Gene regulatory mechanisms underpinning prostate cancer susceptibility

Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development.

Avaliação do desempenho docente e supervisão pedagógica: um estudo de caso num agrupamento de escolas

A introdução de novas exigências na Avaliação do Desempenho Docente (ADD) em Portugal (Decretos-Lei 15/2007 e 75/2010; Decretos Regulamentares 2/2008 e 2/2010) tem gerado nas escolas e nos professores, desde 2008, situações organizacionais complexas, que urge analisar e compreender. As políticas educativas têm vindo a apontar para a necessidade de um maior investimento nos processos de avaliação de professores, dando relevância ao papel a desempenhar pela supervisão pedagógica nesse contexto. A supervisão da prática letiva passou a ser considerada procedimento fundamental, na medida em que se tornou difícil conceber uma avaliação dos docentes que não incluísse sessões de observação em sala de aula. Fruto destas novas políticas de avaliação de professores, a ADD apresentou-se, do ponto de vista normativo, com base em duas funções: sumativa e formativa. Estas funções exigem maiores investimentos, novas práticas e uma reflexão sobre o papel do professor ancorada numa perspetiva holística, transformadora e emancipatória do seu desenvolvimento profissional. O principal objetivo do nosso estudo consiste em compreender as perceções e práticas desenvolvidas pelos docentes face às alterações introduzidas no sistema da ADD no geral, e, em particular, o papel desempenhado pela supervisão pedagógica (SP) na avaliação entre pares, no segundo ciclo avaliativo (2009-2011). A investigação empírica tem por base um estudo de caso desenvolvido num Agrupamento de escolas do Distrito de Aveiro. A recolha de dados foi concretizada através da administração de um questionário a todos os docentes do Agrupamento e da condução de entrevistas a 26 informadores privilegiados do processo avaliativo. Os principais resultados do estudo de caso apontam para: i) a opinião desfavorável dos professores face ao atual modelo de ADD, dada a sua natureza burocrática, complexa, injusta e a sua escassa utilidade prática, preenchendo apenas requisitos legais e de controlo; ii) um processo de SP, concretamente, a observação de aulas, que não contribui para o desenvolvimento profissional dos professores e tem impacte negativo no trabalho docente, acentuando a artificialidade dos procedimentos e aumentando o clima de competição e de conflito; iii) a sensação de desconforto entre os intervenientes, fazendo emergir sentimentos de injustiça, insegurança e ansiedade que, em seu entender, constituem constrangimentos à melhoria das aprendizagens dos alunos e à qualidade da escola; iv) uma escassa implicação na melhoria das práticas futuras e do desenvolvimento profissional dos docentes. Estes resultados constituem um desafio colocado aos investigadores no sentido de identificarem alternativas de ação para poderem lidar com a complexidade inerente ao processo de avaliação na sua relação com a supervisão pedagógica, com vista à melhoria de desempenho das escolas e dos professores.

Role of insulin and insulin-like peptides in bone formation: identification of bone-specific target genes and regulatory mechanisms, and characterization of the insulin-mimetic effect of vanadium

Tese de Doutoramento em Biologia, Especialidade em Biologia Molecular, Universidade do Algarve, 2008

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.

Patterns of distribution in intertidal rocky shores: the role of grazing and competition in structuring communities

Tese de doutoramento, Ciências do Mar, Faculdade de Ciências do Mar e do Ambiente, Universidade do Algarve, 2000

Regulatory interactions between the metabolic sensors SIRT1 and AMPK in modulating PPARα linked functions, in obesity-dependent type 2 diabetes mellitus

Tese de doutoramento, Ciências Biomédicas (Ciências Funcionais), Universidade de Lisboa, Faculdade de Medicina, 2014

Towards the therapeutic use of regulatory T cells for the treatment of human autoimmune diseases

Tese de doutoramento, Medicina (Imunologia Clínica), Universidade de Lisboa, Faculdade de Medicina, 2016

Twelfth Annual Concerto Competition, November 18, 2002

Concert program for Twelfth Annual Concerto Competition, November 18, 2002

Old conflicts, new rivals? Airline competition in the European market

Christoph Franz of Lufthansa recently identified Ryanair, easyJet, Air Berlin and Emirates as the company’s main competitors – gone are the days when it could benchmark itself against BA or Air France-KLM! This paper probes behind the headlines to assess the extent to which different airlines are in competition, using evidence from the UK and mainland European markets. The issue of route versus network competition is addressed. Many regulators have put an emphasis on the former whereas the latter, although less obvious, can be more relevant. For example, BA and American will cease to compete between London and Dallas Fort Worth if their alliance obtains anti-trust immunity but 80% of the passengers on this route are connecting at one or both ends and hence arguably belong to different markets (e.g. London-San Francisco, Zurich-Dallas, Edinburgh-New Orleans) which may be highly contested. The remaining 20% of local traffic is actually insufficient to support a single point to point service in its own right. Estimates are made of the seat capacity major airlines are offering to the local market as distinct from feeding other routes. On a sector such as Manchester–Amsterdam, 60% of KLM’s passengers are transferring at Schiphol as against only 1% of bmibaby’s. Thus although KLM operates 5 flights and 630 seats per day against bmibaby’s 2 flights and 298 seats, in the point to point market bmibaby offers more seats than KLM. The growth of the Low Cost Carriers (LCCs) means that competition increasingly needs to be viewed on city pair markets (e.g. London-Rome) rather than airport pair markets (e.g. Heathrow-Fiumicino). As the stronger LCCs drive out weaker rivals and mainline carriers retrench to their major hubs, some markets now have fewer direct options than existed prior to the low cost boom. Timings and frequencies are considered, in particular the extent to which services are a true alternative especially for business travellers. LCCs typically offer lower frequencies and more unsociable timings (e.g. late evening arrivals at remote airports) as they are more focused on providing the cheapest service rather than the most convenient schedule. Interesting findings on ‘monopoly’ services are presented (including alliances) - certain airlines have many more of these than others. Lufthansa has a significant number of sectors to itself whereas at the other extreme British Airways has direct competition on almost every route in its network. Ryanair and flybe have a higher proportion of monopoly routes than easyJet or Air Berlin. In the domestic US market it has become apparent since deregulation that better financial returns can come from dominating a large number of smaller markets rather than being heavily exposed in the major markets - which are hotly fought over. Regional niches that appear too thin for Ryanair to serve (with its all 189 seat 737-800 fleet) are identified. Fare comparisons in contrasting markets provide some insights to marketing and pricing strategies. Data sources used include OAG (schedules and capacity), AEA (traditional European airlines traffic by region), the UK CAA (airport, airline and route traffic plus survey information of passenger types) and ICAO (international route traffic and capacity by carrier). It is concluded that airlines often have different competitors depending on the context but in surprisingly many cases there are actually few or no direct substitutes. The competitive process set in train by deregulation of European air services in the 1990s is leading back to one of natural monopolies and oblique alternatives. It is the names of the main participants that have changed however!

Strings Concerto Competition, November 17, 2015

Concert Program

Concerto Competition Winners Showcase February 1, 2001

Concert Program for Concerto Competition Winners Showcase February 1, 2001