RCAAP Repository

A emigração macaense, entre as décadas de 1840 e 1950, elegeu dois territórios para destino de todos os que decidiram deixar Macau, principalmente a partir de 1842: Hong Kong e Xangai. O desfecho da I Guerra do Ópio (1839-1842) conduziu a profundas mudanças políticas, económicas e sociais em toda a Ásia Oriental e, em particular na China imperial. Em Macau, a saída das principais casas de comércio teve um forte impacte social, atingindo ainda uma maior dimensão se considerarmos que a emigração foi a resposta encontrada pela comunidade macaense às transformações económicas e sociais que ocorreram na cidade. A abertura ao comércio internacional catapultou Xangai para a liderança das cidades chinesas e atraiu ao seu porto, todos os anos, milhares de migrantes das mais variadas origens nacionais e culturais, entre os quais se encontravam os macaenses. Entre Macau e Xangai iniciou-se um importante fluxo migratório que deu origem à comunidade dos “portugueses de Xangai”. Herdeiros do passado migratório que esteve na origem da comunidade macaense ao longo de muitas décadas, os “portugueses de Xangai” acompanharam, dia a dia, o processo de formação, desenvolvimento e extinção das concessões estrangeiras, revelando estratégias que favoreceram a sua integração na sociedade que os acolheu sem, todavia, perderem os seus laços com Macau, o seu território de origem.

Objective: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation. Methods: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility. Results: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure. Conclusion: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice.

Objective: To evaluate the correlation between diaphragm thickness assessed by ultrasound (US) with respiratory function tests and the diaphragm motor responses, in patients with amyotrophic lateral sclerosis (ALS). Methods: 42 consecutive ALS patients were studied (11 with bulbar-onset), excluding patients with marked orofacial paresis. Investigation included: revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), maximal voluntary ventilation (MVV), maximal inspiratory (MIP) and expiratory (MEP) pressures, nasal inspiratory pressure during sniff (SNIP); peak-to-peak amplitude of the diaphragmatic motor response to phrenic nerve stimulation (Diaphragm-CMAP), diaphragmatic thickness measured by ultrasound during maximal inspiration and during maximal expiration. Patients were analysed in bulbar or spinal subgroups. Correlations and multiple linear regression models were studied. Results: The mean age at disease onset was 58.4 ± 11.1 years and with a mean disease duration of 17.8 ± 13.6 months. Ultrasound studies of diaphragm thickness in full inspiration correlated with diaphragm CMAP in the whole population and in spinal-onset patients; and were similar in the two groups. Multiple linear modelling showed that FVC, SNIP and MVV were dependent on the change of thickness (p=0.001, 0.001 and 0.020, respectively) and that MIP and MEP were related to diaphragm CMAP p=0.003 and p=0.025, respectively). Conclusion: Diaphragm thickness correlates with Diaphragm-CMAP, except in bulbar-onset patients. Respiratory tests are dependent on both diaphragm thickness and Diaphragm-CMAP. Significance: US thickness of the diaphragm correlates with the number of functional motor units as assessed by the phrenic nerve motor amplitude.

The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. We report a 71-year-old man who developed hemorrhagic bullae at sites distant from subcutaneous enoxaparin injections. It is important that clinicians be aware of the different adverse reactions of these widely used drugs.

Objective: Fasciculations are occasionally observed in root lesions, but their site of origin is uncertain. Methods: We studied the origin of fasciculations (FPs) in consecutive patients with mild chronic L5 root lesions, excluding peripheral nerve lesion. We used a novel technique of double-EMG needle recording, in which each needle was placed in the territory of separate motor units. With this technique the observation of synchronous FPs implies an origin proximal to distal axonal branching. Results: FPs were found in 13% of 84 consecutive patients with mild chronic L5 root lesions. In 25% they were synchronous in different motor units. Conclusions: We suggest that in mild L5 root lesions most FPs have an origin at distal branches but some FPs originate proximally (25%), possibly at the site of nerve compression. Significance: The proximal site of compression and more distal sites may both initiate fasciculation potentials in proximal root lesions.

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.

