EGFR and Notch signaling pathways are regulated by distinct isoforms of Drosophila cbl

Activation of cell surface receptors transduces extracellular signals into cellular responses such as proliferation, differentiation and survival. However, the appropriate spatial and temporal down-regulation of signaling receptors is essential for normal development and homeostasis. The Cbl family of E3-ubiquitin ligases plays a major role for the ligand-dependent inactivation of growth factor receptors through ubiquitin-mediated endocytosis and lysosomal degradation. Here, we report the D-cbl mutant phenotypes in the Drosophila eye. D-cbl mutants display overgrowth, inhibition of apoptosis, differentiation defects and increased ommatidial spacing. Many of these phenotypes are caused by lack of down-regulation of the Drosophila EGFR signaling. However, not all D-cbl phenotypes can be explained by inappropriate EGFR activity. We found that D-Cbl also negatively regulates Notch activity during eye and wing development. D-cbl produces two isoforms by alternative splicing. Strikingly, the long isoform, D-CblL, preferentially regulates the EGFR, whereas the short isoform, D-CblS, preferentially regulates Notch. Taken together, these data suggest that D-Cbl controls at least two signaling pathways, EGFR and Notch, through production of two alternatively spliced isoforms during development in Drosophila.^

Joint effects of pulmonary function and aerobic power on survival in a cohort of healthy adults

Objective measurements of physical fitness and pulmonary function are related individually to long-term survival, both in healthy people and in those who are ill. These factors are furthermore known to be related to one another physiologically in people with pulmonary disease, because advanced pulmonary disease causes ventilatory limitation to exercise. Healthy people do not have ventilatory limitation to exercise, but rather have ventilatory reserve. The relationship between pulmonary function and exercise performance in healthy people is minimal. Exercise performance has been shown to modify the effect of pulmonary function on mortality in people with chronic obstructive pulmonary disease, but the relationship between these factors in healthy people has not been studied and is not known. The purpose of this study is to quantify the joint effects of pulmonary function and exercise performance as these bear on mortality in a cohort of healthy adults. This investigation is an historical cohort study over 20 years of follow-up of 29,624 adults who had complete preventive medicine, spirometry and treadmill stress examinations at the Cooper Clinic in Dallas, Texas.^ In 20 years of follow-up, there were 738 evaluable deaths. Forced expiratory volume in one second (FEV$\sb1$) percent of predicted, treadmill time in minutes percent of predicted, age, gender, body mass index, baseline smoking status, serum glucose and serum total cholesterol were all significant, independent predictors of mortality risk. There were no frank interactions, although age had an important increasing effect on the risk associated with smoking when other covariates were controlled for in a proportional-hazards model. There was no confounding effect of exercise performance on pulmonary function. In agreement with the pertinent literature on independent effects, each unit increase in FEV$\sb1$ percent predicted was associated with about eight tenths of a percent reduction in adjusted mortality rate. The concept of physiologic reserve is useful in interpretation of the findings. Since pulmonary function does not limit exercise tolerance in healthy adults, it is reasonable to expect that exercise tolerance would not modify the effect of pulmonary function on mortality. Epidemiologic techniques are useful for elucidating physiological correlates of mortality risk. ^

Mixture modeling for joint analysis of survival, discrete, and continuous data

Mixture modeling is commonly used to model categorical latent variables that represent subpopulations in which population membership is unknown but can be inferred from the data. In relatively recent years, the potential of finite mixture models has been applied in time-to-event data. However, the commonly used survival mixture model assumes that the effects of the covariates involved in failure times differ across latent classes, but the covariate distribution is homogeneous. The aim of this dissertation is to develop a method to examine time-to-event data in the presence of unobserved heterogeneity under a framework of mixture modeling. A joint model is developed to incorporate the latent survival trajectory along with the observed information for the joint analysis of a time-to-event variable, its discrete and continuous covariates, and a latent class variable. It is assumed that the effects of covariates on survival times and the distribution of covariates vary across different latent classes. The unobservable survival trajectories are identified through estimating the probability that a subject belongs to a particular class based on observed information. We applied this method to a Hodgkin lymphoma study with long-term follow-up and observed four distinct latent classes in terms of long-term survival and distributions of prognostic factors. Our results from simulation studies and from the Hodgkin lymphoma study demonstrated the superiority of our joint model compared with the conventional survival model. This flexible inference method provides more accurate estimation and accommodates unobservable heterogeneity among individuals while taking involved interactions between covariates into consideration.^

