Límites de ductilidad y de servicio al cálculo en carga última de estructuras de hormigón armado y de fábrica

En este trabajo se aborda una cuestión central en el diseño en carga última de estructuras de hormigón armado y de fábrica: la posibilidad efectiva de que las deformaciones plásticas necesarias para verificar un estado de rotura puedan ser alcanzadas por las regiones de la estructura que deban desarrollar su capacidad última para verificar tal estado. Así, se parte de las decisiones de diseño que mediante mera estática aseguran un equilibrio de la estructura para las cargas últimas que deba resistir, pero determinando directamente el valor de las deformaciones necesarias para llegar a tal estado. Por tanto, no se acude a los teoremas de rotura sin más, sino que se formula el problema desde un punto de vista elastoplástico. Es decir, no se obvia el recorrido que la estructura deba realizar en un proceso de carga incremental monótono, de modo que las regiones no plastificadas contribuyen a coaccionar las libres deformaciones plásticas que, en la teoría de rotura, se suponen. En términos de trabajo y energía, se introduce en el balance del trabajo de las fuerzas externas y en el de la energía de deformación, aquella parte del sistema que no ha plastificado. Establecido así el balance energético como potencial del sistema es cuando la condición de estacionariedad del mismo hace determinados los campos de desplazamientos y, por tanto, el de las deformaciones plásticas también. En definitiva, se trata de un modo de verificar si la ductilidad de los diseños previstos es suficiente, y en qué medida, para verificar el estado de rotura previsto, para unas determinadas cargas impuestas. Dentro del desarrollo teórico del problema, se encuentran ciertas precisiones importantes. Entre ellas, la verificación de que el estado de rotura a que se llega de manera determinada mediante el balance energético elasto-plástico satisface las condiciones de la solución de rotura que los teoremas de carga última predicen, asegurando, por tanto, que la solución determinada -unicidad del problema elásticocoincide con el teorema de unicidad de la carga de rotura, acotando además cuál es el sistema de equilibrio y cuál es la deformada de colapso, aspectos que los teoremas de rotura no pueden asegurar, sino sólo el valor de la carga última a verificar. Otra precisión se basa en la particularidad de los casos en que el sistema presenta una superficie de rotura plana, haciendo infinitas las posibilidades de equilibrio para una misma deformada de colapso determinada, lo que está en la base de, aparentemente, poder plastificar a antojo en vigas y arcos. Desde el planteamiento anterior, se encuentra entonces que existe una condición inherente a cualquier sistema, definidas unas leyes constitutivas internas, que permite al mismo llegar al inicio del estado de rotura sin demandar deformación plástica alguna, produciéndose la plastificación simultánea de todas las regiones que hayan llegado a su solicitación de rotura. En cierto modo, se daría un colapso de apariencia frágil. En tal caso, el sistema conserva plenamente hasta el final su capacidad dúctil y tal estado actúa como representante canónico de cualquier otra solución de equilibrio que con idéntico criterio de diseño interno se prevea para tal estructura. En la medida que el diseño se acerque o aleje de la solución canónica, la demanda de ductilidad del sistema para verificar la carga última será menor o mayor. Las soluciones que se aparten en exceso de la solución canónica, no verificarán el estado de rotura previsto por falta de ductilidad: la demanda de deformación plástica de alguna región plastificada estará más allá de la capacidad de la misma, revelándose una carga de rotura por falta de ductilidad menor que la que se preveía por mero equilibrio. Para la determinación de las deformaciones plásticas de las rótulas, se ha tomado un modelo formulado