A new fork for clinical application: Targeting forkhead transcription factors in cancer therapy

RAS-ERK-MAPK (Mitogen-activated protein kinase) pathway plays an essential role in proliferation, differentiation, and tumor progression. In this study, we showed that ERK downregulated FOXO3a through directly interacting with and phosphorylating FOXO3a at Serine 294, Serine 344, and Serine 425. ERK-phosphorylated FOXO3a was degraded by MDM2-mediated ubiquitin-proteosome pathway. FOXO3a phosphorylation and degradation consequently promoted cell proliferation and tumorigenesis. However, the non-phosphorylated FOXO3a mutant, which was resistant to the interaction and degradation by MDM2, resulted in inhibition of tumor formation. Forkhead O transcription factors (FOXOs) are important in the regulation of cellular functions including cell cycle arrest and cell death. Perturbation of FOXOs function leads to deregulated cell proliferation and cancer. Inactivation of FOXO proteins by activation of cell survival pathways, such as PI3K/AKT/IKK, is associated with tumorigenesis. Our study will further highlight FOXOs as new therapeutic targets in a broad spectrum of cancers. ^ Chemotherapeutic drug resistance is the most concerned problem in cancer therapy as resistance ultimately leads to treatment failure of cancer patients. In another study, we showed that blocking ERK activity with AZD6244, an established MEK1/2 inhibitor currently under human cancer clinical trials, enhances FOXO3a expression in various human cancer cell lines in vitro, and also in human colon cancer cell xenografts in vivo. Knocking down FOXO3a and its downstream gene Bim impaired AZD6244-induced growth suppression, whereas restoring activation of FOXO3a sensitized human cancer cell to AZD6244-induced growth arrest and apoptosis. More importantly, AZD6244-resistant cancer cells showed impaired endogenous FOXO3a nuclear translocation, reduced FOXO3a-Bim promoter association and significantly decreased Bim expression in response to AZD6244. AZD6244-resistant cancer cells can be sensitized to API-2 (an AKT inhibitor) and LY294002 (a PI3K inhibitor) in suppressing cell growth and colony formation, these inhibitors were known to enhance FOXO3a activity/nuclear translocation through inhibiting PI3K-AKT pathway. This study reveals novel molecular mechanism contributing to AZD6244-resistance through regulation of FOXO3a activity, further provides significant clinical implication of combining AZD6244 with PI3K/AKT inhibitors for sensitizing AZD6244-resistant cancer cells by activating FOXO3a. FOXO3a activation can be an essential pharmacological target and indicator to mediate and predict AZD6244 efficacy in clinical use. ^

Ethnographic and epidemiologic approaches for the programming of prenatal and birth services in Mesa los Hornos, Mexico

The investigator conducted an action-oriented investigation of pregnancy and birth among the women of Mesa los Hornos, an urban squatter slum in Mexico City. Three aims guided the project: (1) To obtain information for improving prenatal and maternity service utilization; (2) To examine the utility of rapid ethnographic and epidemiologic assessment methodologies; (3) To cultivate community involvement in health development.^ Viewing service utilization as a culturally-bound decision, the study included a qualitative phase to explore women's cognition of pregnancy and birth, their perceived needs during pregnancy, and their criteria of service acceptability. A probability-based community survey delineated parameters of service utilization and pregnancy health events, and probed reasons for decisions to use medical services, lay midwives, or other sources of prenatal and labor and delivery assistance. Qualitative survey of service providers at relevant clinics, hospitals, and practices contributed information on service availability and access, and on coordination among private, social security, and public assistance health service sectors. The ethnographic approach to exploring the rationale for use or non-use of services provided a necessary complement to conventional barrier-based assessment, to inform planning of culturally appropriate interventions.^ Information collection and interpretation was conducted under the aegis of an advisory committee of community residents and service agency representatives; the residents' committee formulated recommendations for action based on findings, and forwarded the mandate to governmental social and urban development offices. Recommendations were designed to inform and develop community participation in health care decision-making.^ Rapid research methods are powerful tools for achieving community-based empowerment toward investigation and resolution of local health problems. But while ethnography works well in synergy with quantitative assessment approaches to strengthen the validity and richness of short-term field work, the author strongly urges caution in application of Rapid Ethnographic Assessments. An ethnographic sensibility is essential to the research enterprise for the development of an active and cooperative community base, the design and use of quantitative instruments, the appropriate use of qualitative techniques, and the interpretation of culturally-oriented information. However, prescribed and standardized Rapid Ethnographic Assessment techniques are counter-productive if used as research short-cuts before locale- and subject-specific cultural understanding is achieved. ^

Interfaces entre as políticas educacionais e os marcadores sociais : Quem sao os alunos que fracassam num contexto em todos têm direito a educaçao?

