Identification of potential small molecule binding pockets on Rho family GTPases

Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

Prime Property Institutions for a Subprime Era: Exploring Innovative Models of Residential Development and Finance

This paper breaks new ground toward contractual and institutional innovation in models of homeownership, equity building, and mortgage enforcement. Inspired by recent developments in the affordable housing sector and in other types of public financing schemes, this paper suggests extending institutional and financial strategies such as timeand place-based division of property rights, conditional subsidies, and credit mediation to alleviate the systemic risks of mortgage foreclosure. Alongside a for-profit shared equity scheme that would be led by local governments, we also outline a private market shared equity model, one of bootstrapping home buying with purchase options.

Productivity growth and the exchange rate regime: The role of financial development

This paper offers empirical evidence that a country's choice of exchange rate regime can have a signifficant impact on its medium-term rate of productivity growth. Moreover, the impact depends critically on the country's level of financial development, its degree of market regulation, and its distance from the global technology frontier. We illustrate how each of these channels may operate in a simple stylized growth model in which real exchange rate uncertainty exacerbates the negative investment e¤ects of domestic credit market constraints. The empirical analysis is based on an 83 country data set spanning the years 1960-2000. Our approach delivers results that are in striking contrast to the vast existing empirical exchange rate literature, which largely finds the effects of exchange rate volatility on real activity to be relatively small and insignificant.

The size and distribution of donations: Effects of numbers of potential recipients

Whereas much literature exists on choice overload, little is known about effects of numbers of alternatives in donation decisions. How do these affect both the size and distribution of donations? We hypothesize that donations are affected by the reputation of recipients and increase with their number, albeit at a decreasing rate. Allocations to recipients reflect different concepts of fairness equity and equality. Both may be employed but, since they differ in cognitive and emotional costs, numbers of recipients are important. Using a cognitive (emotional) argument, distributions become more uniform (skewed) as numbers increase. In a survey, respondents indicated how they would donate lottery winnings of 50 Euros. Results indicated that more was donated to NGO s that respondents knew better. Second, total donations increased with the number of recipients albeit at a decreasing rate. Third, distributions of donations became more skewed as numbers increased. We comment on theoretical and practical implications.

Aplicaciones educativas de la teoría vygotskiana. El programa 'Key to learning' = Applications of vigotsky's theory to education. The 'Key to learning' proggram

En ciencias de la educación, las últimas décadas han estado marcadas por un interés en las ideas de Lev S. Vygotski. De hecho, a partir de esas ideas se han propuesto varias aplicaciones educativas. Una de ellas es el “Key to learning”. El artículo propone una visión general de este programa educativo desarrollado a partir de algunos trabajos e ideas de autores rusos contemporáneos. Primero, desarrollamos algunas ideas en torno a la noción de zona de desarrollo próximo (ZpD). Después, sugerimos la teoría de las habilidades de aprendizaje. En este sentido, el objetivo principal de “Key to learning” es mejorar las habilidades de aprendizaje cognitivas, comunicativas y directivas de niños de entre 3 a 7 años de edad. Para este propósito son creadas 12 unidades curriculares que componen el programa. Para concluir se enfatiza la creación de zonas de desarrollo próximo estructuradas como parte de un sistema de enseñanza y aprendizaje que vincula la actividad, la asistencia y la agencia

Evaluation of potential breath biomarkers for active smoking: assessment of smoking habits

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography–mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2,5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short- and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure

A survey of potential vectors of apricot chlorotic leaf roll

A comparative survey was done in leafhopper populations captured in apricot orchards in two areas of Valencia, one with considerable natural spread of apricot chlorotic leaf roll (ACLR), and the other where such natural spread is virtually nonexistent. An identification of the leafhopper species found in the first and in the second area suggest that Neoaliturus haematoceps and/or Neoaliturus fertestratus are the potential vectors of ACLR, at least under the conditions of Valencia province. Psammotettix striatus and Austroagallia sinuata are potential secondary vextors of ACLR.

Evaluation of the Development of Metacognitive Knowledge Supported by the KnowCat System

The aim of this study was to examine the development of the metacognitive knowledge of a group of higher education students who participated actively in an experiment based on a Computer Supported Collaborative Learning environment called KnowCat. Eighteen university students participated in a 12-month learning project during which the KnowCat learning environment was used to support scaffolding process among equals during problem-solving tasks. After using KnowCat, the students were interviewed over their work in this shared workspace. Qualitative analysis revealed that the educational application of KnowCat can favour and improve the development of metacognitive knowledge.

Evaluation of potential breath biomarkers for active smoking: assessment of smoking habits

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography–mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2,5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short- and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure