RCAAP Repository

Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.

Air Traffic Control (ATC) provides services whose objective is to manage aircrafts to ensure safely orderly and expeditious flows of traffic. The LISATM system has a number of Controller Working Positions equipped with surveillance display applications, the Operator Display System (ODS). Due to redundancy requirements, there are two equivalent applications developed with different technologies. This project focused on the Air Situation Display System (ASD), na application which provides a surveillance display with user-interaction capability and is developed in Java technology. The application integrates the Radar Fallback keeping the looks and feels from the ODS System, only being developed in a different programming language. Thus the present work focused on monitoring the performance of high availability Real-Time Human-Machine Interface applications. Recommendations were endorsed for quantifiable performance, being these activities accompanied by a corresponding demonstration of results suitability for the intended context. Modules were defined in order to instrument applications Human-Machine Interface High Performance and High Availability (HMI-HPHA) with features necessary and sufficient for the pursuit of Real- Time performance analysis. These modules were developed using JAVA technology using the Java Management eXtensions (JMX), to manage the created agents. All the monitoring services run in real-time so it can inform the managers of changes of the application state as soon as it happens. This implies that the information provided needs to be not only concise but also adequate to the context.

This article summarizes our work on the imports of South Gaulish terra sigillata from the town of Ammaia, in the southern part of the province of Lusitania and within the geo-sphere of the provincial capital, Augusta Emerita. The assemblage available was fully studied: it includes the assemblages from the excavations of the early 20th century, the excavations of the years 1990 and 2000, as well as the sets of excavations of the RadioPast Project (2008-2011). The subject is analysed with regard to its typological concerns, but mainly with respect to its stratigraphical evolution: Ammaia presents excellent levels from Claudian-Neronian, Flavian, Flavian-Antonine eras and finally between AD 125-150. The empirical data from the first and last stages are particularly important, given the scarcity of stratigraphical information across the Iberian Peninsula, especially concerning the Julian-Claudian period.

Removal of introns from pre-messenger RNAs (pre-mRNAs) via splicing provides a versatile means of genetic regulation that is often disrupted in human diseases. To decipher how splicing occurs in real time, we directly examined with single-molecule sensitivity the kinetics of intron excision from pre-mRNA in the nucleus of living human cells. By using two different RNA labeling methods, MS2 and λN, we show that β-globin introns are transcribed and excised in 20-30 s. Furthermore, we show that replacing the weak polypyrimidine (Py) tract in mouse immunoglobulin μ (IgM) pre-mRNA by a U-rich Py decreases the intron lifetime, thus providing direct evidence that splice-site strength influences splicing kinetics. We also found that RNA polymerase II transcribes at elongation rates ranging between 3 and 6 kb min(-1) and that transcription can be rate limiting for splicing. These results have important implications for a mechanistic understanding of cotranscriptional splicing regulation in the live-cell context.

South Gaulish terra sigillata made its appearance in Portuguese Lower Tagus river valley area at its earliest stages, succeeding its italic predecessor. The author focused its approach in market conditions: regional settlement characteristics, including demographical dimension of urban centres, cultural background of populations and communication networks at place. On the other hand, vessel circulation patterns were considered on the base of potter´s stamps. Quantitative data was addressed, showing the main role played in redistribution by Lisbon, and the almost exclusivity of La Graufesenque imports. Potter´s stamps suggest different circulation for the region when compared to provincial capital, Mérida. Chronological data obtained demonstrated that the floruit of south Gaulish imports occurred in the period 40-65 AD, suffering after a complementary competition by Hispanic productions. In spite of this, imports from the big Gaulish centre persisted until circa 120 AD.

Introduction: Infective endocarditis presents a high rate of morbidity and mortality. Population-based studies addressing mortality caused by infective endocarditis in Portugal are scarce. We aimed to study deaths caused by Infective endocarditis, as well as corresponding demographics and temporal trends. Material and methods: Retrospective cohort study of all patients whose main cause of death was Infective endocarditis in Portugal from 2002 to 2018. The data was obtained from the national death certificate information system. Results: In Portugal, 3634 people died from infective endocarditis throughout the 17-year study period - infective endocarditis specific mortality rate of 2.1 per 100 000 habitants. Of all deceased, 89% were at least 60 years old, and most were women (55%). Overall, 72% died in a healthcare institution. An annual 9% increase in the incidence death rate from Infective endocarditis was observed, with a significant upward trend during the colder months. Discussion: In Portugal, mortality by infective endocarditis increased, mainly affecting older patients and women, and which can partially be explained by factors such as ageing of the population. The management of older patients with infective endocarditis is challenging as they present a higher number of comorbidities, more valvular heart disease and valve implants, invasive medical procedures and are less likely to undergo cardiac surgery. Conclusion: In addition to data on the evolution of demographics in Portugal, it is crucial to study the incidence of infective endocarditis over time to help explain these findings. The identification of factors that can be used to better model national health policies to improve clinical outcomes of infective endocarditis in Portugal is also required.

