A role for the small GTPases RAC1 and RAC1b in the modulation of NIS expression: potentiation of therapy with radioactive iodine in differentiated thyroid carcinoma

Introduction or Background: The Sodium Iodide Symporter (NIS) is responsible for active transport of iodide into thyroid follicular cells. The retention of its functional expression in most of the well-differentiated thyroid carcinomas (DTCs) enables the use of radioactive iodine (RAI) for treatment of metastatic disease. Still, about 30% of patients with advanced forms of DTC became refractory to RAI which makes their management very challenging. The main reason for impaired iodide uptake in refractory-DTC is the defective functional expression of NIS. Several molecular players have been described as critical for TSH-induced NIS expression, an example being the p38 mitogenic kinase. In breast cancer cells, the small GTPase RAC1 was shown to mediate the positive impact of p38 kinase activity on NIS expression. We, on the other hand, have previously shown that overexpression of RAC1b, a tumor-related splicing variant of RAC1, is associated with worse outcomes in DTC and correlates with the MAPK-activating BRAFV600E mutation, which has been related to the loss of NIS. Since RAC1 and RAC1b may act in an antagonistic fashion to regulate specific cellular responses, we asked if RAC1b would be implicated in NIS downregulation observed in DTCs. Methods Section: NIS expression levels were analyzed by RT-qPCR in a RAC1/RAC1b expression model system developed in non-transformed thyroid cell lines. A non-radioactive iodide influx assay was used to confirm the impact of RAC1-signaling on the efficacy of iodide uptake. Results Section: We demonstrate that ectopic overexpression of RAC1b is sufficient to decrease TSH-induced NIS expression, antagonizing the positive effect of RAC1 GTPase. Moreover, we clearly document, for the first time in thyroid cells, that both NIS expression and iodide uptake are downregulated upon RAC1 inhibition, supporting the role of canonical RAC1 signaling in promoting TSH-induced NIS expression. Conclusion: Our findings provide evidence that RAC1 and RAC1b signaling are implicated in the regulation of NIS expression in thyroid cells and suggest that RAC1b overexpression may be one of the mechanisms contributing to the low levels of NIS observed in some subgroups of DTCs, antagonizing RAC1 stimulatory effect on the TSH/cAMP-mediated induction of NIS expression.FCT - PTDC/BIAMOL/31787/2017N/

Stimulation of Piezo1 by mechanical signals promotes bone anabolism

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion o

The case of Madeira International Airport Cristiano Ronaldo

The increased demand for air transportation has enlarged congestion problems in the areas of Passenger Terminals. This study proposes how to optimize the flows of passengers at the airport of Madeira to increase airport efficiency. There are two specific approaches to achieve this study objective. Firstly, we analyse the flow of passengers at the airport terminal to detect where are the most critical congestion points. Secondly, using simulation software (MassMotion) we analyse different layouts of the airport terminal, including ramp area, considering passengers flows of different typologies, to find the most efficient layout configuration. This study optimizes the flow of passengers in the terminal area of the International Airport of Madeira, making it more efficient in routing passengers and thus maintaining control over congestion levels. Thus, the proposed configurations for Check-in, Security, Border Control, Boarding Gates, Embark, Disembark, and Luggage Claim areas allow to considerably reduce (or even eliminate) passenger congestion at these critical points. An airport is a complex transport infrastructure, and therefore any change in its physical structure must be made during its period of operation. Structural modifications must be simulated in software to be validated before being implemented; this was the option of Madeira International Airport, which thus seeks solutions to keep congestion levels under control, increase the efficiency of the terminal, and raise the level of passenger satisfaction.info:eu-repo/semantics/publishedVersio

Utilização de sensores e dos sentidos humanos no apoioà transição do concretopara o abstrato

Apresentam-se e analisam-se os contributos de 4 estudos de caso para a compreensão do potencial da utilização sinérgica dos sentidos e de sensores no apoio à transição do pensamento concreto para o abstrato, em contextos de ensino experimental das ciências no 1º e 2º ciclo do ensino básico. Recolheram-se e analisaram-se evidências de desenvolvimento da abstração sobre tópicos de considerável complexidade, como os de biodiversidade, ser vivo, temperatura e frequência cardíaca

