Elafin prevents lipopolysaccharide-induced AP-1 and NF-kB activation via an effect on the ubiquitin-proteasome pathway

In this paper we follow on from our research into SLPI by assessing the immunomodulatory activity of elafin - an antiprotease related to SLPI and also present on the respiratory tract. We demonstrate for the first time that exogenously applied elafin inhibits lipopolysaccharide-induced activation of the NF-kappaB and AP-1 pathways in monocytes. I designed this project and supervised Marcus Butler during his MD thesis.

Ubiquitin-dependent proteolysis of trihydrophobin 1 (TH1) by the human papilloma virus E6-associated protein (E6-AP).

Human Papilloma virus E6-associated protein (E6-AP), which is known as an E3 ubiquitin ligase, mediates ubiquitination and subsequent degradation of a series of cellular proteins. In this paper, we identify here trihydrophobin 1 (TH1), an integral subunit of the human negative transcription elongation factor (NELF) complex, as a novel E6-AP interaction protein and a target of E6-AP-mediated degradation. Overexpression of E6-AP results in degradation of TH1 in a dose-dependent manner, whereas knock-down of endogenous E6-AP elevates the TH1 protein level. TH1 protein turnover is substantially faster, compared to controls, in cells that overexpressed E6-AP. Wild-type E6-AP promotes the ubiquitination of TH1, while a catalytically inactive point mutant of E6-AP abolishes its ubiquitination. Furthermore, in vitro ubiquitination assay also demonstrates that TH1 can be ubiquitinated by E6-AP. The degradation is blocked by treatment with proteasome inhibitor MG132. Herein, we provide strong evidence that TH1 is a specific substrate that is targeted for degradation through E6-AP-catalyzed polyubiquitination.

Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation

The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in neoplasia altering the tumour suppressive roles of the TP53 family. In order to define the normal role played by TP63 and provide the basis for better understanding how this network is perturbed in disease, we used chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq) to identify >7500 high-confidence TP63-binding regions across the entire genome, in primary human neonatal foreskin keratinocytes (HFKs). Using integrative strategies, we demonstrate that only a subset of these sites are bound by TP53 in response to DNA damage. We identify a role for TP63 in transcriptional regulation of multiple genes genetically linked to cleft palate and identify AP-2alpha (TFAP2A) as a co-regulator of a subset of these genes. We further demonstrate that AP-2gamma (TFAP2C) can bind a subset of these regions and that acute depletion of either TFAP2A or TFAP2C alone is sufficient to reduce terminal differentiation of organotypic epidermal skin equivalents, indicating overlapping physiological functions with TP63.

Privacy Region Protection for H.264/AVC with Enhanced Scrambling Effect and a Low Bitrate Overhead

While video surveillance systems have become ubiquitous in our daily lives, they have introduced concerns over privacy invasion. Recent research to address these privacy issues includes a focus on privacy region protection, whereby existing video scrambling techniques are applied to specific regions of interest (ROI) in a video while the background is left unchanged. Most previous work in this area has only focussed on encrypting the sign bits of nonzero coefficients in the privacy region, which produces a relatively weak scrambling effect. In this paper, to enhance the scrambling effect for privacy protection, it is proposed to encrypt the intra prediction modes (IPM) in addition to the sign bits of nonzero coefficients (SNC) within the privacy region. A major issue with utilising encryption of IPM is that drift error is introduced outside the region of interest. Therefore, a re-encoding method, which is integrated with the encryption of IPM, is also proposed to remove drift error. Compared with a previous technique that uses encryption of IPM, the proposed re-encoding method offers savings in the bitrate overhead while completely removing the drift error. Experimental results and analysis based on H.264/AVC were carried out to verify the effectiveness of the proposed methods. In addition, a spiral binary mask mechanism is proposed that can reduce the bitrate overhead incurred by flagging the position of the privacy region. A definition of the syntax structure for the spiral binary mask is given. As a result of the proposed techniques, the privacy regions in a video sequence can be effectively protected by the enhanced scrambling effect with no drift error and a lower bitrate overhead.