Introduction: Ankylosing Spondylitis (AS) is characterized by excessive local bone formation and concomitant systemic bone loss. Tumor necrosis factor (TNF) plays a central role in the inflammation of axial skeleton and enthesis of AS patients. Despite reduction of inflammation and systemic bone loss, AS patients treated with TNF inhibitors (TNFi) have ongoing local bone formation. The aim of this study was to assess the effect of TNFi in the differentiation and activity of osteoclasts (OC) in AS patients. Methods: 13 AS patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. 25 healthy donors were recruited as controls. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers and cytokines, in vitro OC differentiation assay and qRT-PCR for OC specific genes were performed. Results: RANKL+ circulating lymphocytes (B and T cells) and IL-17A, IL-23 and TGF-β levels were decreased after TNFi treatment. We found no differences in the frequency of the different monocyte subpopulations, however, we found decreased expression of CCR2 and increased expression of CD62L after TNFi treatment. OC number was reduced in patients at baseline when compared to controls. OC specific gene expression was reduced in circulating OC precursors after TNFi treatment. However, when cultured in OC differentiating conditions, OC precursors from AS TNFi-treated patients showed increased activity as compared to baseline. Conclusion: In AS patients, TNFi treatment reduces systemic pro osteoclastogenic stimuli. However, OC precursors from AS patients exposed to TNFi therapy have increased in vitro activity in response to osteoclastogenic stimuli.

Objective: To postulate a new possible cause of a unilaterally reduced arm swing in addition to the known medical conditions such as shoulder pathology, Erb's palsy, stroke, and Parkinson's disease. Methods: Analysis of YouTube videos depicting the gait of highly ranked Russian officials. Results: We found a similar walking pattern in President Vladimir Putin, Prime Minister Dmitry Medvedev and three other highly ranked Russian officials, all presenting with a consistently reduced right arm swing in the absence of other overt neurological abnormalities. Conclusions: We propose that this new gait pattern, which we term "gunslinger's gait," may result from a behavioural adaptation, possibly triggered by KGB or other forms of weapons training where trainees are taught to keep their right hand close to the chest while walking, allowing them to quickly draw a gun when faced with a foe. This should be included in the differential diagnosis of a unilaterally reduced arm swing.

Background: Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need. We have shown, in vitro, that celastrol inhibits both IL-1β and TNF, which play an important role in RA, and, in vivo, that celastrol has significant anti-inflammatory properties. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA). Methods: Celastrol was administered to AIA rats both in the early (4 days after disease induction) and late (11 days after disease induction) phases of arthritis development. The inflammatory score, ankle perimeter and body weight were evaluated during treatment period. Rats were sacrificed after 22 days of disease progression and blood, internal organs and paw samples were collected for toxicological blood parameters and serum proinflammatory cytokine quantification, as well as histopathological and immunohistochemical evaluation, respectively. Results: Here we report that celastrol significantly decreases the number of sublining CD68 macrophages and the overall synovial inflammatory cellularity, and halted joint destruction without side effects. Conclusions: Our results validate celastrol as a promising compound for the treatment of arthritis.

Amyotrophic lateral sclerosis (ALS) is a dreadful degenerative disorder, characterized by rapidly progressing weakness causing respiratory impairment and death, in spite of moderate benefits from non-invasive ventilation, gastrostomy, riluzole treatment and multidisciplinary care (Andersen et al., 2012). Over the years a large of number of drugs have been tested to deal with this disorder, but all trials have been negative except for riluzole. We can observe that different strategies have been explored in the past, from immunosuppression to neuroprotection, from nerve growth factors to antiglutamatergic compounds (de Carvalho et al., 2005). Threshold tracking has been used to investigate axonal excitability in peripheral nerve motor axons in ALS (Vucic and Kiernan, 2006). Increased persistent Na+ conductance and reduced K+ conductance have been described (Vucic and Kiernan, 2006), which tend to become more marked with disease duration and may be a predictor of survival (Cheah et al., 2012). More recently, it has been suggested that motor neurons have an abnormal function of the membrane ion channels, in ALS (Devlin et al., 2015). These observations have opened a new window of opportunity in clinical trials for ALS, for testing drugs that modulate ion channels in order to stabilize membranes.

Safinamide (Xadago™) is an oral α-aminoamide derivative marketed for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties, namely highly selective and reversible inhibition of monoamine oxidase B, and nondopamimetic properties, namely selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release. In 2014, safinamide was approved in the European Economic Area, as "an add-on therapy to stable dose levodopa, alone or in combination with other PD therapies in mid- to late-stage-fluctuating PD patients." In addition, evidence has been provided for safinamide in the treatment of motor symptoms in early PD patients. This article summarizes the pharmacological properties, development program, clinical indications for PD treatment, stratified according to several disease's stages and the safety profile of safinamide. A meta-analysis of the most frequent adverse events among Phase III trials has been also performed.

