High prevalence of malignancy in HIV-positive patients with mediastinal lymphadenopathy: A study in the era of antiretroviral therapy.

Mediastinal lymphadenopathy (MLN) in human immunodeficiency virus (HIV) infection has a wide spectrum of aetiologies with different prognoses and treatments. The decision to pursue a histopathological diagnosis represents a clinical challenge as patients present with non-specific symptoms. This study aimed to determine the aetiology and predictive factors of MLN in a cohort of HIV-infected patients in the combination antiretroviral therapy (cART) era

Emerging and innovative techniques for arsenic removal applied to a small water supply system

The impact of arsenic on human health has led its drinking water MCL to be drastically reduced from 50 to 10 ppb. Consequently, arsenic levels in many water supply sources have become critical. This has resulted in technical and operational impacts on many drinking water treatment plants that have required onerous upgrading to meet the new standard. This becomes a very sensitive issue in the context of water scarcity and climate change, given the expected increasing demand on groundwater sources. This work presents a case study that describes the development of low-cost techniques for efficient arsenic control in drinking water. The results obtained at the Manteigas WTP (Portugal) demonstrate the successful implementation of an effective and flexible process of reactive filtration using iron oxide. At real-scale, very high removal efficiencies of over 95% were obtained.(undefined

THE MOLECULAR MECHANISMS OF IRON AND FERRITIN METABOLISM IN NORMAL AND NEOPLASTIC CELLS

Iron (Fe) is essential for cell growth and replication as many Fe-containing proteins catalyse key reactions involved in energy metabolism (cytochromes, mitochondrial aconitase and Fe-S proteins of the electron transport chain), respiration (hemoglobin and myoglobin) and DNA synthesis (ribonucleotide reductase). If not appropriately shielded, Fe could participate in one-electron transfer reactions that lead to the production of extremely toxic free radicals. The Fe storage protein, ferritin, is essential to protect cells against Fe-mediated oxidative stress by accommodating excess Fe into its protein shell (Xu et al., 2005). However, despite intensive research over the last few decades, many questions relating to intracellular Fe metabolism, e.g. Fe release from ferritin remain unanswered. Therefore, it is important to elucidate the molecular mechanisms of Fe trafficking in cells. At the beginning of my candidature, little was understood regarding the effect of anti-cancer agents, anthracyclines on the Fe-regulated genes, including transferrin receptor-1 (TfR1), N-myc downstream-regulated gene-1 (Ndrg1) and ferritin. Furthermore, the mechanisms of ferritin-Fe release and anthracycline-mediated ferritin-Fe accumulation are unclear. The work presented in Chapters 3 and 4 has addressed these issues. Apart from the studies examining the molecular interactions of anthracyclines with Fe, a mouse model with perturbed Fe metabolism was used and the marked alterations of protein expression in the heart of this knockout mouse model was discussed in Chapter 5. Chapter 3 Anthracyclines are effective anti-cancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron (Fe) and perturb Fe metabolism (Xu et al., 2005). These effects on Fe-trafficking remain poorly understood, but are important to decipher as treatment for anthracycline cardiotoxicity utilises the chelator, dexrazoxane. Incubation of cells with doxorubicin (DOX) up-regulated mRNA levels of the Fe-regulated genes, transferrin receptor-1 (TfR1) and N-myc downstream-regulated gene-1 (Ndrg1). This effect was mediated by Fe-depletion, as it was reversed by adding Fe and was prevented by saturating the anthracycline metal-binding site with Fe. However, DOX did not act like a typical chelator, as it did not induce cellular Fe mobilisation. In the presence of DOX and 59Fe-transferrin, Fe-trafficking studies demonstrated ferritin-59Fe accumulation and decreased cytosolic-59Fe incorporation. This could induce cytosolic Fe-deficiency and increase TfR1 and Ndrg1 mRNA. Up-regulation of TfR1 and Ndrg1 by DOX was independent of anthracycline-mediated radical generation and occurred via HIF-1α-independent mechanisms. Despite increased TfR1 and Ndrg1 mRNA after DOX treatment, this agent decreased TfR1 and Ndrg1 protein expression. Hence, the effects of DOX on Fe metabolism were complex due to its multiple effector mechanisms. Chapter 4 The Fe storage protein, ferritin, can accommodate up to 4500 atoms of Fe in its protein shell (Harrison and Arosio, 1996). However, the underlying mechanism of ferritin-Fe release remains unknown. Previous studies demonstrated that anti-cancer agents, anthracyclines, led to ferritin-59Fe accumulation (Kwok and Richardson, 2003). The increase in ferritin-59Fe was shown to be due to a decrease in the release of Fe from this protein. It could be speculated that DOX may impair the Fe release pathway by preventing the synthesis of essential ferritin partner proteins that induce Fe release. In this study, a native protein purification technique has been utilised to isolate ferritin-associated partners by combining ultra-centrifugation, anion-exchange chromatography, size exclusion chromatography and native gel electrophoresis. In addition to cells in culture (namely, SK-Mel-28 melanoma cells), liver taken from the mouse was used as a physiological in vivo model, as this organ is a major source of ferritin. Four potential partner proteins were identified along with ferritin, e.g. aldehyde dehydrogenase 1 family, member L1 (ALDH1L1). Future studies are required to clarify the relationship of these proteins with cellular Fe metabolism and ferritin-Fe release. Chapter 5 A frequent cause of death in Friedreich’s ataxia patients is cardiomyopathy, but the molecular alterations underlying this condition are unknown. We performed two dimensional electrophoresis to characterise the changes in protein expression of hearts using the muscle creatine kinase frataxin conditional knockout (KO) mouse. Pronounced changes in the protein expression profile were observed in 9-week-old KO mice with severe cardiomyopathy. In contrast, only a few proteins showed altered expression in asymptomatic 4-week-old KO mice. In hearts from frataxin KO mice, components of the iron-dependent complex-I and -II of the mitochondrial electron transport chain and enzymes involved in ATP homeostasis (creatine kinase, adenylate kinase) displayed decreased expression. Interestingly, the KO hearts exhibited increased expression of enzymes involved in the citric acid cycle, catabolism of branched-chain amino acids, ketone body utilisation and pyruvate decarboxylation. This constitutes evidence of metabolic compensation due to decreased expression of electron transport proteins. There was also pronounced up-regulation of proteins involved in stress protection, such as a variety of chaperones, as well as altered expression of proteins involved in cellular structure, motility and general metabolism. This is the first report of the molecular changes at the protein level which could be involved in the cardiomyopathy of the frataxin KO mouse

