Cell division and chromosome segregation in Staphylococcus aureus

Dissertação para a obtenção do grau de doutor em Biologia pelo Instituto de Tecnologia Química e Biológica. Universidade Nova de Lisboa

Measuring chromosome-end fusions in fission yeast

Dissertation presented to obtain the Ph.D degree in Molecular Biology

The impact of Ireland’s current Mental Health Policy on the profile of community mental Health Services

RESUMO: Em 2006, foi aprovada uma nova política governamental para a saúde mental intitulada “Uma Visão para a Mudança”, a qual está neste momento no sétimo ano de implementação. A política descreve um enquadramento para o desenvolvimento e promoção da saúde mental positiva para toda a Comunidade e para a prestação de serviços acessíveis, baseados na comunidade, serviços especializados para pessoas com doença mental. A implementação da política e o tornar a “Vision for Change” uma realidade têm sido problemáticos, com críticas consideráveis por parte dos intervenientes, relativas à lenta e desconexa implementação. Este estudo fornece informação sobre as características dos serviços de três importantes tipos de instituições de saúde mental comunitária a nível nacional, nomeadamente Hospitais de Dia, Centros de Dia e residências comunitárias operantes 24 horas. A pesquisa analisa objetivos e funções, perfis dos pacientes, atividades terapêuticas, a eficácia das redes de comunicação e beneficia da perspectiva dos funcionários sobre o que mudou no terreno ao longo dos últimos sete anos. As questões identificadas a partir das características dos três serviços dizem respeito a todos. Os participantes indicaram que o ethos da recuperação parece ter alcançado um papel mais central no tratamento do paciente na comunidade mas reconheceram que o desafio de integrar os princípios de recuperação na prática clínica se mantém presente. Parece ser reconhecida a importância da planificação do cuidado individual nos serviços comunitários e os entrevistados indicaram que existe um empenho para garantir o envolvimento do usuário do serviço. Há diferenças entre os „pontos de vista do pessoal‟ e os „pontos de vista dos representantes‟ sobre uma série de aspetos da prestação de serviços. Este é o primeiro estudo irlandês deste género a examinar a prestação de serviços das três principais instituições comunitárias de saúde mental num só estudo. Estes serviços representam um enorme investimento em recursos, quer a nível monetário, quer humano. O estudo examinou os desafios e as questões fundamentais que lhe são aplicáveis e que têm impacto nestes três tipos de prestação de serviços. Também forneceu informações sobre os elementos de mudança positiva, os quais se começam a focar lentamente na prestação do serviço, assim como na importância da centralidade do utilizador do serviço e na promoção de um ethos da recuperação.----------ABSTRACT: In 2006, a new Government policy for mental health “A Vision for Change” was endorsed and is currently in the seventh year of implementation. The policy describes a comprehensive framework for building and fostering positive mental health across the entire community and for providing accessible, community based, specialist services for people with mental illness. The implementation of the policy and turning “Vision for Change” into reality has been problematic with considerable criticism from stakeholders concerning slow and disjointed implementation. This study provides information on three key community mental health service settings, namely Day Hospitals, Day Centres and 24 Hour Community Residences at a national level. The research looks at aims and functions, patient profiles, therapeutic activities, effectiveness of key communication networks and gains an insight from staff on what has changed on the ground over the past seven years. Issues identified from the three service settings pertain to all. Participants indicated that the recovery ethos appears to have moved to a more central role in patient care in the community but acknowledged that the challenge of integrating recovery principles in clinical practice remains present. The importance of individual care planning appears to be recognised in community services and respondents indicated that efforts are being made to ensure service user involvement. There were differences between „staff views‟ and „advocate views‟ on a number of aspects of service provision. This is the first Irish study of its kind to examine service provision across the three main community mental health settings in one study. These services represent a huge investment in resources both on a monetary and human level. This study has examined the challenges and key issues which are applicable and impacting on all three types of service provision. It has also provided information on the elements of positive change, which are slowly embedding themselves in service provision such as the importance of the centricity of the service user and the promotion of a recovery ethos.

Fixed-mobile integration

Often, fixed-line incumbents also own the largest mobile network. We consider the effect of this joint ownership on market outcomes. Our model predicts that while fixed-to-mobile call prices to the integrated mobile network are more efficient than under separation, those to rival mobile networks are distorted upwards, amplifying any incumbency advantage. As concerns potential remedies, a uniform off-net pricing constraint leads to higher welfare than functional separation and even allows to maintain some of the efficiency gains.

