Extracellular BMP-antagonist regulation in development and disease: tied up in knots

Developmental processes are regulated by the bone morphogenetic protein (BMP) family of secreted molecules. BMPs bind to serine/threonine kinase receptors and signal through the canonical Smad pathway and other intracellular effectors. Integral to the control of BMPs is a diverse group of secreted BMP antagonists that bind to BMPs and prevent engagement with their cognate receptors. Tight temporospatial regulation of both BMP and BMP-antagonist expression provides an exquisite control system for developing tissues. Additional facets of BMP-antagonist biology, such as crosstalk with Wnt and Sonic hedgehog signaling during development, have been revealed in recent years. In addition, previously unappreciated roles for the BMP antagonists in kidney fibrosis and cancer have been elucidated. This review provides a description of BMP-antagonist biology, together with highlights of recent novel insights into the role of these antagonists in development, signal transduction and human disease.

Service building in dense service provider environments

Genericamente falando, os serviços sobre redes têm vindo a afastar-se de um modelo monolítico para um modelo de criação de serviços que permite ou - como é mais frequente - requer a cooperação entre vários Provedores de Serviço. A Internet, que tem vindo a forçar a convergência de serviços, mostra que começa a ser virtualmente impossível a um único operador fornecer qualquer serviço com um mínimo de interesse para os utilizadores. Esta tese foca-se em serviços de transporte (e.g., connectividade) e discute o impacto das fronteira que as ofertas de serviços têm com o negócio. A questão central é a seguinte: o que muda quando o mesmo serviço é oferecido não apenas por um mas por mais do que um Provedor de Serviço. Por um lado, esta tese cobre, em abs tracto, a noção de Provedor se Serviço, como evoluiu e em que sentido está a evoluir, particularmente num contexto de muitos Provedores de Serviço. Os primeiros capítulos desta tese analizam e propõem arquitecturas para cooperação inter-Provedor-de-Serviço e para serviços comuns tais como multimédia. Por outro lado, oferece-se soluções práticas, com as respectivas avaliações, para alguns problemas, que ainda hoje se mantêm em aberto, tais como encaminhamento inter-domínio, Qualidade-de-Serviço, Mobilidade e distribuição de conteúdos, tais como as contribuições relacionadas com o impacto da noção administrativa de Sistemas Autónomos sobre encaminhamento inter-domínio, uma arquitectura de transporte inter-domínio e o problema que levanta da ineficiência que decorre do planeamento não- cooperativo de Redes de Entrega de Conteúdos.

Study of influence of regulatory polymorphisms of expression in development of breast cancer

The human genome has millions of genetics variants that can affect gene expression. These variants are known as cis-regulatory variants and are responsible for intra-species phenotypic differences and individual susceptibility to disease. One of the diseases affected by cis-regulatory variants is breast cancer. Breast cancer is one of the most common cancers, with approximately 4500 new cases each year in Portugal. Breast cancer has many genes mutated and TP53 has been shown to be relevant for this disease. TP53 is one of the most commonly mutated genes in human cancer and it is involved in cell cycle regulation and apoptosis. Previous work by Maia et al has shown that TP53 has differential allelic expression (DAE), which suggests that this gene may be under the influence of cis-regulatory variants. Also, its DAE pattern is totally altered in breast tumours with normal copy number. We hypothesized that cis-regulatory variants affecting TP53 may have a role in breast cancer development and treatment. The present work aims to identify the cis-regulatory variants playing a role in TP53 expression, using in silico, in vitro and in vivo approaches. By bioinformatic tools we have identified candidate cis-regulatory variants and predicted the possible transcription factor binding sites that they affect. By EMSA we studied DNA-protein interactions in this region of TP53. The in silico analysis allowed us to identified three candidate cis-regulatory SNPs which may affect the binding of seven transcription factors. However, the EMSA experiments have not been conclusive and we have not yet confirmed whether any of the identified SNPs are associated with gene expression control of TP53. We will carry out further experiments to validate our findings.