Protein folding is an essential cellular process, required for proper molecular and cellular function. The cell has evolved as a sophisticated machinery that ensures the quality and stability of the proteome. The network of cellular processes that coordinates protein synthesis, folding, trafficking and clearance, and determines the fate of proteins that do not acquire a native conformation, is responsible for maintaining protein homeostasis (proteostasis) and is referred to as “the proteostasis network” (PN). The key components of the quality control system are molecular chaperones that ensure proper folding under physiological and stress conditions. To restore homeostasis, the PN also relies on stress sensors and inducible pathways, such as the heat shock response (HSR), the unfolded protein response (UPR) and the oxidative stress response. How a protein folds and acquires its native conformation is a matter of high medical relevance since a large number of human diseases are associated with protein misfolding. These conditions are broadly classified as conformational disorders, and they are caused either by genetic mutations that cause protein misfolding and premature degradation (e.g. Cystic Fibrosis and Gaucher’s disease); or by the accumulation of misfolded, aggregated and/or fibrillar protein inclusions that are toxic to the cell. In particular, the phenomenon of protein aggregation is a hallmark of a large number of neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s and Huntington's diseases and several ataxias), muscular dystrophies, metabolic disorders and certain types of cancer. Considerable efforts have been directed at dissecting of the mechanisms of protein aggregation and toxicity, but the full extent of events leading to cell dysfunction is still unclear (Chapter I). The unifying aspect of conformational disorders is, however, the inability of the PN to respond efficiently to misfolded and aggregation-prone proteins so as to prevent cellular toxicity. Therefore, it is urgent and relevant to multiple diseases to identify genetic modifiers that enhance proteostasis function and consequently prevent protein aggregation and toxicity. Research has benefited from powerful model systems that recapitulate important aspects of the human disease. In particular, the nematode Caenorhabditis elegans (C. elegans) is a tractable genetic model organism that combines sufficient complexity so as to allow research on both cellular and organismal (including behavioral) phenotypes, with simplicity that facilitates rapid, high‐throughput testing of hypotheses (Chapter I). Genetic screens performed to date have identified the network’s protective components which, when knocked down or deleted, lead to enhanced aggregation and/or toxicity. These include molecular chaperones, proteasome subunits, components of the autophagy machinery, and the stress-induced transcriptional regulators FOXO/DAF-16 and HSF-1. The work described in this thesis is novel as it focuses on the opposite side of the PN, i.e., the pathways that when down-regulated lead to enhanced folding capacity. We established a screening strategy in C. elegans using RNA interference (RNAi) to identify genetic modifiers that suppress protein aggregation and toxicity of multiple disease-related proteins (Chapter II). Our goal was to identify genes that, when downregulated, enhanced the functional properties of the proteostasis network and restored the folding environment. We thus identified 63 genetic modifiers that suppressed both polyglutamine (polyQ) and mutant superoxide dismutase I (SOD1) aggregation, of which only 23 also suppressed the toxicity phenotype associated with aggregation. This was an important finding as it demonstrated that aggregation and toxicity can be genetically uncoupled. From the initial hits, 9 modifiers systematically reduced the misfolding of endogenous metastable mutant proteins, suggesting a general improvement of the folding environment. We postulated that this effect could be a consequence of activation of the heat shock stress response and chaperone expression by the modifiers. Although, we found that 5 improved folding in a HSF-1/chaperone dependent manner, the remaining modifiers improved folding by altering metabolism and RNA processing functions. Overall, this study introduced new genetic modifiers that promote alternate cellular folding environments broadly protective against misfolding events. We then characterized further the genetic modifier gei-11, a negative regulator of the L-type acetylcholine receptor (AChR) at the neuromuscular junction, to determine the mechanism of proteostasis enhancement (Chapter III). Downregulation of gei-11 increased cholinergic signaling and calcium flux into the cytoplasm of muscle cells, via activation of the voltage-gated calcium channel, EGL-19, and the sarcoplasmic reticulum ryanodine receptor, UNC-68. This resulted in selective activation of HSF-1 and upregulation of cytosolic chaperones that restored the post-synaptic folding environment. Earlier work had identified a loss-of-function deletion mutation in unc-30 that regulates GABA expression in C. elegans neurons, and resulting in enhanced polyQ aggregation in post-synaptic muscle cells (Garcia et al. 2007). Notably, enhanced aggregation occurs when GABAergic signaling is completely inhibited, resulting in maximum cholinergic overstimulation of muscle cells, whereas suppression of aggregation results from a moderate increase in cholinergic signaling. The effects of increased AChR expression are not the same as complete inhibition of GABA signaling, in part because the signaling response (and degree of stimulation) occurs at an intermediate level through a titrated response and waves of Ca2+ release. Therefore, the effect on post-synaptic protein aggregation is a consequence of the degree of imbalance generated between ACh and GABA, with an apparent range for folding improvement by cholinergic signaling. We propose that altogether these studies underscore the importance of the balance between cholinergic and GABAergic signaling as a mechanism for non-autonomous neuronal regulation of proteostasis in postsynaptic cells, and provide compelling evidence that will lead to a better understanding of the control of stress responses through tissue signaling events, which is very relevant for a number of neuromuscular disorders. We have also initiated the characterization of the hit gene let-607 (Appendix II). This gene is predicted to encode the C. elegans ortholog of CREBh, an ER regulated transmembrane protein (RIP) bZIP transcription factor that maintains sterol homeostasis in the liver and mediates UPR. Downregulation of let-607 in C. elegans led to an improvement of proteostasis function through activation of the HSR, upregulation of molecular chaperones and consequent suppression of protein misfolding, in an HSF-1- and XBP-1-dependent manner. UPR induction was found to be epistatic and required for HSR activation by let-607 RNAi. This is not observed for other UPR inducers, revealing specificity of “crosstalk” between the two stress responses through let-607. Currently, we are further characterizing the role of let-607 on UPR and the mechanism involved in UPR-mediated activation of the cytosolic HSR. The studies presented in this thesis emphasize the value of genetic screens and model organisms for the identification of genes and pathways that maintain protein homeostasis and are compromised in disease. Our screening strategy and triage hypotheses revealed novel genes/pathways that can be modulated to improve the PN capacity and help resolving the issue of protein aggregation-toxicity. Even greater value is offered by complementation of these genetic studies with small molecule screens to ultimately identify the suitable targets for therapeutics. This is highlighted in the work on “Chaperone Therapeutics: Small Molecule Proteostasis Regulators of the Heat Shock Response for Protein Conformational Diseases” (Appendix III). In this work we describe the results of a ~900,000 small molecule screen that identified small molecule proteostasis regulator compounds (PRs) that induce HSF-1- dependent chaperone expression and restore protein folding in multiple conformational disease models. The enhancement of proteome stability by the PRs is mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf2 and the chaperone machinery, through mechanisms that are distinct from current known small molecule activators of the HSR. Together, genetic and chemical modulation of the PN reveal new candidates and new mechanisms to be targeted by PRs, establishing promising therapeutic approaches for a variety of protein conformational diseases.

