Neurotrophic Growth Factors for the Treatment of Amyotrophic Lateral Sclerosis: Where Do We Stand?

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 3–5 years after disease onset. Therapeutic options remain limited despite substantial number of approaches that have been tested clinically. Many neurotrophic growth factors are known to promote the survival of neurons and foster regeneration in the central nervous system. Various neurotrophic factors have been investigated pre-clinically and clinically for the treatment of ALS. Although pre-clinical data appeared promising, no neurotrophic factors succeeded yet in a clinical phase III trial. In this review we discuss the rationale behind those factors, possible reasons for clinical failures, and argue for a renewal of hope in this powerful class of drugs for the treatment of ALS

Start-ups: creating your business plan and how to finance it

There is an increasing awareness of the need to be healthier. To create a more active lifestyle, it is important to adapt individual’s training, diet and correct nutrition through correct sports supplements to the one’s needs. Many people do not take supplements due to time constraints and high investment required to buy the available market product. To address this problem, our company (Maxx Supplements) offers individual doses of pre- and post-workout sports supplements available at the gym’s vending machines. To the customer our product is user-friendly, opportune and time-saving. Furthermore, to achieve better acceptance from general public and penetrate the market, our product will be as cheap (1,5€) and as comfortable as possible. In this thesis, a business plan and financing method of the sport supplement was developed and described, while identifying its price, market segment, placement and distribution. Our product will be first financed by relatives and further supported by Business Angels that will not only help financially but also with expertise and network. We estimate to gather 211 522€ that will cover our first three months of production, which we expect to payback in the first year. From a project’s perspective, it has a Net Present Value of 13 516 630€, an Internal Rate of Return of 220%, around 30% Return On Investment for the third to sixth year, a Return on Equity of 124% on the third year and 60%~70% for the remaining, a Growth Rate of near 60% for all years except the second (100%) and Positive Cash Flow of 199 150€ on the third year. Keywords:Recentemente tem havido um aumento no reconhecimento da necessidade de ser mais saudável. De forma a ter um estilo de vida mais saudável, é importante adaptar o exercício físico, dieta e nutrição através de suplementos desportivos, tendo em conta os objectivos. Muitas pessoas descuram os suplementos devido à escassez de tempo e elevado investimento necessário para comprar um produto do mercado. De forma a combater este problema, a nossa empresa oferece doses individuais de suplementos desportivos de pré- e pós-treino nas máquinas automáticas do ginásio. No ponto de vista do consumidor, este produto é fácil de utilizar, oportuno e poupa tempo. De forma a obter uma melhor penetração do mercado, o produto vai ser vendido a 1,5€. Foi também desenvolvido um modelo de negócio. O nosso produto vai ser financiado por familiares e Investidores, que providenciarão, para além de dinheiro, conhecimentos. Preço, mercado alvo, localização e distribuição foram também identificados. Estimamos adquirir 211 522€ que iram financiar os primeiros 3 meses de produção, e que irão ser pagos aos Investidor no primeiro ano. Do ponto de vista do projecto, este tem um Valor Liquido Actual de 13 516 630€, uma Taxa Interna de Rentabilidade de 220%, cerca de 30% de Retorno no Investimento para o terceiro até ao sexto ano, um Retorno dos Capitais Próprios de 124% no terceiro ano e 60%~70% para os restantes anos, um Taxa de Crescimento de 60% para todos os anos, excepto o segundo (100%) e Cash Flows positivos de 199 150€ no terceiro ano

Why do leaders disapoint? A tale of paradoxes and a point of no return

We venture into discovering, through an inductive approach, what are the actions taken by leaders that make their followers feel disappointed, as well as their consequences. After collecting data from professionals of different sectors (public and private), we conducted a semi cluster analysis in order to reach underlying structures that aim to identify the source of these actions, which were found to be in three paradoxes. As for the consequences, three core concepts were also found, which can be used to divide the former into three groups related to the period of time of their effect