ANTI-TUMOR EFFECTS OF THE NOTCH PATHWAY IN GASTROINTESTINAL STROMAL TUMORS

Gastrointestinal Stromal Tumors (GIST) are sarcomas driven by gain-of-function mutations of KIT or PDGFRA. Although, the introduction of tyrosine kinase inhibitors has dramatically changed the history of this disease, evidences emerge that inhibition of KIT or PDGFRA are not sufficient to cure patients. The developmental pathway Notch has a critical role in the cell fate, regulating cell proliferation and differentiation. Dysregulation of Notch pathway has been implicated in a wide variety of cancers functioning as a tumor promoter or a tumor suppressor in a cell context dependent manner. Given that Notch activation deregulates the morphogenesis of mesenchymal cells in the GI track, that Notch acts as a tumor suppressor in neuroendocrine tumors, and finally that the cell of origin of GIST are the Interstitial Cell of Cajal that arise from a mesenchymal origin with some neuroendocrine features, we hypothesized that Notch pathway signaling may play a role in growth, survival and differentiation of GIST cells. To test this hypothesis, we genetically and pharmacologically manipulated the Notch pathway in human GIST cells. In this study, we demonstrated that constitutively active intracellular domain of Notch1 (ICN-1) expression potently induced growth arrest and downregulated KIT expression. We have performed a retrospective analysis of 15 primary GIST patients and found that high mRNA level of Hes1, a major target gene of Notch pathway, correlated with a significantly longer relapse-free survival. Therefore, we have established that treatment with the FDA approved histone deacetylase inhibitor SAHA (Vorinostat) caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch with dominant negative Hes-1 as well as pharmacological inhibition of Notch pathway with a γ-secretase inhibitor partially rescued GIST cells from SAHA treatment. Taken together these results identify anti-tumor effect of Notch1 and a negative cross-talk between Notch1 and KIT pathways in GIST. Consequently, we propose that activation of this pathway with HDAC inhibitors may be a potential therapeutic strategy for GIST patients.

A Genomic Approach to Identify The Notch Pathway as a Putative Tumor Suppressor in Endometrial Cancer

Endometrial cancer is the most common gynecological malignancy and the fourth most frequently diagnosed cancer among women. The molecular changes that distinguish normal endometrium from endometrial carcinoma are not thoroughly understood. Identification of these changes could potentially aid in identifying at-risk women who are especially prone to develop endometrial cancer, such as obese women and women with Lynch Syndrome. A microarray analysis was performed using normal endometrium from thin and obese women and cancerous endometrium from obese women. We validated the differential expression of ten genes whose expression was significantly up-regulated or down-regulated using qRT-PCR. All of the genes had distinct expression levels depending on the endometrial carcinoma histotype. As a result, they could serve as molecular markers to distinguish between normal endometrium and endometrial cancer, as well as between low grade endometrial carcinomas and high grade endometrial carcinomas. Two of the ten genes validated, HEYL and HES1, are down-stream targets of the Notch signaling pathway. HEYL and HES1 were identified by microarray and qRT-PCR to have a significant decrease in expression in endometrial carcinomas compared to normal endometrium. We further analyzed the differential expression of other components of the Notch signaling pathway, Notch4 and Jagged1. They were also identified by qRT-PCR to be significantly down-regulated in endometrial carcinomas compared to normal endometrium. Therefore, we believe the Notch signaling pathway to act as a tumor suppressor in endometrial carcinomas.

