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Objective Enteroendocrine cells (EECs) survey the gut luminal environment and coordinate hormonal, immune and neuronal responses to it. They exhibit well-characterised physiological roles ranging from the control of local gut function to whole body metabolism, but little is known regarding the regulatory networks controlling their differentiation, especially in the human gut. The small molecule isoxazole-9 (ISX-9) has been shown to stimulate neuronal and pancreatic beta-cell differentiation, both closely related to EEC differentiation. Our aim was to use ISX-9 as a tool to explore EEC differentiation. Methods We investigated the effects of ISX-9 on EEC differentiation in mouse and human intestinal organoids, using real-time quantitative polymerase chain reaction (RT-qPCR), fluorescent-activated cell sorting, immunostaining and single-cell RNA sequencing. Results ISX-9 increased the number of neurogenin3-RFP (Ngn3)-positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors that play roles in mouse EEC specification. Single-cell analysis showed induction of Pax4 expression in a developmentally late Ngn3+ population of cells and potentiation of genes associated with progenitors biased toward serotonin-producing enterochromaffin (EC) cells. Further, we observed enrichment of organoids with functional EC cells that was partly dependent on stimulation of calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 overexpression, in ileal organoids, uncovered its importance as a component of early human endocrine specification and highlighted the potential existence of two major endocrine lineages, the early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains classical gut hormone cell types. Conclusion Our data provide proof-of-concept for the controlled manipulation of specific endocrine lineages with small molecules, whilst also shedding new light on human EEC differentiation and its similarity to the mouse. Given their diverse roles, understanding endocrine lineage plasticity and its control could have multiple therapeutic implications., Graphical abstract Image 1, Highlights • ISX-9 promotes flux through the Ngn3 lineage and enriches it with enterochromaffin cells. • ISX-9 engages an enterochromaffin biased transcriptional programme in endocrine fated cells. • Enterochromaffin bias is partly dependent on calcium signalling in progenitor cells. • ISX-9 reveals conserved gut endocrine specification between mouse and human. • Pax4 overexpression in human ileum organoids mimics the effects of ISX-9 on EC bias.

Diabetes is one of the most challenging health concerns facing society. Available drugs treat the symptoms but there is no cure. This presents an urgent need to better understand human diabetes in order to develop improved treatments or target remission. New disease models need to be developed that more accurately describe the pathology of diabetes. Organoid technology provides an opportunity to fill this knowledge gap. Organoids are 3D structures, established from pluripotent stem cells or adult stem/progenitor cells, that recapitulate key aspects of the in vivo tissues they mimic. In this review we briefly introduce organoids and their benefits; we focus on organoids generated from tissues important for glucose homeostasis and tissues associated with diabetic complications. We hope this review serves as a touchstone to demonstrate how organoid technology extends the research toolbox and can deliver a step change of discovery in the field of diabetes. Electronic supplementary material The online version of this article (10.1007/s00125-020-05126-3) contains a slideset of the figures for download, which is available to authorised users.

Esta dissertação analisa de que forma as políticas públicas portuguesas de segurança marítima têm seguido as políticas públicas da União Europeia e qual tem sido o seu impacto sobre o país. A importância de Portugal enquanto fundador da NATO e na defesa da zona do Atlântico Norte foi preterida estrategicamente face a políticas continentais que prevêem um maior sucesso a nível económico. O país é submetido à tomada de decisão da União Europeia, tendo um poder diminuto, onde predomina o poder de coligação face a outros países cujos interesses possam estar alinhados com Portugal neste momento. Analisámos ainda o processo que as estratégias de segurança marítima têm vindo a tomar ao longo dos anos, passando de um domínio da NATO para um vislumbre de uma estratégia autónoma, que facilite a resposta à gestão de crises por parte da EU. De modo a contribuir para a reflexão desta dissertação, foram salientados os processos evolutivos da vigilância marítima e os vários programas lançados e a importância do processo de extensão da plataforma continental portuguesa, onde se releva a área marítima que o país pode vir a deter, garantindo a possibilidade de obter maiores recursos jurídicos e económicos. This dissertation analyses how Portuguese public policies on maritime security have followed European Union public policies and what has been their impact on the country. The importance of Portugal as a founder of NATO and in the defence of the North Atlantic area has been strategically overlooked in face of continental policies that foresee a greater success at an economic level. We used the documental analysis method in order to prove that the country is subjugated by decision making within Europe, having a diminutive power, where the power of coalition predominates in relation to other countries whose interests may be aligned with Portugal at that moment. We also analysed the process that maritime security strategies have been taking over the years, moving from a NATO domain to a glimpse of an autonomous strategy, which facilitates the response to crisis management by the EU. In order to contribute to the reflection of this dissertation, the evolutionary processes of maritime surveillance and the various programmes launched were highlighted, as well as the importance of the process of extending the Portuguese continental shelf, where the maritime area that the country may come to hold was highlighted, ensuring the possibility of obtaining greater legal and economic resources. Mestrado em Ciência Política