A PESA-AGB study

This study uses a MCDA tool to analyse and improve Spanish airports performance and efficiency. Thus, a holistic study using MACBETH (with PESA-AGB) is used. This study has never been applied before in Spanish airports. Firstly, a literature review related to this study keywords is conducted, as well as about benchmarking concept applied specifically to airports. Secondly, several methodologies in used to benchmark airports are reviewed and compared. Thirdly, airport performance and efficiency issues are addressed and described. Finally, the MCDA-MACBETH (with PESA-AGB) tool is applied to 4 Spanish airports. Spanish airports belonging to AENA transported 263,753,406 passengers in 2018 with an increase compared to 2017 of 5.8%. General data enables to conclude that Spanish air transportation system is growing annually and hence there is the need to improve airports performance and efficiency, also to maintain the high levels of quality to address the growing demand. Spanish air transportation system is growing annually and is it upmost important to maintain high levels of quality to address such demand. Through this study, performance and efficiency improvements are seek within several airport key areas such as Safety and Security, Quality Service, Productivity and Effectiveness, Financial and Environment. As far as known, this study has never been applied before in Spanish airports.info:eu-repo/semantics/publishedVersio

Air Budjet: a VTOL virtual operator company in Portugal

Creation of sustainable transportation service for a new and virtual airline company that uses VTOL aircraft in order to increase mobility and flexibility in Portugal. This study started with the VTOL concepts, peripherally and accessibility, and business models and plans reviews. The air service characterization was then carried out using localization and trajectory optimization algorithms, thus allowing to elaborate two applications (software): one for clients to book their flights and another that compiles flight's data booked by clients and optimizes flights routes/trajectories. With this study, it is possible to depict the viability of the economic-financial results of the new virtual company and the application development results with the optimized trajectories. The development of this air service will increase accessibility and mobility in all regions of Portugal and companies that cannot afford the costs of executive aviation, too. In order to facilitate the booking of the flights, an application was created for the client in order to optimize the company costs related to this air service, and thus to make the cost of a trip more appealing; a second application was elaborated that optimizes the trajectories of the aircraft.info:eu-repo/semantics/publishedVersio

Accessibility and local development: interaction between cross-border accessibility and local development in Portugal and Spain

The main objective in this work is to understand road infrastructure’s impact on development, especially in the EU-context and in the border areas between Portugal and Spain. In these areas, a new road infrastructure was built in the last decades, changing completely the accessibility panorama, while the development variables seem to get worst in most of the cross border regions. Some links are still missing, but some already exist and are not having the expected development impact. The analysis is to be done at the municipality level in order to evaluate the regional differences within the cross border area, which is not possible at the higher NUTIII level.Peer Reviewe

The uptake of macronutrients by an active silicon accumulator plant growing in two different substrata

Pennisetum clandestinum (Graminae/Poaceae) an active Si-accumulator, was cultivated in two different substrata, both with reduced Si solubility. Plants growing in organic-rich soils contained much less Ca, K, Na and Si, than species growing in sandy soils. Although the highest macronutrient concentrations were associated to the highest Si levels in the organs of P. clandestinum, the R correlation values indicate that Si does not influence the internal balance and the uptake of these elements. In ca 65% of the cases roots have the highest average values regardless of the type of culture, while the contents of Mg in the shoots and roots of P. clandestinum were generally not significantly different (P>0.05). A significant decline of the macronutrient levels associated to the shoots and roots of P. clandestinum was observed from the 4th to the 6th month assay, especially for Ca in both organs, while for Mg and Na the decline is focused mainly in the shoots; K and Si decline is generally below 10%. When average values of Si in shoots and roots of plants collected from organic- rich and sandy soils were plotted against the average concentrations of Ca, K, Mg and Na in the same organs, weak but positive R correlation values were obtained - the highest R values were observed for Na and K and the lowest for Ca and Mg, regardless of the culture. Exception for the high R value observed for K, although the influence of Si on the K status in the whole plant is time-depending - R values, diminished from the 4th to the 6th month, as it happens in the majority of the cases. In conclusion, P. clandestinum can grow well and healthily in substrata with acid pH values and high carbonate content and low solubility of Si suggesting that the definition of the essentiality of Si, even in a Si-accumulator plant is still a matter of great controversy.publishersversionpublishe