mediante el Método de los Elementos de Contorno, que proporciona un campo continuo de desplazamientos -y, por ende, de deformaciones y de tensiones- incluso en presencia de fisuras en el contorno. Importante cuestión es que se formula la diferencia, nada desdeñable, de la capacidad de rotación plástica de las secciones de hormigón armado en presencia de cortante y en su ausencia. Para las rótulas de fábrica, la diferencia se establece para las condiciones de la excentricidad -asociadas al valor relativo de la compresión-, donde las diferencias entres las regiones plastificadas con esfuerzo normal relativo alto o bajo son reseñables. Por otro lado, si bien de manera un tanto secundaria, las condiciones de servicio también imponen un límite al diseño previo en carga última deseado. La plastificación lleva asociadas deformaciones considerables, sean locales como globales. Tal cosa impone que, en estado de servicio, si la plastificación de alguna región lleva asociadas fisuraciones excesivas para el ambiente del entorno, la solución sea inviable por ello. Asimismo, las deformaciones de las estructuras suponen un límite severo a las posibilidades de su diseño. Especialmente en edificación, las deformaciones activas son un factor crítico a la hora de decidirse por una u otra solución. Por tanto, al límite que se impone por razón de ductilidad, se debe añadir el que se imponga por razón de las condiciones de servicio. Del modo anterior, considerando las condiciones de ductilidad y de servicio en cada caso, se puede tasar cada decisión de diseño con la previsión de cuáles serán las consecuencias en su estado de carga última y de servicio. Es decir, conocidos los límites, podemos acotar cuáles son los diseños a priori que podrán satisfacer seguro las condiciones de ductilidad y de servicio previstas, y en qué medida. Y, en caso de no poderse satisfacer, qué correcciones debieran realizarse sobre el diseño previo para poderlas cumplir. Por último, de las consecuencias que se extraen de lo estudiado, se proponen ciertas líneas de estudio y de experimentación para poder llegar a completar o expandir de manera práctica los resultados obtenidos. ABSTRACT This work deals with a main issue for the ultimate load design in reinforced concrete and masonry structures: the actual possibility that needed yield strains to reach a ultimate state could be reached by yielded regions on the structure that should develop their ultimate capacity to fulfill such a state. Thus, some statically determined design decisions are posed as a start for prescribed ultimate loads to be counteracted, but finding out the determined value of the strains needed to reach the ultimate load state. Therefore, ultimate load theorems are not taken as they are, but a full elasto-plastic formulation point of view is used. As a result, the path the structure must develop in a monotonus increasing loading procedure is not neglected, leading to the fact that non yielded regions will restrict the supposed totally free yield strains under a pure ultimate load theory. In work and energy terms, in the overall account of external forces work and internal strain energy, those domains in the body not reaching their ultimate state are considered. Once thus established the energy balance of the system as its potential, by imposing on it the stationary condition, both displacements and yield strains appear as determined values. Consequently, what proposed is a means for verifying whether the ductility of prescribed designs is enough and the extent to which they are so, for known imposed loads. On the way for the theoretical development of the proposal, some important aspects have been found. Among these, the verification that the conditions for the ultimate state reached under the elastoplastic energy balance fulfills the conditions prescribed for the ultimate load state predicted through the ultimate load theorems, assuring, therefore, that the