A implantaçao da obrigatoriedade do acesso à escola pública de Ensino Fundamental no Brasil, a partir do final dos aos 1980, produziu uma nova realidade no sistema de ensino. Por um lado, a taxa de frequência da escola básica passou de 75,03 (1990) para 92,14 (2010). Em contrapartida, a taxa de analfabetismo de pessoas com mais de 18 anos ainda é de 10,19 e somente 54,92 das pessoas com 18 anos ou mais tem Ensino Fundamental completo. Um conjunto de contradiçoes produzidas e reproduzidas sob o enfoque da justiça escolar a qual, norteia à universalizaçao do acesso a escola básica. Neste sentido, a ideia central desse trabalho foi reconhecer o perfil socioeducacional dos alunos em situaçao de fracasso escolar (repetência, distorçao idade-série e evasao escolar) no estado brasileiro que apresenta o melhor índice desenvolvimento da escola básica. Para tanto, foram analisadas as respostas de 87.607 questionários respondidos por alunos do 9o ano, participantes da Prova Brasil 2011. Com auxílio do software SPSS, foram produzidos procedimentos estatísticos para sistematizar e ampliar a análise que teve com suporte teórico as reflexoes preconizadas por distintos autores da Sociologia da Educaçao

Desarrollo de una guía de control para interfaces de búsqueda por materia en catálogos en línea de acceso web

El presente trabajo pretende desarrollar una guía de control (checklist) que permita evaluar la búsqueda por materia en la interfaz usuario-sistema de los catálogos en línea de bibliotecas accesibles vía Web, y probar su funcionamiento mediante la evaluación de diez interfaces de catálogos de bibliotecas argentinas, desarrollados en su mayoría en Microisis con una interfaz vía CGI para servidores Web y una interfaz de un catálogo español, desarrollado con un producto comercial altamente reconocido y difundido. Asimismo, se selecciona un método de análisis multivariante para el análisis de los resultados como una alternativa del análisis clásico por característica soportada y se evalúa su eficacia y utilidad.

Desarrollo de una guía de control para interfaces de búsqueda por materia en catálogos en línea de acceso web

El presente trabajo pretende desarrollar una guía de control (checklist) que permita evaluar la búsqueda por materia en la interfaz usuario-sistema de los catálogos en línea de bibliotecas accesibles vía Web, y probar su funcionamiento mediante la evaluación de diez interfaces de catálogos de bibliotecas argentinas, desarrollados en su mayoría en Microisis con una interfaz vía CGI para servidores Web y una interfaz de un catálogo español, desarrollado con un producto comercial altamente reconocido y difundido. Asimismo, se selecciona un método de análisis multivariante para el análisis de los resultados como una alternativa del análisis clásico por característica soportada y se evalúa su eficacia y utilidad.

Interfaces entre as políticas educacionais e os marcadores sociais : Quem sao os alunos que fracassam num contexto em todos têm direito a educaçao?

A implantaçao da obrigatoriedade do acesso à escola pública de Ensino Fundamental no Brasil, a partir do final dos aos 1980, produziu uma nova realidade no sistema de ensino. Por um lado, a taxa de frequência da escola básica passou de 75,03 (1990) para 92,14 (2010). Em contrapartida, a taxa de analfabetismo de pessoas com mais de 18 anos ainda é de 10,19 e somente 54,92 das pessoas com 18 anos ou mais tem Ensino Fundamental completo. Um conjunto de contradiçoes produzidas e reproduzidas sob o enfoque da justiça escolar a qual, norteia à universalizaçao do acesso a escola básica. Neste sentido, a ideia central desse trabalho foi reconhecer o perfil socioeducacional dos alunos em situaçao de fracasso escolar (repetência, distorçao idade-série e evasao escolar) no estado brasileiro que apresenta o melhor índice desenvolvimento da escola básica. Para tanto, foram analisadas as respostas de 87.607 questionários respondidos por alunos do 9o ano, participantes da Prova Brasil 2011. Com auxílio do software SPSS, foram produzidos procedimentos estatísticos para sistematizar e ampliar a análise que teve com suporte teórico as reflexoes preconizadas por distintos autores da Sociologia da Educaçao

Desarrollo de una guía de control para interfaces de búsqueda por materia en catálogos en línea de acceso web

El presente trabajo pretende desarrollar una guía de control (checklist) que permita evaluar la búsqueda por materia en la interfaz usuario-sistema de los catálogos en línea de bibliotecas accesibles vía Web, y probar su funcionamiento mediante la evaluación de diez interfaces de catálogos de bibliotecas argentinas, desarrollados en su mayoría en Microisis con una interfaz vía CGI para servidores Web y una interfaz de un catálogo español, desarrollado con un producto comercial altamente reconocido y difundido. Asimismo, se selecciona un método de análisis multivariante para el análisis de los resultados como una alternativa del análisis clásico por característica soportada y se evalúa su eficacia y utilidad.