Collateral, default penalties and infinite horizon equilibrium

Pascoa and Seghir (2009) noticed that when collateralized promises become subject to utility penalties on default, Ponzi schemes may occur. However, equilibrium exists in some interesting cases. Under low penalties, equilibrium exists if the collateral does not yield utility (for example, when it is a productive asset or a security). Equilibrium exists also under more severe penalties and collateral utility gains, when the promise or the collateral are nominal assets and the margin requirements are endogenous: relative inflation rates and margin coefficients can make the income effects dominate the penalty effects. An equilibrium refinement avoids no-trade equilibria with unduly repayment beliefs. Our refinement differs from the one used by Dubey, Geanakoplos and Shubik (2005) as it does not eliminate no trade equilibria whose low delivery rates are consistent with the propensity to default of agents that are on the verge of selling.

Adjusting to external imbalances within the EMU, the case of Portugal

From 1995 to 2010 Portugal has accumulated a negative international asset position of 110 percent of GDP. In a developed and aging economy the number is astonishing and any argument to consider it sustainable must rely on extremely favorable forecasts on growth. Portuguese policy options are reduced in number: no autonomous monetary policy, no currency to devaluate, and limited discretion in changing fiscal deficits and government debt. To start the necessary deleveraging a remaining possible policy is a budget-neutral change of the tax structure that increases private saving and net exports. An increase in the VAT and a decrease in the employer’s social security contribution tax can achieve the desired outcome in the short run if they are complemented with wage moderation. To obtain a substantial improvement in competitiveness and a large decrease in consumption, the changes in the tax rates have to be large. While a precise quantitative assessment is difficult, the initial increase in the effective VAT rate needed to allow the social security tax to decrease by 16 percentage points (pp) is approximately 10 pp. Such a large increase in the effective VAT rate could be obtained by raising most of the reduced VAT rates to the new general VAT rate of 23 percent. The empirical analysis shows that over time the suggested tax swap could generate surpluses and improve the trade balance. A temporary version of the suggested tax-swap has the attractiveness to achieve a sharper increase in the private saving rate maintaining the short run gains in competitiveness. Finally, the temporary version of the fiscal devaluation could be the basis for an automatic stabilizer to external imbalances within a monetary union.Portugal has been running large current account deficits every year since 1995. These deficits have accumulated to an astonishing 110 percent of GDP negative external asset position. The sustainability of such a large external position is questionable and must rely on fantastic productivity growth expectations. The recent global financial crisis appears to have anticipated the international investors reality check on those future expectations with the result of a large increase in the cost of external financing. Today the rebalancing of the current account through an increase in national savings and an improvement in competitiveness must be at the top of the Portuguese authorities “to do” list as the cost of a pull out from international investors is of the order of 10% of GDP. The external rebalancing is difficult as the degrees of freedom of the Portuguese authorities are limited in number: they have no autonomous monetary policy, no currency to devaluate, and little discretion in fiscal policy as deficit limits and debt targets are set by the Stability Growth Pact and the postcrisis consensus on medium-term fiscal consolidation. One possibility that remains is to change the fiscal policy mix for a given budget deficit. The purpose of this paper is to explore the effects of a “fiscal devaluation”1 obtained through a tax swap between employers’ social security contributions and taxes on consumption2. The paper begins by illustrating Portugal’s current account evolution during the euro period. The second section section lays out a model to offer a qualitative assessment of the dynamic outcomes of the the tax swap. I show that the suggested tax swap can in theory achieve the desired outcomes in terms of competitiveness and consumption if complemented with moderation (stickiness) in wages. I also study the effects of a temporary version of the tax swap and show that it achieves a sharper improvement in the current account that accelerate the rebalancing. The third section moves to the empirical analysis and estimates the likely effects of the tax swap for the Portuguese economy. The fourth section concludes.