determinate solution -unicity of the elastic problemcoincides with the unicity ultimate load theorem, determining as well which equilibrium system and which collapse shape are linked to it, being these two last aspects unaffordable by the ultimate load theorems, that make sure only which is the value of the ultimate load leading to collapse. Another aspect is based on the particular case in which the yield surface of the system is flat -i.e. expressed under a linear expression-, turning out infinite the equilibrium possibilities for one determined collapse shape, which is the basis of, apparently, deciding at own free will the yield distribution in beams and arches. From the foresaid approach, is then found that there is an inherent condition in any system, once defined internal constitutive laws, which allows it arrive at the beginning of the ultimate state or collapse without any yield strain demand, reaching the collapse simultaneously for all regions that have come to their ultimate strength. In a certain way, it would appear to be a fragile collapse. In such a case case, the system fully keeps until the end its ductility, and such a state acts as a canonical representative of any other statically determined solution having the same internal design criteria that could be posed for the that same structure. The extent to which a design is closer to or farther from the canonical solution, the ductility demand of the system to verify the ultimate load will be higher or lower. The solutions being far in excess from the canonical solution, will not verify the ultimate state due to lack of ductility: the demand for yield strains of any yielded region will be beyond its capacity, and a shortcoming ultimate load by lack of ductility will appear, lower than the expected by mere equilibrium. For determining the yield strains of plastic hinges, a Boundary Element Method based model has been used, leading to a continuous displacement field -therefore, for strains and stresses as well- even if cracks on the boundary are present. An important aspect is that a remarkable difference is found in the rotation capacity between plastic hinges in reinforced concrete with or without shear. For masonry hinges, such difference appears when dealing with the eccentricity of axial forces -related to their relative value of compression- on the section, where differences between yield regions under high or low relative compressions are remarkable. On the other hand, although in a certain secondary manner, serviceability conditions impose limits to the previous ultimate load stated wanted too. Yield means always big strains and deformations, locally and globally. Such a thing imposes, for serviceability states, that if a yielded region is associated with too large cracking for the environmental conditions, the predicted design will be unsuitable due to this. Furthermore, displacements must be restricted under certain severe limits that restrain the possibilities for a free design. Especially in building structures, active displacements are a critical factor when chosing one or another solution. Then, to the limits due to ductility reasons, other limits dealing with serviceability conditions shoud be added. In the foresaid way, both considering ductility and serviceability conditions in every case, the results for ultimate load and serviceability to which every design decision will lead can be bounded. This means that, once the limits are known, it is possible to bound which a priori designs will fulfill for sure the prescribed ductility and serviceability conditions, and the extent to wich they will be fulfilled, And, in case they were not, which corrections must be performed in the previous design so that it will. Finally, from the consequences derived through what studied, several study and experimental fields are proposed, in order to achieve a completeness and practical expansion of the obtained results.