Interfaces entre as políticas educacionais e os marcadores sociais : Quem sao os alunos que fracassam num contexto em todos têm direito a educaçao?

A implantaçao da obrigatoriedade do acesso à escola pública de Ensino Fundamental no Brasil, a partir do final dos aos 1980, produziu uma nova realidade no sistema de ensino. Por um lado, a taxa de frequência da escola básica passou de 75,03 (1990) para 92,14 (2010). Em contrapartida, a taxa de analfabetismo de pessoas com mais de 18 anos ainda é de 10,19 e somente 54,92 das pessoas com 18 anos ou mais tem Ensino Fundamental completo. Um conjunto de contradiçoes produzidas e reproduzidas sob o enfoque da justiça escolar a qual, norteia à universalizaçao do acesso a escola básica. Neste sentido, a ideia central desse trabalho foi reconhecer o perfil socioeducacional dos alunos em situaçao de fracasso escolar (repetência, distorçao idade-série e evasao escolar) no estado brasileiro que apresenta o melhor índice desenvolvimento da escola básica. Para tanto, foram analisadas as respostas de 87.607 questionários respondidos por alunos do 9o ano, participantes da Prova Brasil 2011. Com auxílio do software SPSS, foram produzidos procedimentos estatísticos para sistematizar e ampliar a análise que teve com suporte teórico as reflexoes preconizadas por distintos autores da Sociologia da Educaçao

Compilation, application and challenge of IDE-JETRO's International Input-Output tables

International input-output tables are among the most useful tools for economic analysis. Since these tables provide detailed information about international production networks, they have recently attracted considerable attention in research on spatial economics, global value chains, and issues relating to trade in value-added. The Institute of Developing Economies at the Japan External Trade Organization (IDE-JETRO) has more than 40 years of experience in the construction and analysis of international input-output tables. This paper explains the development of IDE-JETRO’s multi-regional input-output projects including the construction of the Asian International Input-Output table and the Transnational Interregional Input-Output table between China and Japan. To help users understand the features of the tables, this paper also gives examples of their application.

Lock-free Parallel Dynamic Programming

We show a method for parallelizing top down dynamic programs in a straightforward way by a careful choice of a lock-free shared hash table implementation and randomization of the order in which the dynamic program computes its subproblems. This generic approach is applied to dynamic programs for knapsack, shortest paths, and RNA structure alignment, as well as to a state-of-the-art solution for minimizing the máximum number of open stacks. Experimental results are provided on three different modern multicore architectures which show that this parallelization is effective and reasonably scalable. In particular, we obtain over 10 times speedup for 32 threads on the open stacks problem.

Using the Journalistic Metaphor to Design User Interfaces That Explain Sensor Data

Facilitating general access to data from sensor networks (including traffic, hydrology and other domains) increases their utility. In this paper we argue that the journalistic metaphor can be effectively used to automatically generate multimedia presentations that help non-expert users analyze and understand sensor data. The journalistic layout and style are familiar to most users. Furthermore, the journalistic approach of ordering information from most general to most specific helps users obtain a high-level understanding while providing them the freedom to choose the depth of analysis to which they want to go. We describe the general characteristics and architectural requirements for an interactive intelligent user interface for exploring sensor data that uses the journalistic metaphor. We also describe our experience in developing this interface in real-world domains (e.g., hydrology).