Adenosine A2A receptors contribute to the radial migration of cortical projection neurons through the regulation of neuronal polarization and axon formation

Cortical interneurons born in the subpallium reach the cortex through tangential migration, whereas pyramidal cells reach their final position by radial migration. Purinergic signaling via P2Y1 receptors controls the migration of intermediate precursor cells from the ventricular zone to the subventricular zone. It was also reported that the blockade of A2A receptors (A2AR) controls the tangential migration of somatostatin+ interneurons. Here we found that A2AR control radial migration of cortical projection neurons. In A2AR-knockout (KO) mouse embryos or naïve mouse embryos exposed to an A2AR antagonist, we observed an accumulation of early-born migrating neurons in the lower intermediate zone at late embryogenesis. In utero knockdown of A2AR also caused an accumulation of neurons at the lower intermediate zone before birth. This entails the presently identified ability of A2AR to promote multipolar–bipolar transition and axon formation, critical for the transition of migrating neurons from the intermediate zone to the cortical plate. This effect seems to require extracellular ATP-derived adenosine since a similar accumulation of neurons at the lower intermediate zone was observed in mice lacking ecto-5′-nucleotidase (CD73-KO). These findings frame adenosine as a fine-tune regulator of the wiring of cortical inhibitory and excitatory networks.European Regional Development Fund, through the Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000008; BrainHealth2020); COMPETE 2020-Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT—Fundação para a Ciência e Tecnologia (PTDC/NEU-NMC/3567/2014 to R.J.R.; POCI-01-0145-FEDER-028160 to J.M.M.); Center for Neuroscience and Cell Biology (POCI-01-0145-FEDER-007440; UIDB/04539/2020); Spanish Ministry of Science, Innovation and Universities (PGC2018/096631-B-100 to G.L-B.).Peer reviewe

