O esverdeamento da economia e os tributos verdes : um duro caminho rumo à sustentabilidade da gestão dos resíduos sólidos urbanos (RSU)

Tese (doutorado)—Universidade de Brasília, Centro de Desenvolvimento Sustentável, 2013.

Flower abscission and fruit set on table grapes (Vitis vinifera L.): unraveling physiological and molecular mechanisms

Doutoramento em Engenharia Agronómica - Instituto Superior de Agronomia - UL

Reformas na gestão hospitalar:análise dos efeitos da empresarialização

Tese de Doutoramento em Ciências Sociais na Especialidade de Administração da Saúde

Intervenções socioeducativas no contexto do tratamento : estudo de caso de crianças com cancro em contexto de acolhimento

Dissertação apresentada para obtenção do grau de Mestre em Educação Social e Intervenção Comunitária

Intervenções socioeducativas no contexto do tratamento : estudo de caso de crianças com cancro em contexto de acolhimento

Dissertação apresentada para obtenção do grau de Mestre em Educação Social e Intervenção Comunitária

Investigating Angiotensin II in cardiac remodelling and the counter-regulatory actions of Angiotensin-(1-9)

Cardiovascular diseases (CVDs) including, hypertension, coronary heart disease and heart failure are the leading cause of death worldwide. Hypertension, a chronic increase in blood pressure above 140/90 mmHg, is the single main contributor to deaths due to heart disease and stroke. In the heart, hypertension results in adaptive cardiac remodelling, including LV hypertrophy to normalize wall stress and maintain cardiac contractile function. However, chronic increases in BP results in the development of hypertensive heart disease (HHD). HHD describes the maladaptive changes during cardiac remodelling which result in reduced systolic and diastolic function and eventually heart failure. This includes ventricular dilation due to eccentric hypertrophy, cardiac fibrosis which stiffens the ventricular wall and microvascular rarefaction resulting in a decrease in coronary blood flow albeit an increase in energy demand. Chronic activation of the renin-angiotensin-system (RAS) with its effector peptide angiotensin (Ang)II plays a key role in the development of hypertension and the maladaptive changes in HHD. Ang II acts via the angiotensin type 1 receptor (AT1R) to mediate most of its pathological actions during HHD, including stimulation of cardiomyocyte hypertrophy, activation of cardiac fibroblasts and increased collagen deposition. The counter-regulatory axis of the RAS which is centred on the ACE2/Ang-(1-7)/Mas axis has been demonstrated to counteract the pathological actions of Ang II in the heart and vasculature. Ang-(1-7) via the Mas receptor prevents Ang II-induced cardiac hypertrophy and fibrosis and improves cardiac contractile function in animal models of HHD. In contrast, less is known about Ang-(1-9) although evidence has demonstrated that Ang-(1-9) also antagonises Ang II and is anti-hypertrophic and anti-fibrotic in animal models of acute cardiac remodelling. However, so far it is not well documented whether Ang-(1-9) can reverse established cardiac dysfunction and remodelling and whether it is beneficial when administered chronically. Therefore, the main aim of this thesis was to assess the effects of chronic Ang-(1-9) administration on cardiac structure and function in a model of Ang II-induced cardiac remodelling. Furthermore, this thesis aimed to investigate novel pathways contributing to the pathological remodelling in response to Ang II. First, a mouse model of chronic Ang II infusion was established and characterised by comparing the structural and functional effects of the infusion of a low and high dose of Ang II after 6 weeks. Echocardiographic measurements demonstrated that low dose Ang II infusion resulted in a gradual decline in cardiac function while a high dose of Ang II induced acute cardiac