Background: During exposure therapy, patients report increases in fear that generally decrease within and across exposure sessions. Our main aim was to characterize these changes in fear ratings mathematically; a secondary aim was to test whether the resulting model would help to predict treatment outcome. Methods: We applied tools of computational psychiatry to a previously published dataset in which 30 women with spider phobia were randomly assigned to virtual-reality exposures in a single context or in multiple contexts (n = 15 each). Patients provided fear ratings every minute during exposures. We characterized fear decrease within exposures and return of fear between exposures using a set of mathematical models; we selected the best model using Bayesian techniques. In the multiple-contexts group, we tested the predictions of the best model in a separate, test exposure, and we investigated the ability of model parameters to predict treatment outcome. Results: The best model characterized fear decrease within exposures in both groups as an exponential decay with constant decay rate across exposures. The best model for each group had only two parameters but captured with remarkable accuracy the patterns of fear change, both at the group level and for individual subjects. The best model also made remarkably accurate predictions for the test exposure. One of the model's parameters helped predict treatment outcome. Conclusions: Individual patterns of fear change during exposure therapy can be characterized mathematically. This mathematical characterization helps predict treatment outcome.

Introduction: Airway pressure in the first 100 ms of an occluded inspiration (P0.1) evaluates respiratory center activity. Its increase compensates for respiratory muscle weakness in amyotrophic lateral sclerosis (ALS). We aimed to evaluate if an exhaustion over disease progression emerges. Methods: Consecutive ALS patients with P0.1 at baseline (T0) above 90th percentile for the whole population were included. There were two patient categories within this population: G1 patients had respiratory function tests (RFT) at T0 and 6 months later (T1); G2 patients were immediately adapted to noninvasive ventilation at T0. Functional ALS rating scale (ALSFRS) and its subscores, RFT including maximal inspiratory pressure (MIP), P0.1 percentage (%P0.1), P0.1/MIP, blood gas analyses, phrenic nerve motor amplitude and nocturnal pulsed oximetry (NPO) were compared at T0 between groups (Mann-Whitney U test) and longitudinal progression in G1 was assessed (Wilcoxon test). p < 0.05 was taken as significant. Results: Forty-nine patients were studied: 13 men, mean disease duration 17.1 ± 19.5 months, 21 with spinal-onset; 27 bulbar-onset; one with respiratory presentation. In G1, there was a progressive deterioration in all variables but P0.1/MIP did not significantly change (p = 0.394). PCO2 (p = 0.045) and bicarbonate ion (HCO3-p = 0.054) increased. In G2, the ALSFRS (p = 0.049) scores were lower, PCO2 (p = 0.057) and HCO3- (p = 0.016) higher, and reduced arterial oxygen saturation (SpO2<90%) at NPO (p = 0.007). Discussion: Patients with high central respiratory drive responses did not develop a short-term "exhaustion phenomenon". Both metabolic and central respiratory mechanisms interact to compensate for respiratory muscle weakness. The role of spasticity and the respiratory-metabolic-renal buffering system deserves further studies.