Equity in access to MRI equipment: the Portuguese case

Magnetic resonance imaging (MRI) is a method of image diagnose proven to be of undeniable importance when it comes to neuro and cardio related diseases. In fact, these diseases (such as: ischemic heart disease, stroke and acute myocardial infection) have high incidence in Portugal. For these reasons, the allocation of this medical technology should not be considered with light thoughts. In fact, making decision of resource allocation in health care can be a very complex and contested matter. The impacts of new technology allocation, such MRI, can be assessed in a variety of ways. However, a fundamental component should always be present: the use of evidence-based decision-making methods. One of these methods is Technology Assessment (TA). This paper aims to characterize the equity on access of the Portuguese population in general, to a specific medical device such as MRI, under the TA point of view. It is hoped to promote a bridge of scientific knowledge between the gap on research and policy-making through TA that can emerge as a tool to aid decision-makers in the organization of health systems. There are gaps in providing healthcare, due to geographical imbalances, with some areas unable to provide certain specialized services, as hospitals in the countryside do not provide all medical specialties. Portugal has also a large independent private sector that provides diagnostic and therapeutic services to NHS users under contracts called conventions. These medical contracts cover ambulatory health facilities for laboratory tests and examinations such as diagnostic tests and Radiology. However, there is no convention from the NHS when concerning the MRI exam. Therefore, this reality can be considered a limitation in the access of the general population to this kind of clinical exam. TA can play an useful and important role in helping the decision-makers to explore potential gains that might be achieved by introducing a more rational decision making into health care management, namely into the Radiology area, regarding the allocation of MRI equipment.

Oi merger with Portugal Telecom: A strategic partnership

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA – School of Business and Economics

A system’s approach to cache hierarchy-aware decomposition of data-parallel computations

Dissertação para obtenção do Grau de Mestre em Engenharia Informática

Clearing the cloudy crystal balls: Hybrid modelling for energy and climate change mitigation scenarios – A case study for Portugal

Dissertação para obtenção do Grau de Doutor em Ambiente

A framework for efficient model transformations

The reported productivity gains while using models and model transformations to develop entire systems, after almost a decade of experience applying model-driven approaches for system development, are already undeniable benefits of this approach. However, the slowness of higher-level, rule based model transformation languages hinders the applicability of this approach to industrial scales. Lower-level, and efficient, languages can be used but productivity and easy maintenance seize to exist. The abstraction penalty problem is not new, it also exists for high-level, object oriented languages but everyone is using them now. Why is not everyone using rule based model transformation languages then? In this thesis, we propose a framework, comprised of a language and its respective environment, designed to tackle the most performance critical operation of high-level model transformation languages: the pattern matching. This framework shows that it is possible to mitigate the performance penalty while still using high-level model transformation languages.

Thermal performance of cool facades: evaluation by Infrared Thermography

High reflective paints (cool paints) are used on flat roofs to reduce heat gains from the incidence of solar radiation and thus improve the thermal comfort and energy efficiency of buildings, especially in summer periods. Given the application potential of these paints on vertical surfaces, a research study has been developed to evaluate the thermal performance of reflective paints on walls under real exposure conditions. Accordingly, different reflective paints have been applied as the final coating of an ETICS type solution, on the facades of a full scale experimental cell built at LNEC campus. For being applied in an ETICS system a paint has to fulfill several requirements, whether aesthetic or functional (such as the adhesion between the coating layers or the durability of the insulation), essential for its efficient performance. Since this construction coating system is subject to a prolonged sun exposure, various problems may arise, such as paint degradation or deterioration of the thermal insulation properties, particularly when dark colors are applied. To evaluate the thermal performance of the chosen paints, the method of non-destructive analysis by Infrared Thermography was used. Thermography allows knowing the temperature distribution of facades by measuring the radiation emitted by their surfaces. To complement the thermographic diagnosis, thermocouples were placed between the insulation and the paint system of the experimental cell. Additional laboratory tests allowed the characterization of the optical properties (reflectance and emittance) of the different reflective paints used in this study. The comparative analysis of the thermal performance of reflective and conventional paints revealed that the reflective paint allows a reduction of the facade surface temperature, reducing the risk of loss of insulating properties of the ETICS system and thus ensuring its longevity and functionality. The color of the paint used affects, naturally, the reflective ability of the surface and may have an important role in energy balance of the building. This paper also showed the potential of infrared thermography in the evaluation of the thermal performance of reflective paints.

Thomsen-Friedenreich antigens in bladder cancer: evaluation of their prognostic value