contractile dysfunction. Both doses equally induced the development of cardiac hypertrophy and cardiac fibrosis characterised by an increase in the deposition of collagen I and collagen III. Moreover, increases in gene expression of fibrotic and hypertrophic markers could be detected following high dose Ang II infusion over 6 weeks. Following this characterisation, the high dose infusion model was used to assess the effects of Ang-(1-9) on cardiac structural and functional remodelling in established disease. Initially, it was evaluated whether Ang-(1-9) can reverse Ang II-induced cardiac disease by administering Ang-(1-9) for 2-4 weeks following an initial 2 week infusion of a high dose of Ang II to induce cardiac contractile dysfunction. The infusion of Ang-(1-9) for 2 weeks was associated with a significant improvement of LV fractional shortening compared to Ang II infusion. However, after 4 weeks fractional shortening declined to Ang II levels. Despite the transient improvement in cardiac contractile function, Ang-(1-9) did not modulate blood pressure, LV hypertrophy or cardiac fibrosis. To further investigate the direct cardiac effects of Ang-(1-9), cardiac contractile performance in response to Ang-(1-9) was evaluated in the isolated Langendorff-perfused rat heart. Perfusion of Ang-(1-9) in the paced and spontaneously beating rat heart mediated a positive inotropic effect characterised by an increase in LV developed pressure, cardiac contractility and relaxation. This was in contrast to Ang II and Ang-(1-7). Furthermore, the positive inotropic effect to Ang-(1-9) was blocked by the AT1R antagonist losartan and the protein kinase A inhibitor H89. Next, endothelial-to-mesenchymal transition (EndMT) as a novel pathway that may contribute to Ang II-induced cardiac remodelling was assessed in Ang II-infused mice in vivo and in human coronary artery endothelial cells (HCAEC) in vitro. Infusion of Ang II to mice for 2-6 weeks resulted in a significant decrease in myocardial capillary density and this was associated with the occurrence of dual labelling of endothelial cells for endothelial and mesenchymal markers. In vitro stimulation of HCAEC with TGFβ and Ang II revealed that Ang II exacerbated TGF-induced gene expression of mesenchymal markers. This was not correlated with any changes in SMAD2 or ERK1/2 phosphorylation with co-stimulation of TGFβ and Ang II. However, superoxide production was significantly increased in HCAEC stimulated with Ang II but not TGFβ. Finally, the role of Ang II in microvesicle (MV)-mediated cardiomyocyte hypertrophy was investigated. MVs purified from neonatal rat cardiac fibroblasts were found to contain detectable Ang II and this was increased by stimulation of fibroblasts with Ang II. Treatment of cardiomyocytes with MVs derived from Ang II-stimulated fibroblasts induced cardiomyocyte hypertrophy which could be blocked by the AT1R antagonist losartan and an inhibitor of MV synthesis and release brefeldin A. Furthermore, Ang II was found to be present in MVs isolated from serum and plasma of Ang II-infused mice and SHRSP and WKY rats. Overall, the findings of this thesis demonstrate for the first time that the actions of Ang-(1-9) in cardiac pathology are dependent on its time of administration and that Ang-(1-9) can reverse Ang II-induced cardiac contractile dysfunction by acting as a positive inotrope. Furthermore, this thesis demonstrates evidence for an involvement of EndMT and MV signalling as novel pathways contributing to Ang II-induced cardiac fibrosis and hypertrophy, respectively. These findings provide incentive to further investigate the therapeutic potential of Ang-(1-9) in the treatment of cardiac contractile dysfunction in heart disease, establish the importance of novel pathways in Ang II-mediated cardiac remodelling and evaluate the significance of the presence of Ang II in plasma-derived MVs.

TECTONIC CONTROLS ON FLUVIAL LANDSCAPE DEVELOPMENT IN CENTRAL-EASTERN PORTUGAL: INSIGHTS FROM LONG PROFILE TRIBUTARY STREAM ANALYSES

This study examines the long profiles of tributaries of the Tejo (Tagus) and Zêzere rivers in central eastern Portugal (West Iberia) in order to provide new insights into the patterns, timing and controls on drainage development during the Pleistocene to Holocene incision stage. The long profiles were extracted from lower order tributary streams associated with the trunk drainage of the Tejo River and one main tributary, the Zêzere River (Fig. 1). These streams flow through a landscape strongly influenced by variations in bedrock lithology (mainly granites and metasediments), fault structures delimiting crustal blocks with distinct uplift rates, and a base-level lowering history (tectonic uplift / eustatic). The long profiles of the tributaries of the Tejo and Zêzere rivers record a series of transient and permanent knickpoints. The permanent knickpoints have direct correlation with the bedrock strength, corresponding to the outcropping of very hard quartzites or to the transition from softer (slates/metagreywaques) to harder (granite) basement. The analyzed streams/rivers record also an older transient knickpoint/knickzone separating: a) an upstream relict graded profile, with lower steepness and higher concavity, that reflects a long period of quasi-equilibrium conditions reached after the beginning of the incision stage; and b) a downstream reach displaying a rejuvenated long profile, with steeper gradient and lower concavity, particularly for the final segment, which is often convex (Fig. 2). The rejuvenated reaches testify the upstream propagation of several incision waves that are the response of each stream to continuous or increasing crustal uplift and dominant periods of base-level lowering by the trunk drainages, coeval of low sea level conditions. The long profiles and their morphological configurations enabled spatial and relative temporal patterns of incision to be quantified for each individual tributary stream. The incision values of streams flowing in uplifted blocks of the Portuguese Central Range (PCR) (ca.380-280 m) indicate differential uplift and are higher than the incision values of streams flowing on the adjacent South Portugal planation surface – the Meseta (ca. 200 m). The normalized steepness index, calculated using the method of Wobus et al. (2006), proved to be sensitive to active tectonics, as lower ksn values were found in relict graded profiles of streams located in less uplifted blocks, (e.g. Sertã stream in the PCR), or in those flowing through tectonic depressions. Fig. 1 – Geological map of the study area. 1 – fluvial terraces (Pleistocene); 2 – sedimentary cover (Paleogene and Neogene); 3 – slates and metasandstones (Devonian); 4 – slates and quartzites (Silurian); 5 – quartzites (Ordovician); 6 – slates and metagreywackes (Precambrian to Cambrian); 7 – slates, metagreywackes and limestones (Precambrian); 8 – granites and ortogneisses; 9 – diorites and gabros; 10 - fault. SFf – Sobreira Formosa fault; Sf – Sertã fault; Pf – Ponsul fault; Gf – Grade fault. The differential uplift indicated by the distribution of the ksn values and by the fluvial incision was likely accumulated on a few major faults, as the Sobreira Formosa fault (SFf), thus corroborating the tectonic activity of these faults. Due to the fact that the relict graded profiles can be correlated with other geomorphic references documented in the study area, namely the T1 terrace of the Tagus River (with an age of ca. 1 Myr), the following incision rates can be estimated: a) for the studied streams located in uplifted blocks of the PCR, 0.38 m/kyr to 0.28 m/kyr; b) for the streams flowing on the South Portugal planation surface, 0.20 m/kyr. The differential uplift inferred between crustal blocks in the study area corroborates the neotectonic activity of the bordering faults, which has been proposed in previous studies based upon less robust data. Fig. 2 – Longitudinal profile of the Nisa stream a tributary of the Tejo River. Note the equilibrium relict profile upstream the older transient knickpoint (hatched line) and the downstream rejuvenated profile (continuous line). Legend: tKP – transient knickpoint; rKp – resistant knickpoint; Mt – schist and phyllite; Gr – granite; Hf – hornfels; Og – orthogneisse. In the inset Distance – Slope plots, fill circles correspond to the relict graded profile, crosses correspond to the rejuvenated profile located downstream the older transient knickpoint (tKP).

Proposal for Academic Achievement and Permanence of Students in the 7th Grade (1)

This paper analyzes the impact of change processes experienced by many student populations when completing primary education (1st-6th grade) and starting secondary education (7th-11th grade). Based on the research conducted, this paper describes situations and aspects that may result in conditional factors for the student’s adjustment at this level: time-space changes, as well as organizational and dynamic changes that would set the new educational environment and social context in which this new stage will be developed. Such conditional factors that affect learning in incoming students: programs, teaching methodology, learning styles and new evaluation methods will be discussed. As a result of this research, a proposal is presented to facilitate transition from primary to the secondary education. This proposal includes guidelines for awareness and strengthening of pedagogical mediation, which would contribute to the permanence of students from all types of institutions in the education system.  (1) [Translator’s note: The Costa Rican education system is composed of primary education (1st-6th grade) and secondary education (7th-11th grade).]