O balanced scorecard e a administração local:aplicação à divisão financeira do município de Vila Franca de Xira

Dissertação, Mestrado, Contabilidade e Finanças, Instituto Politécnico de Santarém, Escola Superior de Gestão e Tecnologia, 2014

Artefactos tangíveis e adaptáveis no ambiente doméstico

Recentemente assistimos a uma evolução da relação do Homem com a tecnologia, em larga medida acompanhada por novos modelos de interacção que modificam a forma de conceber os artefactos e constroem novos contextos de uso. Procuramos investigar, na presente tese, uma das abordagens emergentes, o universo dos media tangíveis, articulando a perspectiva do design da tecnologia orientada para a Human-Computer Interation (HCI), com a dimensão social, cultural e estética no uso da tecnologia. Os media tangíveis, ao contrário do que sucede com os conteúdos digitais convencionais, têm espessura e expressão física e, porque são dotados de um corpo que habita o espaço das disposições físicas, estão sujeitos à acção do mundo cultural e das práticas sociais que regem os demais objectos físicos que podemos encontrar no nosso quotidiano. Esta nova relação com a tecnologia digital obrigará as disciplinas que se encontram mais próximas do desenvolvimento tecnológico, tais como o Design de Interacção e a HCI, a abrirem-se aos contributos e abordagens das ciências humanas. Admitindo que a natureza subjacente ao processo da adaptabilidade no ambiente doméstico altera o equilíbrio da relação entre o design e o uso da tecnologia, julgamos ser essencial o desenvolvimento de uma fenomenologia da interação. Por outro lado, a adaptabilidade dos media tangíveis apresenta um conjunto de dificuldades, não apenas de ordem técnica, mas também de natureza conceptual, que têm dificultado o desenvolvimento e a implementação no terreno de tecnologias personalizáveis. Um dos objectivos da presente tese consiste em investigar um quadro conceptual capaz de enquadrar o fenómeno da adaptabilidade dos media tangíveis, e desenvolver uma tecnologia que possa servir de objecto a um estudo empírico com base numa abordagem etnográfica.

Pregnancy and newborns disorders followed by urine metabolomics

Chapter 1 introduces the scope of the work by identifying the clinically relevant prenatal disorders and presently available diagnostic methods. The methodology followed in this work is presented, along with a brief account of the principles of the analytical and statistical tools employed. A thorough description of the state of the art of metabolomics in prenatal research concludes the chapter, highlighting the merit of this novel strategy to identify robust disease biomarkers. The scarce use of maternal and newborn urine in previous reports enlightens the relevance of this work. Chapter 2 presents a description of all the experimental details involved in the work performed, comprising sampling, sample collection and preparation issues, data acquisition protocols and data analysis procedures. The proton Nuclear Magnetic Resonance (NMR) characterization of maternal urine composition in healthy pregnancies is presented in Chapter 3. The urinary metabolic profile characteristic of each pregnancy trimester was defined and a 21-metabolite signature found descriptive of the metabolic adaptations occurring throughout pregnancy. 8 metabolites were found, for the first time to our knowledge, to vary in connection to pregnancy, while known metabolic effects were confirmed. This chapter includes a study of the effects of non-fasting (used in this work) as a possible confounder. Chapter 4 describes the metabolomic study of 2nd trimester maternal urine for the diagnosis of fetal disorders and prediction of later-developing complications. This was achieved by applying a novel variable selection method developed in the context of this work. It was found that fetal malformations (FM) (and, specifically those of the central nervous system, CNS) and chromosomal disorders (CD) (and, specifically, trisomy 21, T21) are accompanied by changes in energy, amino acids, lipids and nucleotides metabolic pathways, with CD causing a further deregulation in sugars metabolism, urea cycle and/or creatinine biosynthesis. Multivariate analysis models´ validation revealed classification rates (CR) of 84% for FM (87%, CNS) and 85% for CD (94%, T21). For later-diagnosed preterm delivery (PTD), preeclampsia (PE) and intrauterine growth restriction (IUGR), it is found that urinary NMR profiles have early predictive value, with CRs ranging from 84% for PTD (11-20 gestational weeks, g.w., prior to diagnosis), 94% for PE (18-24 g.w. pre-diagnosis) and 94% for IUGR (2-22 g.w. pre-diagnosis). This chapter includes results obtained for an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) study of pre-PTD samples and correlation with NMR data. One possible marker was detected, although its identification was not possible. Chapter 5 relates to the NMR metabolomic study of gestational diabetes mellitus (GDM), establishing a potentially predictive urinary metabolic profile for GDM, 2-21 g.w. prior to diagnosis (CR 83%). Furthermore, the NMR spectrum was shown to carry information on individual phenotypes, able to predict future insulin treatment requirement (CR 94%). Chapter 6 describes results that demonstrate the impact of delivery mode (CR 88%) and gender (CR 76%) on newborn urinary profile. It was also found that newborn prematurity, respiratory depression, large for gestational age growth and malformations induce relevant metabolic perturbations (CR 82-92%), as well as maternal conditions, namely GDM (CR 82%) and maternal psychiatric disorders (CR 91%). Finally, the main conclusions of this thesis are presented in Chapter 7, highlighting the value of maternal or newborn urine metabolomics for pregnancy monitoring and disease prediction, towards the development of new early and non-invasive diagnostic methods.