Nueva York : la revitalización del espacio público a partir de 1950

A partir de la segunda mitad del siglo XX, Nueva York experimenta una apertura al público de espacios nuevos, transformados u olvidados mediante la adaptación de mecanismos, ya sean formales o informales, de caracter permanente o temporal, para la incorporación de uso público en un contexto urbano limitado y congestionado. Estos recursos espaciales son mediadores entre el espacio público y el privado, y son el resultado físico de la negociación entre la legislación urbana, los interes privados de los promotores y las demandas de los ciudadanos. La tesis estudia una selección de obras, entre los años 1950 y 2015, que incorporan notables oportunidades para el uso colectivo, pero que han propiciado la creación de dos tipos de espacios: los “espaciosoasis”, aquellos que potencian una verdadera interacción social entre los usuarios; y los “espacios-vitrina”, para ver y no tocar, en los que el usuario participa indirectamente y, sin promover interacción alguna, atraen al público foráneo y rechazan al local. La diversidad de usos, la sensibilidad social, la supervisión cercana y la facilidad de mantenimiento de la pequeña escala posibilitan que los “espacios-oasis” sean claves a la hora de mantener el fragil y vulnerable equilibrio de la vida urbana. La tesis profundiza en la contextualización de las obras en relación con el apoyo de las políticas públicas y contexto cíclico de los constantes altibajos económicos. El papel del alcalde neoyorkino es clave a la hora decidir el mayor o mejor respaldo de la administración local a las obras que tienen una incidencia en el ámbito de lo público, por lo que la tesis estructura las obras en relación a las transiciones entre las alcaldías más importantes. La presión del mercado inmobiliario, los intereses privados y políticos, la excesiva comercialización y programación de estos espacios dificultan el lento y opaco proceso de la incorporación de uso público en la ciudad y compremeten el verdadero carácter cívico del espacio abierto urbano. La investigación estudia estos factores a través de una reflexión sobre el verdadero sentido de la revitalización de lo público, entendida en relación con las interacciones que fomenta y que se producen más allá de las intenciones del proyecto arquitectónico. El objetivo y el alcance de esta investigación permite reflexionar, discutir y explorar el uso y la participación cívica en el entorno construido, para de esta forma poder entender la evolución de las condiciones sociales, económicas, arquitectónicas y urbanas del espacio público. ABSTRACT During the second half of the twentieth century, New York experienced a launch of new spaces, changed or forgotten through the adoption of mechanisms, whether formal or informal, permanent or temporary, for the incorporation of spaces for public use in a limited and congested urban context. These assets are mediators between the public and private space, and are the physical result of negotiations between the urban legislation, the private interests of the developer and the demands of citizens. The dissertation examines a selection of projects, between 1950 and 2015, that incorporate remarkable spatial opportunities for collective use, which led to the creation of two types of spaces: “oasis-space”, those that enhance social interaction between patrons; and “vitrinespace”, space to be seen but not touched, where the user participates indirectly and does not promote any interaction, attracting an outside public and rejecting the local. Diversity of uses, social sensitivity, close supervision and ease of maintenance that enable small-scale “oasis spaces” are key when it comes to keeping the fragile and vulnerable balance of urban life. The investigation explains the contextualization of the projects in relation with the support of public politics and the cyclical context of constantly changing economics. The role of the New York mayor is key at the time of deciding the level of administrative support for the projects that occur at a point of overlap between the public and the private, which is why the thesis analyzes the projects in relationship to the transitions between the cities most influential mayors. Pressure from the housing market, private and political interests, excessive commercialization and programming of these spaces impede the slow and opaque process of incorporating them for public use in the city and compromise the true civic character open urban space. The research explores these factors by reflecting on the true meaning of the revitalization of the public, understood in relation to interactions it encourages and that occur outside of the intentions of the architectural project. The objective and scope of this study allows for reflecting on, discussing and exploring civic participation and use of the built environment, as a way to understand the evolution of social, economic, architectural and urban conditions of public space.

O CONSUMISMO E A DIMENSÃO ESPIRITUAL DAS MARCAS: UMA ANÁLISE CRÍTICA

Esta tese objetiva comprovar que, na sociedade de consumo, indivíduos consumistas transcendem sua relação funcional com as mercadorias, buscando nas marcas de prestígio uma dimensão espiritual, que substitui ou complementa as experiências religiosas tradicionais, e que se revela fetichizada. O consumismo é superlativo de compras, posses e uso, uma dependência de bens não essenciais (supérfluos) para atender aos desejos sem fim. É impossível satisfazer a desejos sem fim: daí a expressão meta transcendental do consumo, posicionada além do alcance e da capacidade de atingi-la. A dimensão transcendente do consumo, por meio do simbolismo das mercadorias potencializado pelas marcas de prestígio, propicia encantamento e sentido ao indivíduo, e se presta a preencher o espaço outrora ocupado pela família, Igreja e comunidade. O sujeito busca, na mercadoria fetichizada pela marca, satisfazer seu desejo mimético, e/ou compensar valores frágeis ou ausentes, o que é reforçado pela propaganda. O sentido último da vida dos indivíduos materialistas produz efeitos imediatos que são positivos para eles e para a economia, mas potencialmente negativos mais à frente para o planeta, para sociedade e para os indivíduos.