RESUMO: Introdução. O cancro de bexiga é uma patologia comum que representa o 6° e o 5° cancro mais incidente em Portugal e na Itália, respetivamente. Em mais de metade dos casos ocorre reincidência durante o primeiro ano, requerendo acompanhamento clínico ao longo da vida. A instilação intravesical de Bacillus Calmette-Guérin (BCG) (uma estirpe atenuada do Mycobacterium bovis) representa uma imunoterapia eficaz no combate ao cancro de bexiga, no entanto, muitos aspetos da interação de BCG com as células tumorais bem como com as células do sistema imunitário permanecem por desvendar. As células tumorais de bexiga expressam frequentemente as formas sialiladas dos antigénios de Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). Contudo ainda se desconhece o significado da sua expressão na malignidade tumoral e se afeta a eficácia da terapêutica BCG. Objetivo do estudo. Investigar o papel dos antigénios sT e sTn no fenótipo maligno de células de cancro de bexiga bem como na resposta mediada pelo sistema imunitário à terapia com BCG. Metodologia. Para tal, foram utilizadas as linhas celulares de cancro da bexiga HT1376 e MCR, geneticamente modificadas por transdução com vetores codificantes para as sialiltransferases ST3GAL1 ou ST6GALNAC1, de forma a expressar homogeneamente os antigénios sT ou sTn respetivamente. Estes modelos celulares foram estudados após confronto com BCG. O nível de BCG internalizado foi avaliado por citometria de fluxo. O perfil global de expressão genética dos modelos celulares antes e após incubação com BCG foi analisado pela tecnologia de microarray. O perfil de citocinas secretadas pelos modelos celulares após incubação com BCG, bem como de macrófagos estimulados pelo secretoma de células de cancro de bexiga que por sua vez foram estimuladas previamente por BCG, foi estudado pelo sistema multiplex de “imuno-esferas”. Resultados. A análise do transcritoma dos modelos celulares revelou que grupos de genes envolvidos em funções específicas foram modulados em paralelo nos dois modelos celulares, após transdução, independentemente da sialiltransferase expressa. Ou seja, em células que expressavam a sialiltransferase ST3GAL1 ou ST6GALNAC1, os genes envolvidos na regulação da segregação cromossómica e na reparação do DNA foram consistentemente regulados negativamente. Genes descritos na literatura como marcadores para o cancro de bexiga foram também modulados. A incubação com BCG resultou numa tendência ao aumento da expressão de genes relevantes na preservação e estabilidade genómica e menor malignidade, no entanto, apenas em células que expressavam sT ou sTn. Entre as dez citocinas testadas, apenas a IL-6 e IL-8 foram expressas pelas linhas celulares de cancro da bexiga, com indução destas após estimulação com BCG, e principalmente em células que expressavam ST3GAL1 ou ST6GALNAC1. Em macrófagos, citocinas inflamatórias, tais como IL-1β, IL-6 e TNFα, e a citocina anti-inflamatória IL-10, foram induzidas apenas pelo secretoma de células de cancro da bexiga confrontadas com BCG, com maior relevância quando estas expressavam ST3GAL1 ou ST6GALNAC1, prevendo a estimulação de macrófagos semelhantes aos de tipo M1 e uma melhor resposta à terapia com BCG. Conclusões. O efeito geral da expressão destas sialiltransferases e dos produtos enzimáticos sT ou sTn nas células de cancro de bexiga conduz a um fenótipo de maior malignidade. Contudo, a maior avidez de estas na produção de citocinas inflamatórias após confronto com BCG, bem como a maior capacidade de estimulação de macrófagos, predirá uma resposta à terapia com BCG mais eficaz em tumores que expressem os antigénios de TF sialilados. Tais conclusões são totalmente concordantes com os nossos mais recentes dados clínicos obtidos em colaboração, que mostram que em doentes com cancro de bexiga que expressam sTn respondem melhor a terapia BCG. ----------ABSTRACT: Background. Bladder cancer is a common malignancy representing the 6th and the 5th most incident cancer in Portugal and in Italy, respectively. More than half of the cases relapse within one year, requiring though a lifelong follow-up. Intravesical instillation of Bacillus Calmette-Guérin (BCG) (an attenuated strain of Mycobacterium bovis) represents an effective immunotherapy of bladder cancer, although many aspects of the interaction of BCG with cancer cells and host immune cells remain obscure. Bladder cancer cells often express the sialylated forms of the Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). However, it’s still unknown the sense of such expression in tumour malignancy and in the BCG therapy efficacy. Aim of the study. To investigate the role of the sT and sTn antigens on the malignant phenotype of bladder cancer cells and the immune mediated response to BCG therapy. Experimental. We have utilized populations of the bladder cancer cell lines HT1376 and MCR, genetically modified by transduction with the sialyltransferases ST3GAL1 or ST6GALNAC1 to express homogeneously sT or sTn antigens. The level of BCG internalized was assessed by flow cytometry. The whole gene expression profile of BCG-challenged or unchallenged bladder cancer cell lines was studied by microarray technology. The profile of cytokines secreted by BCG-challenged bladder cancer cells and that of macrophages challenged by the secretome of BCG-challenged bladder cancer cells was studied by multiplex immune-beads assay. Results. Transcriptome analysis of the sialyltransferase-transduced cells revealed that groups of genes involved in specific functions were regulated in parallel in the two cell lines, regardless the sialyltransferase expressed. Namely, in sialyltransferase-expressing cells, genes involved in the proper chromosomal segregation and in the DNA repair were consistently down-regulated, while genes reported in literature as markers for bladder cancer were modulated. BCG-challenging induced a tendency to up-regulation of the genes preserving genomic stability and reducing malignancy, but only in cells expressing either sT or sTn. Among the ten cytokines tested, only IL-6 and IL-8 were expressed by bladder cancer cell lines and up-regulated by BCG-challenging, mainly in sialyltransferases-expressing cells. In macrophages, inflammatory cytokines, such as IL-1β, IL-6 and TNFα, and the antinflammatory IL-10 were induced only by the secretome of BCG-challenged bladder cancer cells, particularly when expressing either sialyltransferase, predicting the stimulation of M1-like macrophages and a better response to BCG therapy. Conclusions. The general effect of the expression of the two sialyltransferases and their products in the bladder cancer cells is toward a more malignant phenotype. However, the stronger ability of sialyltransferase expressing cells to produce inflammatory cytokines upon BCG-challenging and to stimulate macrophages predicts a more effective response to BCG in tumours expressing the sialylated TF antigens. This is fully consistent with our recent clinical data obtained in collaboration, showing that patients with bladder cancer expressing sTn respond better to BCG therapy.