Manutenção preventiva ou manutenção corretiva em linhas aéreas de média tensão? Utilização do data envelopment analysis como auxiliar de gestão dos ativos técnicos de manutenção

O uso de Data Envelopment Analysis (DEA) no setor de distribuição de energia elétrica tem dado origem à publicação de vários artigos científicos. No geral, estes artigos focam-se na comparação da eficiência das empresas de distribuição de eletricidade. Na generalidade dos artigos, o tratamento da informação tem sido predominantemente descritivo e classificatório, sem focar no processo de transformação. Em contraste, o trabalho que se apresenta aqui pretende mostrar as potencialidades do DEA na análise de variáveis do processo de transformação e procura explorar o seu potencial para a identificação dos programas e intervenções que contribuem para a melhoria efetiva no processo de distribuição de eletricidade. É nossa convicção que as avaliações de natureza formativa, com fins de aprendizagem, são mais eficazes do que os estudos sumativos porque contribuem para uma melhor compreensão das estruturas e processos, sendo portanto mais adequadas para contribuir para a melhoria do desempenho. Neste trabalho, apresenta-se uma questão importante no contexto da análise DEA: a de investigar, se as diferenças de eficiência são devidas a um programa específico de gestão ou às características de conceção. Para o efeito, o estudo recorre a dois métodos diferentes para realizar este tipo de análise. Em primeiro lugar, aplicamos a estatística de rank de Mann-Whitney aos scores do DEA, a fim de avaliar a significância estatística das diferenças observadas entre um programa de tratamento e o programa de controlo. Em segundo lugar, procedemos a uma análise dinâmica com o Índice de Produtividade de Malmquist, a fim de estudar o impacto da introdução de uma nova tecnologia num grupo de unidades. O estudo de caso desenvolvido centra-se na avaliação do desempenho de linhas de média tensão afetas a uma das regiões de serviço de uma empresa de distribuição de energia elétrica, regulada pelo Sistema Público de Distribuição de Energia em Portugal (ERSE). Os resultados do estudo de caso mostram que a aplicação do DEA tem um grande potencial para contribuir para a melhoria dos processos e deve ser explorado noutros contextos.

A relevância do justo valor: entidades com títulos cotados nas bolsas de Lisboa e de Madrid

Dissertação de Mestrado, Contabilidade, Faculdade de Economia, Universidade do Algarve, 2015

Determinantes da estrutura de capital das PME do Distrito de Faro

Dissertação de mestrado, Finanças Empresariais, Faculdade de Economia, Universidade do Algarve, 2014

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bias

NCRF 2: demonstração dos fluxos de caixa e suas implicações fiscais e de auditoria

Dissertação para obtenção do Grau de Mestre em Auditoria Orientador: Mestre Adalmiro Álvaro Malheiro de Castro Andrade Pereira