuses on the study of Jorge Oteiza’s investigations on the aesthetic functionality of space, especially on his artistic activity developed in 1958, a decisive year in the life of the sculptor, in which he gave end to his process of experimentation on the spatial nature of the statue. In this outcome it was fundamental the functional relationship that he propounded, at the time of returning to work after his triumph in the IV Bienal de São Paulo in 1957, between sculpture and architecture. The first, understood as a purely spatial organism, should respond to the conditions of its environment (umwelt), the architectonic space. Its function: set it up aesthetically to meet the spiritual needs of the inhabitant. Following the aesthetic canon that he had just announced in Brazil for sculpture, the spatial disoccupation (the liberation of the spatial energy of the statue, the breaking of the neutrality of the free space) the aim was not to superficially beautify architecture but to activate its inner void. Oteiza, who had always been very interested in architecture and who had previously collaborated on numerous occasions with the best architects in the country, was in this year when he deepened in a more systematic way (theoretically and practically) about the art-architecture relationship. In fact, he named as the last work of his line of experimentation in sculpture to his proposal for the competition of the Monument to José Batlle in Montevideo, which, developed together with the architect Roberto Puig, was ended at the end of the year. The project proposed on an urban scale, and as a concrete example, the theoretical model of integration architecture + (art = 0) which he had elaborated the previous months, the empty integration. In the explanatory text accompanying the project (a text that exceeded the normal extents of a competition statement) he demanded the need of the aesthetic awareness of space, as an act of individual freedom, and it declared the end of the role of man as passive spectator in front of the work of art, claiming his actively participation in it. For him, the notion of the aesthetic space was not an inborn condition in man; first it was discovered, then learned, evolved and finally forgotten (once converted into a habit). To counteract blindness of the spatial sensitivity of man, he proposed the education of spatial perception, to emotionally influence the spontaneous reflection in front of the spatial game of forms in nature and the natural spectacle of the city. Learn to read the emotional language of space, to think visually. The work of art was thus a spiritual catalyst of the world’s contour, a modifier of the surrounding spatial life that corrected visual habits and conditioned stimuli and reflexes. From an emotional resonance with the psychological definition of the term (such as deep psychic power that invites or urges action), as opposed to instinct, drive (being the source of all spontaneous behavior) is likely to be modified by experience, by education, by culture, by desire. It is from this approach in terms of energy from which the notion drives of space is proposed, as a (reversible) formula between the spatial energy released in the process of disoccupation defined by Oteiza and characterizing of the work as a charged void (in sculpture, in architecture), and the deep psychic energy that invites or encourages the taking possession of the space (the absolute spatial will with which Oteiza defined its model of Art = 0, zero as a formal expression). If man changes his environment at the same time that is conditioned by it, it is essential an aesthetic awareness of space that shows him, among all the possibilities that it offers, what he needs (what is what he lacks), in order to take possession of it, for an effective being or existing in space. It is this characterization as energy by what drives of space lie between man and his (built) environment and allow the transformation between spatial and psychological energy; between his habitat and his habits. Around this same time, Oteiza defined a House as an articulated set of charged voids, as a work of pure plastic that is not art but according to the inhabitant. It is this inhabitant, educated in aesthetic awareness of space, who actively participating in the interpretation of the spaces provided by the architect, feeling and moved by the drives of the space, will make proper use of the architecture; from an art as object to an art as behavior, he will transform his inhabitation into an art, the art of inhabitation.

Tumor burden and clonality in multiple intestinal neoplasia mouse/normal mouse aggregation chimeras

Aggregation chimeras were formed between C57BL/6 mice heterozygous for the Apcmin (Min) mutation and wild-type SWR mice, that differ in their Pla2g2a status, a modifier of Apcmin, and also in their resistance to intestinal polyp formation. Variation in the dolichos biflorus agglutinin-staining patterns of the intestines of these mouse strains was used to determine the chimeric composition of the intestine in individual mice and to examine the clonal composition of adenomas. Macroscopic adenoma numbers in chimeric mice were compared with the expected adenoma numbers based on the percentage of C57BL/6J-Apcmin/+ epithelium in individual mice. These results unexpectedly show that there was no apparent inhibitory effect of the SWR-derived (Pla2g2a wild-type) tissue on adenoma formation in the C57BL/6J-Apcmin/+ epithelium. This suggests that the main genetic modifiers of the Min phenotype act at a cellular or crypt-restricted level with no discernable systemic effect. All adenomas were seen to contain C57BL/6J-Apcmin/+-derived epithelium, confirming that the germ-line mutation of the mApc gene is necessary to initiate tumorigenesis in this model system, and that the mApc gene acts in a cell autonomous fashion.