O CONSUMISMO E A DIMENSÃO ESPIRITUAL DAS MARCAS: UMA ANÁLISE CRÍTICA

Esta tese objetiva comprovar que, na sociedade de consumo, indivíduos consumistas transcendem sua relação funcional com as mercadorias, buscando nas marcas de prestígio uma dimensão espiritual, que substitui ou complementa as experiências religiosas tradicionais, e que se revela fetichizada. O consumismo é superlativo de compras, posses e uso, uma dependência de bens não essenciais (supérfluos) para atender aos desejos sem fim. É impossível satisfazer a desejos sem fim: daí a expressão meta transcendental do consumo, posicionada além do alcance e da capacidade de atingi-la. A dimensão transcendente do consumo, por meio do simbolismo das mercadorias potencializado pelas marcas de prestígio, propicia encantamento e sentido ao indivíduo, e se presta a preencher o espaço outrora ocupado pela família, Igreja e comunidade. O sujeito busca, na mercadoria fetichizada pela marca, satisfazer seu desejo mimético, e/ou compensar valores frágeis ou ausentes, o que é reforçado pela propaganda. O sentido último da vida dos indivíduos materialistas produz efeitos imediatos que são positivos para eles e para a economia, mas potencialmente negativos mais à frente para o planeta, para sociedade e para os indivíduos.

CONHECIMENTOS E PREVENÇÃO DE DST/AIDS EM ADOLESCENTES

A Psicologia da Saúde vem se desdobrando para atender a demanda da saúde pública, principalmente sobre prevenção de doenças e promoção da saúde. No que se refere a epidemia da AIDS e outras doenças sexualmente transmissíveis, o adolescente tem sido o público mais vulnerável. A adolescência é considerada uma fase perturbada e perturbadora. Nesse período da vida o adolescente está mais sujeito à contaminação das DST/AIDS em razão da instabilidade emocional e sua postura frente a valores e padrões de conduta. Este estudo tem por objetivo descrever conhecimentos e comportamentos de proteção e risco de práticas sexuais de adolescentes; descrever dados sócio-econômicos e demográficos desses adolescentes, descrever o conhecimento dos adolescentes em relação as DST/AIDS e descrever os comportamentos de proteção e riscos a respeito das DST/AIDS. A população deste estudo foi constituída por 95 adolescentes de ambos os gêneros, com um predomínio do gênero masculino, faixa etária entre 14 e 21 anos e com renda familiar média de 4 (quatro) salários mínimos. Trata-se de pesquisa descritiva, para o qual utilizou-se um questionário de autopreenchimento composto por questões norteadas ao tema. A coleta de dados ocorreu em sala de aula no período noturno, de uma escola estadual do município de Guarulhos. Após o término do preenchimento do questionário, os adolescentes assistiram uma palestra de prevenção e orientação sobre DST/AIDS, onde elucidaram dúvidas. Os resultados demonstram 67,4% dos adolescentes, tanto o gênero feminino quanto o gênero masculino, tem dificuldades de definir o conceito de sexualidade e 84,2% sabem corretamente a definição de doenças sexualmente transmissíveis. A maioria dos adolescentes (67,4%) respondeu conhecer algum tipo de doença sexualmente transmissível, destacando-se aqui a AIDS e a gonorréia. O gênero masculino teve início da vida sexual aos 10 anos e o gênero feminino aos 13 anos, representando 53,7% com vida sexual ativa. Neste estudo 58,9% informam saber quais são os comportamentos de proteção, porém entre estes, apenas 55,8% utilizam o preservativo masculino (camisinha). Não há diferenças significativas quanto à modalidade de relacionamento e o uso constante do preservativo masculino. Verificou-se que 63,1% dos adolescentes obtém informações e conhecimentos sobre as DST/AIDS através dos profissionais da educação e da saúde. Portanto, a sala de aula passa a ser um fator de proteção. Esse estudo confirma que parte dos adolescentes tem conhecimento e informações sobre conceitos relativos as DST/AIDS, porém quanto às práticas para um comportamento de proteção frente às mesmas apresentam conhecimentos frágeis, gerando assim comportamentos de risco. Estas situações comprometem a tomada de comportamentos de proteção. Portanto, um programa contínuo da área da saúde e da educação dentro da escola que desenvolva atividades interativas a fim de transformar o comportamento do adolescente sobre informações e conhecimentos em consciência de comportamentos de proteção efetivas poderá melhorar essa relação entre ter o conhecimento e utilizá-lo na prática.(AU)