Relational and Allegorical Semantics for Constraint Logic Programming

El cálculo de relaciones binarias fue creado por De Morgan en 1860 para ser posteriormente desarrollado en gran medida por Peirce y Schröder. Tarski, Givant, Freyd y Scedrov demostraron que las álgebras relacionales son capaces de formalizar la lógica de primer orden, la lógica de orden superior así como la teoría de conjuntos. A partir de los resultados matemáticos de Tarski y Freyd, esta tesis desarrolla semánticas denotacionales y operacionales para la programación lógica con restricciones usando el álgebra relacional como base. La idea principal es la utilización del concepto de semántica ejecutable, semánticas cuya característica principal es el que la ejecución es posible utilizando el razonamiento estándar del universo semántico, este caso, razonamiento ecuacional. En el caso de este trabajo, se muestra que las álgebras relacionales distributivas con un operador de punto fijo capturan toda la teoría y metateoría estándar de la programación lógica con restricciones incluyendo los árboles utilizados en la búsqueda de demostraciones. La mayor parte de técnicas de optimización de programas, evaluación parcial e interpretación abstracta pueden ser llevadas a cabo utilizando las semánticas aquí presentadas. La demostración de la corrección de la implementación resulta extremadamente sencilla. En la primera parte de la tesis, un programa lógico con restricciones es traducido a un conjunto de términos relacionales. La interpretación estándar en la teoría de conjuntos de dichas relaciones coincide con la semántica estándar para CLP. Las consultas contra el programa traducido son llevadas a cabo mediante la reescritura de relaciones. Para concluir la primera parte, se demuestra la corrección y equivalencia operacional de esta nueva semántica, así como se define un algoritmo de unificación mediante la reescritura de relaciones. La segunda parte de la tesis desarrolla una semántica para la programación lógica con restricciones usando la teoría de alegorías—versión categórica del álgebra de relaciones—de Freyd. Para ello, se definen dos nuevos conceptos de Categoría Regular de Lawvere y _-Alegoría, en las cuales es posible interpretar un programa lógico. La ventaja fundamental que el enfoque categórico aporta es la definición de una máquina categórica que mejora e sistema de reescritura presentado en la primera parte. Gracias al uso de relaciones tabulares, la máquina modela la ejecución eficiente sin salir de un marco estrictamente formal. Utilizando la reescritura de diagramas, se define un algoritmo para el cálculo de pullbacks en Categorías Regulares de Lawvere. Los dominios de las tabulaciones aportan información sobre la utilización de memoria y variable libres, mientras que el estado compartido queda capturado por los diagramas. La especificación de la máquina induce la derivación formal de un juego de instrucciones eficiente. El marco categórico aporta otras importantes ventajas, como la posibilidad de incorporar tipos de datos algebraicos, funciones y otras extensiones a Prolog, a la vez que se conserva el carácter 100% declarativo de nuestra semántica. ABSTRACT The calculus of binary relations was introduced by De Morgan in 1860, to be greatly developed by Peirce and Schröder, as well as many others in the twentieth century. Using different formulations of relational structures, Tarski, Givant, Freyd, and Scedrov have shown how relation algebras can provide a variable-free way of formalizing first order logic, higher order logic and set theory, among other formal systems. Building on those mathematical results, we develop denotational and operational semantics for Constraint Logic Programming using relation algebra. The idea of executable semantics plays a fundamental role in this work, both as a philosophical and technical foundation. We call a semantics executable when program execution can be carried out using the regular theory and tools that define the semantic universe. Throughout this work, the use of pure algebraic reasoning is the basis of denotational and operational results, eliminating all the classical non-equational meta-theory associated to traditional semantics for Logic Programming. All algebraic reasoning, including execution, is performed in an algebraic way, to the point we could state that the denotational semantics of a CLP program is directly executable. Techniques like optimization, partial evaluation and abstract interpretation find a natural place in our algebraic models. Other properties, like correctness of the implementation or program transformation are easy to check, as they are carried out using instances of the general equational theory. In the first part of the work, we translate Constraint Logic Programs to binary relations in a modified version of the distributive relation algebras used by Tarski. Execution is carried out by a rewriting system. We prove adequacy and operational equivalence of the semantics. In the second part of the work, the relation algebraic approach is improved by using allegory theory, a categorical version of the algebra of relations developed by Freyd and Scedrov. The use of allegories lifts the semantics to typed relations, which capture the number of logical variables used by a predicate or program state in a declarative way. A logic program is interpreted in a _-allegory, which is in turn generated from a new notion of Regular Lawvere Category. As in the untyped case, program translation coincides with program interpretation. Thus, we develop a categorical machine directly from the semantics. The machine is based on relation composition, with a pullback calculation algorithm at its core. The algorithm is defined with the help of a notion of diagram rewriting. In this operational interpretation, types represent information about memory allocation and the execution mechanism is more efficient, thanks to the faithful representation of shared state by categorical projections. We finish the work by illustrating how the categorical semantics allows the incorporation into Prolog of constructs typical of Functional Programming, like abstract data types, and strict and lazy functions.

A User Centered Design Approach for Patient Interfaces to a Diabetes IT Platform

Improving patient self-management can have a greater impact than improving any clinical treatment (WHO). We propose here a systematic and comprehensive user centered design approach for delivering a technological platform for diabetes disease management. The system was developed under the METABO research project framework, involving patients from 3 different clinical centers in Parma, Modena and Madrid.

Using SCXML to integrate semantic sensor information into context-aware user interfaces

This paper describes a novel architecture to introduce automatic annotation and processing of semantic sensor data within context-aware applications. Based on the well-known state-charts technologies, and represented using W3C SCXML language combined with Semantic Web technologies, our architecture is able to provide enriched higher-level semantic representations of user’s context. This capability to detect and model relevant user situations allows a seamless modeling of the actual interaction situation, which can be integrated during the design of multimodal user interfaces (also based on SCXML) for them to be adequately adapted. Therefore, the final result of this contribution can be described as a flexible context-aware SCXML-based architecture, suitable for both designing a wide range of multimodal context-aware user interfaces, and implementing the automatic enrichment of sensor data, making it available to the entire Semantic Sensor Web