Measuring Incineration Plants' Performance using Combined Data Envelopment Analysis, Goal Programming and Mixed Integer Linear Programming

Incineration plants produce heat and power from waste, reduce waste disposal to landfills, and discharge harmful emissions and bottom ash. The objective of the incineration plant is to maximize desirable outputs (heat and power) and minimize undesirable outputs (emissions and bottom ash). Therefore, studying the overall impact of incineration plants in a region so as to maximize the benefits and minimize the environmental impact is significant. Majority of prior works focus on plant specific decision making issues including performance analysis. This study proposes a hybrid Data Envelopment Analysis (DEA), Goal Programming (GP) and Mixed Integer Linear Programming (MILP) model to assess the performance of incineration plants, in a specific region, to enhance overall power production, consumption of waste and reduction of emissions. This model not only helps the plant operators to evaluate the effectiveness of incineration but also facilitates the policy makers to plan for overall waste management of the region through decision-making on adding and closing plants on the basis of their efficiency. Majority of prior studies on incineration plants emphasize on how to improve their performance on heat and power production and neglect the waste management aspects. Additionally, optimizing benefits and minimizing negative outputs through fixing targets in order to make decision on shutting down the suboptimal plants has not been modeled in prior research. This research combines both the aspects and addresses the overall performance enhancement of incineration plants within a region from both policy makers and plant operators’ perspectives. The proposed combined DEA, GP and MILP model enables to optimize incineration plants performance within a region by deriving efficiency of each plant and identifying plants to close down on the basis of their performance. The proposed model has been applied to a group of 22 incineration plants in the UK using secondary data in order to demonstrate the effectiveness of the model.

Adenosine A2A receptors control synaptic remodeling in the adult brain

The molecular mechanisms underlying circuit re-wiring in the mature brain remains ill-defined. An eloquent example of adult circuit remodelling is the hippocampal mossy fiber (MF) sprouting found in diseases such as temporal lobe epilepsy. The molecular determinants underlying this retrograde re-wiring remain unclear. This may involve signaling system(s) controlling axon specification/growth during neurodevelopment reactivated during epileptogenesis. Since adenosine A2A receptors (A2AR) control axon formation/outgrowth and synapse stabilization during development, we now examined the contribution of A2AR to MF sprouting. A2AR blockade significantly attenuated status epilepticus(SE)-induced MF sprouting in a rat pilocarpine model. This involves A2AR located in dentate granule cells since their knockdown selectively in dentate granule cells reduced MF sprouting, most likely through the ability of A2AR to induce the formation/outgrowth of abnormal secondary axons found in rat hippocampal neurons. These A2AR should be activated by extracellular ATP-derived adenosine since a similar prevention/attenuation of SE-induced hippocampal MF sprouting was observed in CD73 knockout mice. These findings demonstrate that A2AR contribute to epilepsy-related MF sprouting, most likely through the reactivation of the ability of A2AR to control axon formation/outgrowth observed during neurodevelopment. These results frame the CD73-A2AR axis as a regulator of circuit remodeling in the mature brain.This work was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0145-FEDER-000008 (BrainHealth2020), and through the COMPETE 2020-Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT—Fundação para a Ciência e Tecnologia, under the projects POCI-01-0145-FEDER-028160 (to J.M.M), UIDB/04539/2020, UIDP/04539/2020 and LA/P/0058/2020, as well as EXPL/NEU-NMC/0671/2012 by FCT (to R.J.R.), LCF/PR/HP17/52190001 by La Caixa Foundation (to R.A.C.) and PID2019-105234RB-I00 by the Spanish Agency of Research (AEI) (to J.L.). X.X. was supported by European Neuroscience Campus (M.Curie:Cycle4-2013-PT-07).Peer reviewe

Interactive multicriteria decision support system for spatial planning analysis

This paper builds upon previous work entailing, in a first stage, the development of a geographic information system based environmental modelling approach and, in a second stage, the development of a stand-alone, more generic integrated spatial decision support system. The latter system was designed to address general spatial decision problems in a way that enables interactive definition of mathematical models, the spatial entities involved and their attributes. This manuscript focuses primarily on a further development to implement a multicriteria modelling framework supporting sophisticated evaluation and comparison of hypothetical alternative scenarios in the context of spatial decision problems. Typically several conflicting and generally incommensurable criteria are involved, which derive from the multidimensional nature of most of the decision problems. In such circumstances, multicriteria techniques are recommended to be used in the analysis process. Overall, at the very beginning, the decision maker is not fully aware of the whole problem in hand and hence an effective learning process needs to be undertaken. Operating interactively with the methods above, either simultaneously or following a given sequence, the decision maker may become effectively acquainted with the whole problem by investigating possible coherences among results obtained and also by analysing sensitivity of variations in input data