CONHECIMENTOS E PREVENÇÃO DE DST/AIDS EM ADOLESCENTES

A Psicologia da Saúde vem se desdobrando para atender a demanda da saúde pública, principalmente sobre prevenção de doenças e promoção da saúde. No que se refere a epidemia da AIDS e outras doenças sexualmente transmissíveis, o adolescente tem sido o público mais vulnerável. A adolescência é considerada uma fase perturbada e perturbadora. Nesse período da vida o adolescente está mais sujeito à contaminação das DST/AIDS em razão da instabilidade emocional e sua postura frente a valores e padrões de conduta. Este estudo tem por objetivo descrever conhecimentos e comportamentos de proteção e risco de práticas sexuais de adolescentes; descrever dados sócio-econômicos e demográficos desses adolescentes, descrever o conhecimento dos adolescentes em relação as DST/AIDS e descrever os comportamentos de proteção e riscos a respeito das DST/AIDS. A população deste estudo foi constituída por 95 adolescentes de ambos os gêneros, com um predomínio do gênero masculino, faixa etária entre 14 e 21 anos e com renda familiar média de 4 (quatro) salários mínimos. Trata-se de pesquisa descritiva, para o qual utilizou-se um questionário de autopreenchimento composto por questões norteadas ao tema. A coleta de dados ocorreu em sala de aula no período noturno, de uma escola estadual do município de Guarulhos. Após o término do preenchimento do questionário, os adolescentes assistiram uma palestra de prevenção e orientação sobre DST/AIDS, onde elucidaram dúvidas. Os resultados demonstram 67,4% dos adolescentes, tanto o gênero feminino quanto o gênero masculino, tem dificuldades de definir o conceito de sexualidade e 84,2% sabem corretamente a definição de doenças sexualmente transmissíveis. A maioria dos adolescentes (67,4%) respondeu conhecer algum tipo de doença sexualmente transmissível, destacando-se aqui a AIDS e a gonorréia. O gênero masculino teve início da vida sexual aos 10 anos e o gênero feminino aos 13 anos, representando 53,7% com vida sexual ativa. Neste estudo 58,9% informam saber quais são os comportamentos de proteção, porém entre estes, apenas 55,8% utilizam o preservativo masculino (camisinha). Não há diferenças significativas quanto à modalidade de relacionamento e o uso constante do preservativo masculino. Verificou-se que 63,1% dos adolescentes obtém informações e conhecimentos sobre as DST/AIDS através dos profissionais da educação e da saúde. Portanto, a sala de aula passa a ser um fator de proteção. Esse estudo confirma que parte dos adolescentes tem conhecimento e informações sobre conceitos relativos as DST/AIDS, porém quanto às práticas para um comportamento de proteção frente às mesmas apresentam conhecimentos frágeis, gerando assim comportamentos de risco. Estas situações comprometem a tomada de comportamentos de proteção. Portanto, um programa contínuo da área da saúde e da educação dentro da escola que desenvolva atividades interativas a fim de transformar o comportamento do adolescente sobre informações e conhecimentos em consciência de comportamentos de proteção efetivas poderá melhorar essa relação entre ter o conhecimento e utilizá-lo na prática.(AU)

In situ atomic force microscopy study of Alzheimer’s β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation

We have applied in situ atomic force microscopy to directly observe the aggregation of Alzheimer’s β-amyloid peptide (Aβ) in contact with two model solid surfaces: hydrophilic mica and hydrophobic graphite. The time course of aggregation was followed by continuous imaging of surfaces remaining in contact with 10–500 μM solutions of Aβ in PBS (pH 7.4). Visualization of fragile nanoscale aggregates of Aβ was made possible by the application of a tapping mode of imaging, which minimizes the lateral forces between the probe tip and the sample. The size and the shape of Aβ aggregates, as well as the kinetics of their formation, exhibited pronounced dependence on the physicochemical nature of the surface. On hydrophilic mica, Aβ formed particulate, pseudomicellar aggregates, which at higher Aβ concentration had the tendency to form linear assemblies, reminiscent of protofibrillar species described recently in the literature. In contrast, on hydrophobic graphite Aβ formed uniform, elongated sheets. The dimensions of those sheets were consistent with the dimensions of β-sheets with extended peptide chains perpendicular to the long axis of the aggregate. The sheets of Aβ were oriented along three directions at 120° to each other, resembling the crystallographic symmetry of a graphite surface. Such substrate-templated self-assembly may be the distinguishing feature of β-sheets in comparison with α-helices. These studies show that in situ atomic force microscopy enables direct assessment of amyloid aggregation in physiological fluids and suggest that Aβ fibril formation may be driven by interactions at the interface of aqueous solutions and hydrophobic substrates, as occurs in membranes and lipoprotein particles in vivo.

Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: Founder effect and premutations

Friedreich’s ataxia, the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for ≈17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through “premutation” intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.

Regeneration of broken tip links and restoration of mechanical transduction in hair cells

A hair cell’s tip links are thought to gate mechanoelectrical transduction channels. The susceptibility of tip links to acoustic trauma raises questions as to whether these fragile structures can be regenerated. We broke tip links with the calcium chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid and found that they can regenerate, albeit imperfectly, over several hours. The time course of tip-link regeneration suggests that this process may underlie recovery from temporary threshold shifts induced by noise exposure. Cycloheximide does not block tip-link regeneration, indicating that new protein synthesis is not required. The calcium ionophore ionomycin prevents regeneration, suggesting regeneration normally may be stimulated by the reduction in stereociliary Ca2+ when gating springs rupture and transduction channels close. Supporting the equivalence of tip links with gating springs, mechanoelectrical transduction returns over the same time period as tip links; strikingly, adaptation is substantially reduced, even 24 hr after breaking tip links.

Replacement of Fhit in cancer cells suppresses tumorigenicity

The candidate tumor suppressor gene, FHIT, encompasses the common human chromosomal fragile site at 3p14.2, the hereditary renal cancer translocation breakpoint, and cancer cell homozygous deletions. Fhit hydrolyzes dinucleotide 5′,5‴-P1,P3-triphosphate in vitro and mutation of a central histidine abolishes hydrolase activity. To study Fhit function, wild-type and mutant FHIT genes were transfected into cancer cell lines that lacked endogenous Fhit. No consistent effect of exogenous Fhit on growth in culture was observed, but Fhit and hydrolase “dead” Fhit mutant proteins suppressed tumorigenicity in nude mice, indicating that 5′,5‴-P1,P3-triphosphate hydrolysis is not required for tumor suppression.

FHIT gene therapy prevents tumor development in Fhit-deficient mice

The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral or adenoassociated viral vectors expressing the human FHIT gene, in heterozygous Fhit+/− knockout mice, that are prone to tumor development after carcinogen exposure. We therefore suggest that FHIT gene therapy could be a novel clinical approach not only in treatment of early stages of cancer, but also in prevention of human cancer.

Characterization of complex mineral assemblages: Implications for contaminant transport and environmental remediation

Surface reactive phases of soils and aquifers, comprised of phyllosilicate and metal oxohydroxide minerals along with humic substances, play a critical role in the regulation of contaminant fate and transport. Much of our knowledge concerning contaminant-mineral interactions at the molecular level, however, is derived from extensive experimentation on model mineral systems. Although these investigations have provided a foundation for understanding reactive surface functional groups on individual mineral phases, the information cannot be readily extrapolated to complex mineral assemblages in natural systems. Recent studies have elucidated the role of less abundant mineral and organic substrates as important surface chemical modifiers and have demonstrated complex coupling of reactivity between permanent-charge phyllosilicates and variable-charge Fe-oxohydroxide phases. Surface chemical modifiers were observed to control colloid generation and transport processes in surface and subsurface environments as well as the transport of solutes and ionic tracers. The surface charging mechanisms operative in the complex mineral assemblages cannot be predicted based on bulk mineralogy or by considering surface reactivity of less abundant mineral phases based on results from model systems. The fragile nature of mineral assemblages isolated from natural systems requires novel techniques and experimental approaches for investigating their surface chemistry and reactivity free of artifacts. A complete understanding of the surface chemistry of complex mineral assemblages is prerequisite to accurately assessing environmental and human health risks of contaminants or in designing environmentally sound, cost-effective chemical and biological remediation strategies.