La siguiente monografía evidencia la problemática situación que viven actualmente las víctimas del conflicto armado en el municipio de Ituango (Antioquia) a través de una propuesta arquitectónica que busca restaurar íntegramente la calidad de vida de la población mediante un enfoque social y económico, proyectando espacios de alojamiento autosustentable y productivo que impulsen las estrategias socio-económicas planteadas mediante equipamientos comunales, logrando así convertir el proyecto en una referencia hacia la memoria y la sensibilización del país con las víctimas. The following monograph shows the problematic situation currently experienced by the victims of the armed conflict in the municipality of Ituango (Antioquia) through an architectural proposal that seeks to fully restore the quality of life of the population through a social and economic approach, projecting spaces of self-sustaining and productive accommodation that promotes the socio-economic strategies proposed through communal facilities, thus making the project a reference to the memory and awareness of the country with the victims. Arquitecto Pregrado

Dynamic optical networks will be crucial in global optical communications in the next 5-10 years.On-demand services, fuelled by applications such as cloud computing and grid computing, are the main drivers for the availability of an increasingly dynamic network infrastructure. Efficient network planning tools that deal with Routing and Wavelength Assignment problems are of paramount relevance in this dynamics cenario. In this work, a simulator for planning dynamic optical networks was developed, and several real networks were tested, such as National Science Foundation Network, British Telecom, US Backbone Network, and also bidirectional ring networks. In this simulator, we have implemented a graph coloring wavelength assignment algorithm named Small-Bucket algorithm that allows recoloring to occur. A comparison performance with the First-fit algorithm is performed in terms of the blocking probability, number of recolorings, number of colors used and simulation time. It is concluded that the Small-Bucket algorithm originate slower blocking probabilities than the ones obtained with the First-fit algorithm. However, to reach these low blocking probabilities, the Small-Bucket algorithm makes use of a larger number of wavelengths and recolorings. As redes ópticas dinâmicas serão cruciais nas comunicações ópticas globais nos proximos 5-10 anos. Os principais impulsionadores deste dinamismo são os serviços on-demand, suportados por aplicações como computação em nuvem e computação em grelha, conduzindo à necessidade de uma infraestrutura de rede cada vez mais dinâmica. Ferramentas de planeamento de rede eficientes, que lidam com os problemas de encaminhamento e atribuição de comprimentos de onda serão de extrema relevância neste cenário dinâmico. Neste trabalho foi desenvolvido um simulador para o planeamento de redes ópticas dinâmicas, e várias redes reais foram testadas, como a National Science Foundation Network, a British Telecom, a US Backbone Network e também redes bidirecionais em anel. Neste simulador, implementa-se um algoritmo de coloração de grafos denominado algoritmo Small-Bucket, que permite a ocorrência de recolorações de nós. Este algoritmo é comparado como algoritmo First-fit, em termos de probabilidade de bloqueio, número de recolorações, número de cores usadas e tempo de simulação. Conclui-se que o algoritmo Small-Bucket produz menores probabilidades de bloqueio do que as obtidas com o algoritmo First-fit. No entanto, para atingir essas baixas probabilidades de bloqueio, o algoritmo Small-Bucket faz uso de um maior número de comprimentos de onda e recolorações.

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Porto Biomechanics Laboratory is a technological centre of the University of Porto dedicated to teaching, scientific and technological research, innovation, to provide specialized technical services and transference of knowledge and technology (product development) in Biomechanics (human and animal) of ergonomic, clinical, sports or biomimetic interest (e.g. design, computer animation and model development). LABIOMEP-UP mission is to catalyse the growth potential and competitive edge of University of Porto in all domains directly or indirectly related to Biomechanics, including the interaction with industry., El Laboratorio de Biomecánica de Porto es un centro tecnológico de la Universidad de Porto dedicado a la docencia, la investigación científica y tecnológica, la innovación, proporcionar servicios técnicos especializados y transferencia de conocimiento y tecnología (desarrollo de productos) en Biomecánica (humana y animal) de ergonomía, clínica, deportiva, o interés biomimético (por ejemplo, diseño, animación por computadora y desarrollo de modelos). La misión de LABIOMEP-UP es catalizar el potencial de crecimiento y la ventaja competitiva de la Universidad de Oporto en todos los dominios relacionados directa o indirectamente con la biomecánica, incluida la interacción con la industria., O Laboratório de Biomecânica do Porto (LABIOMEP-UP) é um centro de competências da Universidade do Porto dedicado ao ensino, investigação científica e tecnológica, inovação, prestação de serviços técnicos especializados e transferência de conhecimento e tecnologia em Biomecânica (humana e animal) de interesse ergonómico, clínico, desportivo ou biomimético (ex: design, animação computacional e desenvolvimento de modelos). A missão do LABIOMEP-UP é catalisar o potencial de crescimento e vantagem competitiva da Universidade do Porto em todos os domínios direta ou indiretamente relacionados com a Biomecânica, incluindo a interação com o tecido industrial e comercial.