Study of genes involved in her2-positive breast cancer progression for identification of new therapeutic targets

HER2 overexpression is observed in 20-30% of invasive breast carcinomas and it is correlated with poor prognosis. Although targeted therapies have revolutionized the treatment of HER2-positive breast cancer, a high number of patients presented primary or acquired resistance to monoclonal antibodies and tyrosine kinase inhibitors. Tumor heterogenicity, epithelial to mesenchymal transition (EMT) and cancer stem cells are key factors in target therapy resistance and tumor progression. The aim of this project was to discover alternative therapeutic strategies to over-come tumor resistance by harnessing immune system and looking for new targetable molecules. The results reported introduce a virus-like particles-based vaccine against HER2 as promising therapeutic approach to treat HER2-positive tumors. The high and persistent anti-HER2 antibody titers elicited by the vaccine significantly inhibited tumor growth and metastases onset. Furthermore, the polyclonal response induced by the vaccine also inhibited human HER2-positive breast cancer cells resistant to trastuzumab in vitro, suggesting its efficacy also on trastuzumab resistant tumors. To identify new therapeutic targets to treat progressed breast cancer, we took advantage from a dynamic model of HER2 expression obtained in our laboratory, in which HER2 loss and cancer progression were associated with the acquisition of EMT and stemness features. Targeting EMT-involved molecules, such as PDGFR-β, or the induction of epithelial markers, like E-cadherin, proved to be successful strategy to impair HER2-negative tumor growth. Density alterations, which might be induced by anti-HER2 target therapies, in cell culture condition of a cell line with a labile HER2 expression, caused HER2 loss probably as consequence of more aggressive subpopulations which prevail over the others. These subpopulations showed an increased EMT and stemness profile, confirming that targeting EMT-involved molecules or antigen expressed by cancer stem cells together with anti-HER2 target therapies is a valid strategy to inhibit HER2-positive cells and simultaneously prevent selection of more aggressive clone.

Role of CARM1 (PRMT4) in high grade serous ovarian cancer metabolism and function of PRMT5 in ARID1A- deficient endometrial cancer invasion

The arginine methyltransferase CARM1 (PRMT4) is amplified and overexpressed in ~20% of high-grade serous ovarian cancer (HGSOC) and correlates with a poor survival. Therapeutic approaches based on CARM1 expression remain to be an unmet need. Here we show that fatty acid metabolism represents a metabolic vulnerability for HGSOC in a CARM1 expression status dependent manner. CARM1 promotes the de novo synthesis of fatty acids and monounsaturated fatty acids (MUFAs). The disruption of MUFAs synthesis by inhibition of SCD1 results in excessive accumulation of cytotoxic saturated fatty acids and it is synthetic lethal with CARM1 expression. Collectively, our data show that the pharmacological inhibition of MUFAs synthesis via SCD1 inhibition represents a therapeutic strategy for CARM1-high HGSOC. Another arginine methyltransferase, PRMT5, has been identified by our CRISPR screening analysis as a promising candidate for invasive ARID1A-deficient endometrial cancer. Endometrial Cancer frequently harbor somatic inactivating mutation of ARID1A that can promote an invasive phenotype. Our in vitro approach validated the CRISPR screening showing that both PRTM5 knock down and its pharmaceutical inhibition specifically hamper the invasion of ARID1A inactivated cells. Mechanistically, PRMT5 directly regulates the epithelia to mesenchymal transition pathway genes interacting with the SWI/SNF complexes. Moreover, in vivo experiments showed that PRMT5 inhibition contrasted the myometrium invasion highlighting PRMT5 inhibition as promising therapeutic strategy for ARID1A- inactivated aggressive endometrial cancer.

Conceptualization of an Electric Compact SUV for the American and Italian Market using the IDeS Method

Electric cars are increasingly popular due to a transition of mobility towards more sustainable forms. From an increasingly green and pollution reduction perspective, there are more and more incentives that encourage customers to invest in electric cars. Using the Industrial Design and Structure (IDeS) research method, this project has the aim to design a new electric compact SUV suitable for all people who live in the city, and for people who move outside urban areas. In order to achieve the goal of developing a new car in the industrial automotive environment, the compact SUV segment was chosen because it is a vehicle very requested by the costumers and it is successful in the market due to its versatility. IDeS is a combination of innovative and advanced systematic approaches used to set up a new industrial project. The IDeS methodology is sequentially composed of Quality Function Deployment (QFD), Benchmarking (BM), Top-Flop analysis (TFA), Stylistic Design Engineering (SDE), Design for X, Prototyping, Testing, Budgeting, and Planning. The work is based on a series of steps and the sequence of these must be meticulously scheduled, imposing deadlines along the work. Starting from an analysis of the market and competitors, the study of the best and worst existing parameters in the competitor’s market is done, arriving at the idea of a better product in terms of numbers and innovation. After identifying the characteristics that the new car should have, the other step is the styling part, with the definition of the style and the design of the machine on a 3D CAD. Finally, it switches to the prototyping and testing phase to see if the product is able to work. Ultimately, intending to place the car on the market, it is essential to estimate the necessary budget for a possible investment in this project.