The old problems of glass and the glass transition, and the many new twists.

In this paper I review the ways in which the glassy state is obtained both in nature and in materials science and highlight a "new twist"--the recent recognition of polymorphism within the glassy state. The formation of glass by continuous cooling (viscous slowdown) is then examined, the strong/fragile liquids classification is reviewed, and a new twist-the possibility that the slowdown is a result of an avoided critical point-is noted. The three canonical characteristics of relaxing liquids are correlated through the fragility. As a further new twist, the conversion of strong liquids to fragile liquids by pressure-induced coordination number increases is demonstrated. It is then shown that, for comparable systems, it is possible to have the same conversion accomplished via a first-order transition within the liquid state during quenching. This occurs in the systems in which "polyamorphism" (polymorphism in the glassy state) is observed, and the whole phenomenology is accounted for by Poole's bond-modified van der Waals model. The sudden loss of some liquid degrees of freedom through such weak first-order transitions is then related to the polyamorphic transition between native and denatured hydrated proteins, since the latter are also glass-forming systems--water-plasticized, hydrogen bond-cross-linked chain polymers (and single molecule glass formers). The circle is closed with a final new twist by noting that a short time scale phenomenon much studied by protein physicists-namely, the onset of a sharp change in d/dT ( is the Debye-Waller factor)--is general for glass-forming liquids, including computer-simulated strong and fragile ionic liquids, and is closely correlated with the experimental glass transition temperature. The latter thus originates in strong anharmonicity in certain components of the vibrational density of states, which permits the system to access the multiple minima of its configuration space. The connection between the anharmonicity in these modes, vibrational localization, the Kauzmann temperature, and the fragility of the liquid is proposed as the key problem in glass science.

Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension.

Gene targeting allows precise, predetermined changes to be made in a chosen gene in the mouse genome. To date, targeting has been used most often for generation of animals completely lacking the product of a gene of interest. The resulting "knockout" mice have confirmed some hypotheses, have upset others, but have rarely been uninformative. Models of several human genetic diseases have been produced by targeting--including Gaucher disease, cystic fibrosis, and the fragile X syndrome. These diseases are primarily determined by defects in single genes, and their modes of inheritance are well understood. When the disease under study has a complex etiology with multiple genetic and environmental components, the generation of animal models becomes more difficult but no less valuable. The problems associated with dissecting out the individual genetic factors also increases substantially and the distinction between causation and correlation is often difficult. To prove causation in a complex system requires rigorous adherence to the principle that the experiments must allow detection of the effects of changing only a single variable at one time. Gene targeting experiments, when properly designed, can test the effects of a precise genetic change completely free from the effects of differences in any other genes (linked or unlinked to the test gene). They therefore allow proofs of causation.

An n-allele model for progressive amplification in the FMR1 locus.

An n-allele model is developed for the FMR1 locus, which causes the fragile X syndrome, where n is the number of triplet repeats in the first exon. Frequencies in the general population and in index families are used to generate an n to n + delta transition matrix that predicts specific risks in satisfactory agreement with observation. However, until sequencing distinguishes between stable and unstable alleles with the same value of n, it is premature to infer whether allelic frequencies at the FMR1 locus are at equilibrium or, as some have suggested, are evolving toward higher frequencies of the pathogenic allele.