A tipicidade é uma dimensão chave no processamento de conceitos e refere-se ao grau em que um item é representativo da sua categoria. Itens típicos são processados mais facilmente em tarefas de categorização e de nomeação do que itens atípicos. O presente estudo tem como objetivo investigar as bases neuronais da categorização dos objetos e as regiões cerebrais envolvidas no processamento da tipicidade dos objetos. Estudos prévios centraram-se sobretudo na região do lobo temporal anterior e têm fornecido resultados contraditórios entre si. No presente estudo de fMRI, 26 jovens adultos realizaram uma tarefa de categorização, tendo sido manipulada a pertença à categoria e a tipicidade dos conceitos. Os resultados comportamentais e neuronais revelaram um efeito de interação. Objetos típicos foram categorizados mais rápida e acertadamente do que objetos atípicos, mas apenas quando pertenciam à categoria apresentada. A nível neuronal, verificou-se que quando os itens pertenciam à categoria, objetos típicos recrutaram o precuneus esquerdo associado à decisão com base na semelhança, enquanto os objetos atípicos elicitaram maior ativação no lobo frontal inferior esquerdo, que tem sido associado ao controlo semântico. Os resultados confirmam o papel central da tipicidade no processamento semântico e em particular na categorização e informam sobre as bases neuronais da variabilidade intra-categorial.