Oxidative Stress And Susceptibility To Mitochondrial Permeability Transition Precedes The Onset Of Diabetes In Autoimmune Non-obese Diabetic Mice.

Beta cell destruction in type 1 diabetes (TID) is associated with cellular oxidative stress and mitochondrial pathway of cell death. The aim of this study was to determine whether oxidative stress and mitochondrial dysfunction are present in T1D model (non-obese diabetic mouse, NOD) and if they are related to the stages of disease development. NOD mice were studied at three stages: non-diabetic, pre-diabetic, and diabetic and compared with age-matched Balb/c mice. Mitochondria respiration rates measured at phosphorylating and resting states in liver and soleus biopsies and in isolated liver mitochondria were similar in NOD and Balb/c mice at the three disease stages. However, NOD liver mitochondria were more susceptible to calcium-induced mitochondrial permeability transition as determined by cyclosporine-A-sensitive swelling and by decreased calcium retention capacity in all three stages of diabetes development. Mitochondria H2O2 production rate was higher in non-diabetic, but unaltered in pre-diabetic and diabetic NOD mice. The global cell reactive oxygen species (ROS), but not specific mitochondria ROS production, was significantly increased in NOD lymphomononuclear and stem cells in all disease stages. In addition, marked elevated rates of 2',7'-dichlorodihydrofluorescein (H2DCF) oxidation were observed in pancreatic islets from non-diabetic NOD mice. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) and lipidomic approach, we identified oxidized lipid markers in NOD liver mitochondria for each disease stage, most of them being derivatives of diacylglycerols and phospholipids. These results suggest that the cellular oxidative stress precedes the establishment of diabetes and may be the cause of mitochondrial dysfunction that is involved in beta cell death.

Transition From Glass To Digital Slide Microscopy In The Teaching Of Oral Pathology In A Brazilian Dental School.

Several medical and dental schools have described their experience in the transition from conventional to digital microscopy in the teaching of general pathology and histology disciplines; however, this transitional process has scarcely been reported in the teaching of oral pathology. Therefore, the objective of the current study is to report the transition from conventional glass slide to virtual microscopy in oral pathology teaching, a unique experience in Latin America. An Aperio ScanScope® scanner was used to digitalize histological slides used in practical lectures of oral pathology. The challenges and benefits observed by the group of Professors from the Piracicaba Dental School (Brazil) are described and a questionnaire to evaluate the students' compliance to this new methodology was applied. An improvement in the classes was described by the Professors who mainly dealt with questions related to pathological changes instead of technical problems; also, a higher interaction with the students was described. The simplicity of the software used and the high quality of the virtual slides, requiring a smaller time to identify microscopic structures, were considered important for a better teaching process. Virtual microscopy used to teach oral pathology represents a useful educational methodology, with an excellent compliance of the dental students.

Transition to complete synchronization in phase-coupled oscillators with nearest neighbor coupling

We investigate synchronization in a Kuramoto-like model with nearest neighbor coupling. Upon analyzing the behavior of individual oscillators at the onset of complete synchronization, we show that the time interval between bursts in the time dependence of the frequencies of the oscillators exhibits universal scaling and blows up at the critical coupling strength. We also bring out a key mechanism that leads to phase locking. Finally, we deduce forms for the phases and frequencies at the onset of complete synchronization.

Entanglement and classical instabilities: Fingerprints of electron-hole-to-exciton phase transition in a simple model

We propose a schematic model to study the formation of excitons in bilayer electron systems. The phase transition is signalized both in the quantum and classical versions of the model. In the present contribution we show that not only the quantum ground state but also higher energy states, up to the energy of the corresponding classical separatrix orbit, ""sense"" the transition. We also show two types of one-to-one correspondences in this system: On the one hand, between the changes in the degree of entanglement for these low-lying quantum states and the changes in the density of energy levels; on the other hand, between the variation in the expected number of excitons for a given quantum state and the behavior of the corresponding classical orbit.