International Collection of JGOFS (Joint Global Ocean Flux Study), Volume 2: Integrated Data Sets (1989-2003)

The JGOFS International Collection Volume 2: Integrated Data Sets CD is a coherent, organised compilation of existing data sets produced by member countries which participated in JGOFS. In most cases, the data were gathered from the JGOFS International Collection, Volume 1: Discrete Datasets DVD. To produce Vol. 1 data were taken from the original sources and copied "as is" on the DVD. For Vol. 2 data and metadata have been harmonized using the conversion software PanTool and the import routine of PANGAEA checking for completeness of metadata and defining the relations between data and metadata. Prior to the import, data had performed a technical quality control, i.e. format and readability of the file, availability and combination of parameters and units, range of values.

Design Patterns in Software Maintenance: An Experiment Replication at UPM - Experiences with the RESER'11 Joint Replication Project

Replication of software engineering experiments is crucial for dealing with validity threats to experiments in this area. Even though the empirical software engineering community is aware of the importance of replication, the replication rate is still very low. The RESER'11 Joint Replication Project aims to tackle this problem by simultaneously running a series of several replications of the same experiment. In this article, we report the results of the replication run at the Universidad Politécnica de Madrid. Our results are inconsistent with the original experiment. However, we have identified possible causes for them. We also discuss our experiences (in terms of pros and cons) during the replication.

Approximate Analytical Model for the Squeeze-Film Lubrication of the Human Ankle Joint with Synovial Fluid Filtrated by Articular Cartilage

The aim of this article is to propose an analytical approximate squeeze-film lubrication model of the human ankle joint for a quick assessment of the synovial pressure field and the load carrying due to the squeeze motion. The model starts from the theory of boosted lubrication for the human articular joints lubrication (Walker et al., Rheum Dis 27:512–520, 1968; Maroudas, Lubrication and wear in joints. Sector, London, 1969) and takes into account the fluid transport across the articular cartilage using Darcy’s equation to depict the synovial fluid motion through a porous cartilage matrix. The human ankle joint is assumed to be cylindrical enabling motion in the sagittal plane only. The proposed model is based on a modified Reynolds equation; its integration allows to obtain a quick assessment on the synovial pressure field showing a good agreement with those obtained numerically (Hlavacek, J Biomech 33:1415–1422, 2000). The analytical integration allows the closed form description of the synovial fluid film force and the calculation of the unsteady gap thickness.

A policy-driven architecture for supporting joint degrees through e-learning services