Background: Elucidating mechanisms of brain damage in cerebral venous thrombosis (CVT) would be instrumental to develop targeted therapies and improve prognosis prediction. Matrix metalloproteinase-9 (MMP-9), a gelatinase that degrades major components of the basal lamina, has been associated to blood-brain barrier disruption. We aimed to assess, in patients with CVT, the temporal change in serum concentrations of MMP-9 and its association with key imaging and clinical outcomes. Methods: Pathophysiology of Venous Infarction-PRediction of InfarctiOn and RecanalIzaTion in CVT (PRIORITy-CVT) was a multicenter prospective cohort study of patients with newly diagnosed CVT. Serial collection of peripheral blood samples performed on day 1, 3, and 8, and standardized magnetic resonance imaging on day 1, 8, and 90. MMP-9 was quantified using enzyme-linked immunosorbent assay in 59 patients and 22 healthy controls. Primary outcomes were parenchymal brain lesion, early evolution of brain lesion, early recanalization, and functional outcome on day 90. Results: CVT patients with parenchymal brain lesion had higher baseline concentrations of MMP-9 compared with controls (adjusted p = 0.001). The area under receiver operating characteristic curve value for MMP-9 for predicting brain lesion was 0.71 (95% confidence interval [CI]: 0.57-0.85, p = 0.009). Patients with venous recanalization showed early decline of circulating MMP-9 and significantly lower levels on day 8 (p = 0.021). Higher MMP-9 on day 8 was associated with persistent venous occlusion (odds ratio: 1.20 [per 20 ng/mL], 95% CI: 1.02-1.43, p = 0.030). Conclusion: We report a novel relationship among MMP-9, parenchymal brain damage, and early venous recanalization, suggesting that circulating MMP-9 is a dynamic marker of brain tissue damage in patients with CVT.

Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement. Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10-16 weeks). Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes. Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform.

More than 300 potters’ stamps on Gaulish terra sigillata, located in the deposits of the National Museum of Roman Art (MNAR), were subjected to a systematic analysis. All were found in the early archaeological investigations carried out in the capital of Lusitania, Augusta Emerita, down into the 1980s. Through them, this study deliberates an initial approach – chronological, typological and economic – to the commercial contacts that Mérida had with Gallia.

The fish-salting production centre at Troia received various imports of terra sigillata from the 1st century to the 6th century. Although it did not reach the significance of the African Red Slip Ware, Gaulish Sigillata is the second most important group of imports of this category on this archaeological site. The recognition of a Tiberian foundation level with Gaulish vessels dates the arrival of this tableware. Nevertheless, we agree with the assumption of previous studies that the majority of the pieces from this assemblage corresponds to the Claudian period onwards. The purpose of this paper is to present the current state regarding terra sigillata studies at Troia, more precisely related to the Gaulish productions and their significance in the largest fish-salting centre of the Roman Empire.

O núcleo de investigadores dedicado aos estudos de cultura do Centro de Estudos Anglísticos da Universidade de Lisboa empenhou boa parte da sua actividade, no ano de 2008-2009, na preparação de duas jornadas temáticas sobre o Império Britânico. Para a escolha deste objecto de investigação convergiram os interesses individuais dos investigadores, mobilizados para o estudo sistemático de conceitos como império e imperialismo, colónia e colonialismo, de ideologias como o liberalismo, ou para o estudo de representações de identidade. Com o intuito comum de examinar criticamente uma multiplicidade de discursos sobre o Império Britânico, as comunicações que agora são publicadas sustentam diferentes possibilidades de aproximação metodológica aos estudos de cultura e posicionam o diálogo entre elas como instrumento de desenvolvimento do conhecimento em torno de um mesmo objecto. O Império Britânico é, assim, interpelado na sua origem enquanto portador de uma “missão civilizadora” e são examinados discursos de supremacia europeia crescentemente desconstruídos pelas novas linhas de análise cultural, sensíveis estas à dissonância, à dúvida, ao silêncio e ao “não dito” das culturas em presença. O confronto e o conflito entre a cultura dominante e as culturas subordinadas, a construção de novas identidades, a instabilidade dos sujeitos foram, nestas jornadas, objecto de apresentações inovadoras em suportes visuais, como a pintura, a fotografia ou o filme.

Research carried out recently in different contexts at Roman sites in the Algarve and Alentejo has defined distinct sets of South Gaulish sigillata, so elucidating an understanding of the main consumption trends in that region. In this work, recent and older sets of data concerning this category of tableware imported from La Graufesenque are revisited, presented and discussed. The plain and decorated forms are analyzed, as well as the potter’s stamps from sites in southern areas of the present Portuguese territory, which in Roman times corresponded to the province of Lusitania. Even in the case of samples with very unequal compositions, we have identified different consumption patterns between the Alentejo and the Algarve sites, and have compared them with each other and with sets from other regions of Lusitania and Baetica.