The consequences of the pandemic are numerous and continue to be felt in society. We saw our lives change radically in a matter of months and were affected socially, economically, and culturally. This dissertation entitled "Artistic Institutions and Curatorial Practices in Times of Pandemic" aims to investigate and analyze the impact of the Covid-19 pandemic on Portuguese culture and the measures taken to control and solve this crisis, in one year between March 2020, when the virus arrived in Portugal, and March 2021. The focus of this dissertation is the analysis of three Portuguese Artistic Institutions: the National Museum of Contemporary Art, a public institution located in downtown Lisbon; the Mechanical Music Museum, a private space located in the rural area of the council of Palmela; and the Common House, an exhibition space inside the Rectory Building of the University of Porto

The map is a visual device that allows sharing information about a territory and therefore about its communities. Its graphic ability to sythetise optimized the dissemination of geographic and demographic information. However, it is also this ability that establishes some of its limitations as a communicational device. The development of the Internet transported the map to the online space. Today, the constant and growing relationship between individuals and online content has sparked reflections on the impacts of the Internet on users' daily lives. Following the idea that there is a relationship between maps and everyday life, this study explores the possible representational limitations of the map as a graphic and communication device. Along with that, it considers what possible implications of the observer's perspective towards both the map and the Internet space may arise, and how these fields intersect in the concept of the digital map. Finally, we intend to explore in an analytical, critical and practical way how design responds to this reality. As a result, three components shape this study: the first develops a theoretical discussion around the map and its transition to the digital medium, followed by how the practices of design and of counter-cartography intersect in response to the impact of dominant cartography; the second develops a study of practical cases that supports the development methodology carried out on the project Ocupar, Construir, Habitar; and the third component consists of a report for this same project. The Ocupar, Construir, Habitar project thus follows a counter-cartographic approach in response to instances of negligence in the mapping of territories by State agents and replicated in digital mapping services such as Google Maps. The focus is the Bairro 6 de Maio, an ilegal settlement that existed in Amadora, Portugal, between 1973 and 2021. Presented as a printed publication and an online platform, this project explores an alternative practice of collaborative mapping that uses the testimony of people from the community of the settlement. Thus, this work is constituted as a denunciation of injustices and social inequalities, being as well configured as a cartographic record that historically documents the relationship between this community and its territory

Para fazer face aos incêndios florestais o Sistema de Defesa da Floresta contra Incêndios estabelece faixas de gestão de combustíveis como forma de auxiliar o combate e mitigação deste problema. O objetivo do trabalho foi elaborar um modelo capaz de identificar o controlo da biomassa nestas faixas através da análise do NDVI em séries temporais de imagens Sentinel 2. O modelo busca diferenças estatisticamente significativas, através do Welch t-test, nas informações contidas nas imagens. O modelo foi aplicado no concelho de Figueiró dos Vinhos e os resultados mostraram-se promissores na identificação de áreas onde não foi feita a gestão, ou seja, áreas de infração à legislação.

A bicicleta é um elemento basilar da mobilidade sustentável, uma vez que a sua utilização não gera emissões poluentes. Para aumentar a competitividade e segurança desta modalidade é necessário criar vias próprias para a circulação de velocípedes. Sabendo que a existência de infraestrutura ciclável gera uma maior utilização, é necessário investir no melhor planeamento da mesma, podendo-se recorrer ao uso dos Sistemas de Informação Geográfica (SIG). Este estudo explica e analisa a utilização do modo ciclável em Lisboa, bem como a metodologia utilizada para a elaboração do mapa de potencial ciclável de Lisboa, através de uma Combinação Linear Ponderada (CLP).

Nativo do sudoeste asiático, o mosquito tigre asiático (Aedes albopictus), tem vindo a estabelecer-se progressivamente em áreas do Continente Europeu como espécie invasora. Este mosquito é vetor eficiente de doenças como a Dengue e Chicungunha. Estudos anteriores demonstraram estar associado com a vegetação em meios urbanos. A deteção remota de vegetação na Cidade de Barcelona, feita através da análise multitemporal de imagens Sentinel-2 MSI, permitiu testar a relação entre o coberto vegetal e as ocorrências deste vetor. A análise dos resultados revela uma elevada correlação positiva entre a sua ocorrência e a vegetação, com uma grande influência da vegetação temporária.

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