Remoção de arsénio em sistemas em sistemas de abastecimento de água. Um caso de estudo

A presença de arsénio nas origens de água para consumo humano é um problema que tem suscitado uma preocupação crescente a nível mundial devido à sua repercussão na saúde pública, originando, a sua exposição prolongada, lesões cutâneas graves e perturbações neurológicas incapacitantes. Vários estudos epidemiológicos vieram confirmar a potencial acção cancerígena de algumas espécies de arsénio, levando a OMS a recomendar uma redução drástica no valor-guia (de 0,050 para 0,010 ppm) da norma de qualidade da água para consumo humano. A União Europeia aprovou a Directiva n.º 98/83/CE (Drinking Water Directive - DWD), que impôs a adopção desse novo limite (0,010 ppm) a partir de 25/12/2003, mantendo-se esse valor paramétrico na legislação portuguesa em vigor (DL 306/2007, de 27 de Agosto). Esta alteração legislativa colocou muitas origens de água de pequenos e médios sistemas de abastecimento numa situação de incumprimento, ainda que sazonal, implicando que as entidades gestoras desses sistemas de abastecimento de água tivessem de promover a adaptação das técnicas utilizadas para remoção de arsénio em ETA já existentes, através da realização de obras de reconversão, ou de construir/ampliar ETA, de modo a instalar processos de remoção de arsénio até então não necessários. Quando a substituição dessas origens de água se revela impossível ou demasiado dispendiosa, a remoção do arsénio na água bruta coloca-se como a única opção viável para se obter uma água segura para consumo humano, tornando pertinente o desenvolvimento de tecnologias de remoção inovadoras, mais eficientes e economicamente sustentáveis, aplicáveis a sistemas de abastecimento. de pequenos e médios aglomerados populacionais. Neste trabalho faz-se uma síntese dos principais impactos da ingestão (por via hídrica) de arsénio na saúde humana e dos principais processos de tratamento (convencionais e emergentes) utilizados nas águas para consumo humano, incluindo uma análise das respectivas eficiências, de modo a estabelecer critérios de selecção dessas tecnologias em função das características da água bruta a tratar e/ou dos esquemas de tratamento, no caso de ETA já existentes. Neste contexto, apresenta-se o caso de estudo da reabilitação da ETA de Manteigas, efectuada pela empresa Águas do Zêzere e Côa (AdZC), onde se implementou, com o sucesso que os resultados obtidos demonstram, uma solução eficaz e economicamente sustentável de correcção dos níveis de arsénio numa água bruta com excelente qualidade microbiológica, baseada num processo de filtração reactiva, que utiliza o óxido de ferro como material adsorvente, permitindo eficiências de remoção muito elevadas (superiores a 90%

Information literacy in portuguese school libraries: a longitudinal study of master degree dissertations

Since the beginning of the 21st century, a rapid growth in access to information and communication technologies has been observed in Portugal, as well as in other European countries. School libraries (SL) and teacher librarians (TL) play a fundamental role as they have been increasingly considered by school communities as an essential resource for developing information literacy (IL) competences. The methodology for this study was a meta-analysis of the results of a body of master dissertations, completed between 2007 and 2017, at Universidade Aberta, Portugal. A first group of the analysed dissertations indicated that in general, TL misunderstood the concept of IL, were still not aware of its importance and most of their work was still related to traditional library activities. In more recent years we have identified some important improvements in Portuguese SL and in research studies and evidence of that progress is shown.This work is financed by national funds by FCT - Foundation for Science and Technology under the project UID/HIS/00057/2013 (POCI-01-0145-FEDER-007702), FCT/Portugal, COMPETE, FEDER, Portugal 2020.info:eu-repo/semantics/acceptedVersio