En un mercado de educación superior cada vez más competitivo, la colaboración entre universidades es una efectiva estrategia para acceder al mercado global. El desarrollo de titulaciones conjuntas es un importante mecanismo para fortalecer las colaboraciones académicas y diversificar los conocimientos. Las titulaciones conjuntas están siendo cada vez más implementadas en las universidades de todo el mundo. En Europa, el proceso de Bolonia y el programa Erasmus, están fomentado el reconocimiento de titulaciones conjuntas y dobles y promoviendo la colaboración entre las instituciones académicas. En el imparable proceso de la globalización y convergencia educativa, el uso de sistemas de e-learning para soportar cursos tanto semipresencial como online es una tendencia en crecimiento. Dado que los sistemas de e-learning soportan una amplia variedad de cursos, es necesario encontrar una solución adecuada que permita a las universidades soportar y gestionar las titulaciones conjuntas a través de sus sistemas de e-learning en conformidad con los acuerdos de colaboración establecidos por las universidades participantes. Esta tesis doctoral abordará las siguientes preguntas de investigación: 1. ¿Qué factores deben tenerse en cuenta en la implementación y gestión de titulaciones conjuntas? 2. ¿Cómo pueden los sistemas actuales de e-learning soportar el desarrollo de titulaciones conjuntas? 3. ¿Qué otros servicios y sistemas necesitan ser adaptados por las universidades interesadas en participar en una titulación conjunta a través de sus sistemas de e-learning? La implementación de titulaciones conjuntas a través de sistemas de e-learning es compleja e implica retos técnicos, administrativos, culturales, financieros, jurídicos y de seguridad. Esta tesis doctoral propone una serie de contribuciones que pueden ayudar a resolver algunos de los retos identificados. En primer lugar se ha elaborado un modelo conceptual que incluye la información del contexto de las titulaciones conjuntas que es relevante para la implementación de estas titulaciones en los sistemas de e-learning. Después de definir el modelo conceptual, se ha propuesto una arquitectura basada en políticas para la implementación de titulaciones interinstitucionales a través de sistemas de e-learning de acuerdo a los términos estipulados en los acuerdos de colaboración que son firmados por las universidades participantes. El autor se ha centrado en el componente de gestión de flujos de trabajo de esta arquitectura. Por último y con el fin de permitir la interoperabilidad de repositorios de objetos educativos, los componentes básicos a implementar han sido identificados y validados. El uso de servicios multimedia en educación es una tendencia creciente, proporcionando servicios de e-learning que permiten mejorar la comunicación y la interacción entre profesores y alumnos. Dentro de estos servicios, nos hemos centrado en el uso de la videoconferencia y la grabación de clases como servicios adecuados para el desarrollo de cursos impartidos en escenarios de educación colaborativos. Las contribuciones han sido validadas en proyectos de investigación de ámbito nacional y europeo en los que el autor ha participado. Abstract In an increasingly competitive higher education market, collaboration between universities is an effective strategy for gaining access to the global market. The development of joint degrees is an important mechanism for strengthening academic research collaborations and diversifying knowledge. Joint degrees are becoming increasingly implemented in universities around the world. In Europe, the Bologna process and the Erasmus programme have encouraged both the global recognition of joint and double degrees and promoted close collaboration between academic institutions. In the unstoppable process of globalization and educational convergence, the use of e-learning systems for supporting both blended and online courses is becoming a growing trend. Since e-learning systems covers a wide range of courses, it becomes necessary to find a suitable solution that enables universities to support and manage joint degrees through their e-learning systems in accordance with the collaboration agreements established by the universities involved. This dissertation will address the following research questions: 1. What factors need to be considered in the implementation and management of joint degrees? 2. How can the current e-learning systems support the development of joint degrees? 3. What other services and systems need to be adapted by universities interested in participating in a joint degree through their e-learning systems? The implementation of joint degrees using e-learning systems is complex and involves technical, administrative, security, cultural, financial and legal challenges. This dissertation proposes a series of contributions to help solve some of the identified challenges. One of the cornerstones of this proposal is a conceptual model of all the relevant issues related to the support of joint degrees by means of e-learning systems. After defining the conceptual model, this dissertation proposes a policy-driven architecture for implementing inter-institutional degree collaborations through e-learning systems as stipulated by a collaboration agreement signed by two universities. The author has focused on the workflow management component of this architecture. Finally, the building blocks for achieving interoperability of learning object repositories have been identified and validated. The use of multimedia services in education is a growing trend, providing rich e-learning services that improve the communication and interaction between teachers and students. Within these e-learning services, we have focused on the use of videoconferencing and lecture recording as the best-suited services to support collaborative learning scenarios. The contributions have been validated within national and European research projects that the author has been involved in.

Parametric study of the expansive joint model for cracking of concrete due to rebar corrosion

Un modelo numérico llamado elemento junta expansiva fue programado para simular la expansión mecánica del óxido y estudiar la fisuración en el hormigón circundante. El elemento junta expansiva trabaja con elementos finitos con fisura cohesiva embebida adaptable para simular la fractura del hormigón según el modelo de fisura cohesiva. Se ha comprobado que el modelo reproduce correctamente el patrón de fisuración del hormigón que se obtiene en ensayos de corrosión acelerada. En este trabajo, se realiza un estudio paramétrico del elemento junta expansiva para establecer los límites de los parámetros constitutivos del óxido. Se simula una cierta expansión variando los valores de los parámetros del óxido y se estudian la apertura de fisura y las tensiones resultantes en el hormigón. Se determina el rango de valores para los que los resultados de las simulaciones son prácticamente iguales, con el menor número posible de iteraciones.