A importância do setor convencionado das análises clínicas do SNS

RESUMO: Nos últimos anos, dado a atual conjuntura económica e social que o País atravessa, tem-se assistido a adoção de uma série de medidas de contenção de gastos em saúde, nomeadamente, com o setor convencionado das análises clínicas, que têm posto em causa a estrutura do próprio Serviço Nacional de Saúde (SNS). A presente dissertação centra-se, na importância que o setor convencionado das análises clínicas adquiriu ao longo dos 30 anos de existência do SNS, assim como a sua capacidade instalada, recursos humanos e financeiros que muito têm contribuído para os ganhos em saúde em Portugal.Metodologia  Desk research, compilação da informação com vista à preparação das entrevistas e consolidação da informação;  Entrevistas com stakeholders, entrevistas a alguns representantes do setor convencionado das análises clínicas;  Contextualização, análises da informação obtida nos dois pontos anteriores. ---------------ABSTRACT: In recent years, giving the current economic and social situation that the country is experiencing, there has been the adoption of a number of cost containment measures in health, in particular, agreed with the setor of clinical pathology, which have called into question the structure of the own National Health Service. This dissertation focuses on the importance of the agreed clinical pathology sector acquired over the 30 years of the National Health Service existence, as well as its installed capacity, human and financial resources that have greatly contributed to the health gains in Portugal.Methodology  Desk research, information collection for the preparation of interviews and consolidation of information;  Interviews with stakeholders, interviews with some representatives of the agreed field of clinical pathology;  Context, information analysis obtained in the previous two points.

Perceptions of the usefulness of external support to immunization coverage in Guinea-Bissau: a Delphi analysis of the GAVI-Alliance cash-based support

INTRODUCTION: Although many countries have improved vaccination coverage in recent years, some, including Guinea-Bissau, failed to meet expected targets. This paper tries to understand the main barriers to better vaccination coverage in the context of the GAVI-Alliance (The Global Alliance for Vaccines and Immunisation) cash-based support provided to Guinea-Bissau. METHODS: The analysis is based on a document analysis and a three round Delphi study with a final consensus meeting. RESULTS: Consensus attributed about 25% of the failure to perform better to implementation problems; and about 10% to governance and also 10% to scarce resources. The qualitative analysis validates the importance of implementation issues and upgraded the relevance of the human resources crisis as an important drawback. The recommendations were balanced in their upstream-downstream focus but were blind to health information issues and logistical difficulties. CONCLUSIONS: It is commendable that such a fragile state, with all sorts of barriers, manages to sustain a slow steady growth of its vaccination coverage. Not reaching the targets set reflects the inappropriateness of those targets rather than a lack of commitment of the health workforce. In the unstable context of countries such as Guinea-Bissau, the predictability of the funds from global health initiatives like the GAVI-Alliance seem to make all the difference in achieving small consistent health gains even in the presence of other major bottlenecks.