Characterization of the CHD family of proteins

The murine gene CHD1 (MmCHD1) was previously isolated in a search for proteins that bound a DNA promoter element. The presence of chromo (chromatin organization modifier) domains and an SNF2-related helicase/ATPase domain led to speculation that this gene regulated chromatin structure or gene transcription. This study describes the cloning and characterization of three novel human genes related to MmCHD1. Examination of sequence databases produced several more related genes, most of which were not known to be similar to MmCHD1, yielding a total of 12 highly conserved CHD genes from organisms as diverse as yeast and mammals. The major region of sequence variation is in the C-terminal part of the protein, a region with DNA-binding activity in MmCHD1. Targeted deletion of ScCHD1, the sole Saccharomyces cerevesiae CHD gene, was performed with deletion strains being less sensitive than wild type to the cytotoxic effect of 6-azauracil. This finding suggested that enhanced transcriptional arrest at RNA polymerase II pause sites due to 6-azauracil-induced nucleotide pool depletion was reduced in the deletion strain and that ScCHD1 inhibited transcription. This observation, along with the known roles of other proteins with chromo or SNF2-related helicase/ATPase domains, suggests that alteration of gene expression by CHD genes might occur by modifications of chromatin structure, with altered access of the transcriptional apparatus to its chromosomal DNA template.

The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition

The high-molecular-weight serine proteinase inhibitors (serpins) are restricted, generally, to inhibiting proteinases of the serine mechanistic class. However, the viral serpin, cytokine response modifier A, and the human serpins, antichymotrypsin and squamous cell carcinoma antigen 1 (SCCA1), inhibit different members of the cysteine proteinase class. Although serpins employ a mobile reactive site loop (RSL) to bait and trap their target serine proteinases, the mechanism by which they inactivate cysteine proteinases is unknown. Our previous studies suggest that SCCA1 inhibits papain-like cysteine proteinases in a manner similar to that observed for serpin–serine proteinase interactions. However, we could not preclude the possibility of an inhibitory mechanism that did not require the serpin RSL. To test this possibility, we employed site-directed mutagenesis to alter the different residues within the RSL. Mutations to either the hinge or the variable region of the RSL abolished inhibitory activity. Moreover, RSL swaps between SCCA1 and the nearly identical serpin, SCCA2 (an inhibitor of chymotrypsin-like serine proteinases), reversed their target specificities. Thus, there were no unique motifs within the framework of SCCA1 that independently accounted for cysteine proteinase inhibitory activity. Collectively, these data suggested that the sequence and mobility of the RSL of SCCA1 are essential for cysteine proteinase inhibition and that serpins are likely to utilize a common RSL-dependent mechanism to inhibit both serine and cysteine proteinases.

A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus

Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with ≈50% of familial cases being heterozygous for mutations in the receptor tyrosine kinase RET. Even when identified, the penetrance of RET mutations is only 50–70%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with RET, lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe RET mutations (group I); and the six remaining families, five of which are RET-linked families with no sequence alterations and one RET-unlinked family (group II). Although the presence of RET mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.

Effects of ligand activation of peroxisome proliferator-activated receptor γ in human prostate cancer

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear hormone receptor that plays a key role in the differentiation of adipocytes. Activation of this receptor in liposarcomas and breast and colon cancer cells also induces cell growth inhibition and differentiation. In the present study, we show that PPARγ is expressed in human prostate adenocarcinomas and cell lines derived from these tumors. Activation of this receptor with specific ligands exerts an inhibitory effect on the growth of prostate cancer cell lines. Further, we show that prostate cancer and cell lines do not have intragenic mutations in the PPARγ gene, although 40% of the informative tumors have hemizygous deletions of this gene. Based on our preclinical data, we conducted a phase II clinical study in patients with advanced prostate cancer using troglitazone, a PPARγ ligand used for the treatment of type 2 diabetes. Forty-one men with histologically confirmed prostate cancer and no symptomatic metastatic disease were treated orally with troglitazone. An unexpectedly high incidence of prolonged stabilization of prostate-specific antigen was seen in patients treated with troglitazone. In addition, one patient had a dramatic decrease in serum prostate-specific antigen to nearly undetectable levels. These data suggest that PPARγ may serve as a biological modifier in human prostate cancer and its therapeutic potential in this disease should be further investigated.

Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase

γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, is synthesized by two glutamate decarboxylase isoforms, GAD65 and GAD67. The separate role of the two isoforms is unknown, but differences in saturation with cofactor and subcellular localization suggest that GAD65 may provide reserve pools of GABA for regulation of inhibitory neurotransmission. We have disrupted the gene encoding GAD65 and backcrossed the mutation into the C57BL/6 strain of mice. In contrast to GAD67−/− animals, which are born with developmental abnormalities and die shortly after birth, GAD65−/− mice appear normal at birth. Basal GABA levels and holo-GAD activity are normal, but the pyridoxal 5′ phosphate-inducible apo-enzyme reservoir is significantly decreased. GAD65−/− mice develop spontaneous seizures that result in increased mortality. Seizures can be precipitated by fear or mild stress. Seizure susceptibility is dramatically increased in GAD65−/− mice backcrossed into a second genetic background, the nonobese diabetic (NOD/LtJ) strain of mice enabling electroencephalogram analysis of the seizures. The generally higher basal brain GABA levels in this backcross are significantly decreased by the GAD65−/− mutation, suggesting that the relative contribution of GABA synthesized by GAD65 to total brain GABA levels is genetically determined. Seizure-associated c-fos-like immunoreactivity reveals the involvement of limbic regions of the brain. These data suggest that GABA synthesized by GAD65 is important in the dynamic regulation of neural network excitability, implicate at least one modifier locus in the NOD/LtJ strain, and present GAD65−/− animals as a model of epilepsy involving GABA-ergic pathways.