A contextualized study of the sigillata from an excavation at the so-called East or Carteia Gate in Baelo Claudia is presented. This work revealed the transformation that this area of the city underwent from the Julio-Claudian era to the 6th century AD. Construction debris, rubbish dumps, as well as material from a funerary context all contribute to compose a very complete image of how the commercial pattern of consumption of fine wares appears in this important settlement: and so reveals more of the dynamics of trade in the Straits of Gibraltar.

This paper deals with the study of three sets of Gaulish sigillata from contexts in the Roman port area of Seville. The chronological sequence of the assemblages, dated between the end of the Julio-Claudian and the end of the Flavian period, has allowed the evolution of the consumption patterns of this type of pottery in the city of Seville to be investigated. A statistical analysis of the volume of imported types and the size of the pieces obtained at different chronological moments, when compared to data from various contexts of reference throughout the Empire, have revealed the existence of a series of consumption patterns, and moreover ones specific to different areas within the Roman world.

Although the presence of Gallic amphorae in the former province of Lusitania has been known for a long time, there is still little detailed knowledge about this type of container and the existing information is scattered. With this study, we present an updated account of Gaulish amphorae in Lusitania, after carrying out a systematic and exhaustive analysis of the published specimens and assemblages, and including also a significant number of unpublished sets. We then proceed to a brief characterization of the types recognized in the territory and a synopsis about their investigation, before posing a set of five interrelated questions that structure our approach: what? (which types and which products were identified), where? (where were they documented), how much and when? (the proportions of these imports and their fluctuations over time) and how? (geography of their distribution in Lusitania and the trade dynamics).

Esta Newsletter (NL) resulta de uma parceria entre o Instituto de Saúde Baseada na Evidência e a Cochrane Portugal, e tem como objectivo disponibilizar informação sobre áreas interessantes para a prática clínica, com base na melhor evidência científica. São incluídos estudos relevantes, criticamente avaliados pela sua validade, importância dos resultados e aplicabilidade prática, resumidos numa óptica de suporte à decisão. É dada prioridade a estudos de causalidade incluindo-se ainda, quando justificado, estudos qualitativos e metodológicos, assim como revisões científicas. O conteúdo da NL é da exclusiva responsabilidade do(s) seu(s) autor(es).

Peer observation of teaching has been adopted as a method to improve the quality of teaching. It involves observers providing descriptive feedback to their peers on learning and teaching practices. However, although extensively described in the literature in the education field, its use as a tool for development beyond teaching skills has not been explored deeply, nor the best practices described. Therefore, the objective of this study was to compare quantitative with qualitative peer observation, as well as to investigate the role of interdisciplinarity in the observation process. The present study results from experimental observation work carried out by four professors of higher education. Veterinary science, social work, pharmaceutical sciences, and education, the disciplinary areas of origin of the teachers, were the ecosystems in which the initial observation techniques were explored and applied, and the intention was to share good practices and pedagogical improvements through peer support. This study reports the experience of building an observation grid and its application, as well as the lessons learned during the observation experience. The aim was to evaluate whether the constructive criticism was focused on the pedagogical practices rather than on the content, which can be useful in understanding if the learning objectives are being attained, from the teacher’s point of view. As such, we employed and assessed peer observation as a constructive, developmental process for higher education teachers from different fields of knowledge. The study concludes that feedback by peers is essential for the development of professional practice in higher education teaching, with the experience of qualitative observation being a fundamental path for teacher self-reflection in the search for their own authenticity. It further supports the notion that interdisciplinary differences, methodologies, styles, contexts, and practices can be used in a constructive way to improve course content and delivery, and, ultimately, to reinforce good teaching.

Este artigo pretende caracterizar as concepções e práticas pedagógicas dos professores do Ensino Fundamental e entender o posicionamento da escola em análise face à utilização das tecnologias digitais nas aulas, numa altura em que “o movimento no sentido da personalização já se encontra avançado na medicina e precisamos de avançar rapidamente para este, também no mundo da educação” (ROBINSON, 2019). O estudo empírico enquadra-se numa abordagem qualitativa, mediante a modalidade de estudo de caso, assumindo um cariz interpretativo. Os dados foram recolhidos por meio de análise documental, observação e entrevista, tendo-se procedido à análise de conteúdo dos mesmos, com recurso à triangulação. Participaram, neste estudo, 6 professores do Ensino Fundamental, de uma escola privada de Lisboa, Portugal. Os resultados apontam para a existência de vontade, confiança e competências por parte dos docentes, embora a utilização das tecnologias pelos alunos, em contexto escolar, não seja expressiva