Novel Combined approaches to PTC mutation correction in CFTR

Tese de mestrado, Biologia Molecular e Genética, 2024, Universidade de Lisboa, Faculdade de CiênciasCystic Fibrosis (CF) is a life-threatening genetic disease caused by deleterious mutations in the CFTR gene. Of all variants, 8,4% are nonsense mutations (class I) which are associated with premature termination codons (PTCs), which produce severe phenotypes of CF. In this work, a HEK cell line expressing a G542X CFTR minigene (HEK-GX) was used to test compounds for their PTC readthrough and NMD inhibitory activities. Preliminary screening demonstrated that G418 and SMG1i were the most useful control compounds at concentrations 500uM and 1uM, respectively. The library of novel compounds’ screen identified 7 compounds with Z-score > 1, with each having a p-value < 0,01 (**). Compound 17 showed predominantly mCherry fluorescence, while compounds 7, 10, 13 and 15 showed GFP fluorescence. Finally, compounds 11 and 40 had significant fluorescence at both wavelengths. An autofluorescence screen conducted by comparing fluorescence intensity in HEK-GX cells and HEKWild Type (WT CFTR) cell lines, following identical treatments, showed mostly constant autofluorescence for all compounds, although exceptionally high for compound 17, being absent for compounds 40 and 46. qPCR analysis was performed in 16-HBE cell lines expressing gene edited CFTR with PTC variant (Y122X, G542X, or W1282X legacy names) using wild-type line as control. Compounds 11 and 17 were tested at concentrations of 2 and 10uM. Compound 17 failed to significantly raise the abundance of CFTR mRNA in all three variants, ruling it as a false positive. Compound 11 was the most promising of the compound library so far (Fold change mean 2,822 ± 0,010 at the concentration of 2uM). In summary, Compound 11 was the most promising out of the tested compounds, but a wider range of concentrations should be tested, and protein analysis by Western Blotting should be used to assess PTC readthrough potential. Additionally, compounds’ 40 and 47 tests should be repeated

Análise da performance da equipa profissional do Oriental Dragon Football Cluib na época desportiva 2014/2015

O presente trabalho visa a elaboração de um relatório final de estágio, no âmbito da conclusão do curso e obtenção do grau de Mestre em Desporto, Especialização em Treino Desportivo, ministrado pela Escola Superior de Desporto de Rio Maior. Pretende-se com este relatório apresentar o percurso formativo pessoal enquanto treinador na equipa do Oriental Dragon F.C., ao longo da época desportiva 2014/2015, num contexto de futebo profissional, cuja equipa era constituída por jogadores de nacionalidade chinesa e que tinha por competição a “Future Stars Football League”, campeonato organizado pela Associação de Futebol de Setúbal e pela empresa WSport7. O relatório está dividido em quatro capítulos. O primeiro está relacionado com o contexto do estágio, realizando-se uma apresentação do clube, dos jogadores, do local onde o estágio decorreu do quadro competitivo formal e toda a atividade desenvolvida. O segundo capítulo apresenta um enquadramento conceptual ao nível do planeamento e no terceiro capítulo faz-se o balanço do estágio onde se apresentam as conclusões retiradas durante a época desportiva. O quarto e último capítulo serve para evidenciar o estudo realizado sobre as bolas paradas da equipa tendo-se para o efeito observado os 26 jogos do campeonato, onde se marcaram 62 golos dos quais 13 foram alcançados através de bola parada (pontapé de canto e pontapé livre). Neste estudo concluiu-se que foram marcados mais golos em casa (9) do que fora (4), obteve-se mais golos através de pontapé livre (9) do que através de pontapé de canto (4) e verificou-se que há relação direta entre o treino e a competição, porque 11 golos dos 13 golos alcançados refletiram os comportamentos treinados e definidos previamente no plano estratégico.This work aims to draw up a final report stage, in the context of graduation and the degree of Master of Sport, Expertise Sports Training, taught by the Escola Superior de Desporto de Rio Maior-IPS. The aim of this report present the personal training path as a coach in the Oriental Dragon F.C. over the sports season 2014/2015, in the context of professional football, whose team consisted of players of Chinese nationality and who was the competition "Future Stars Football League" championship organized by the Setúbal Football Association and the WSport7 company. The report is divided into four chapters. The first is related to the stage of context, performing a presentation of the club, the players, the place where the internship took place, the championship and all the activity developed. The second chapter presents a conceptual framework to the planning level and in the third chapter there is the stage where the balance sheet present the conclusions drawn during the sports season. The fourth and final chapter is to highlight the study of the set plays of the team and it was observed 26 league games, where we scored 62 goals, including 13 goals were achieved through set plays (corner kick and free kick). It was concluded that score more goals in the house (9) than outside (4), we obtained more goals through free kick (9) than at a corner kick (4) and it was found that there is a direct relationship between training and competition, because 11 of the 13 goals achieved reflect the behaviors trained and previously defined in the strategic plan.N/

Deteção de ataques de negação de serviços distribuídos na origem

From year to year new records of the amount of traffic in an attack are established, which demonstrate not only the constant presence of distributed denialof-service attacks, but also its evolution, demarcating itself from the other network threats. The increasing importance of resource availability alongside the security debate on network devices and infrastructures is continuous, given the preponderant role in both the home and corporate domains. In the face of the constant threat, the latest network security systems have been applying pattern recognition techniques to infer, detect, and react more quickly and assertively. This dissertation proposes methodologies to infer network activities patterns, based on their traffic: follows a behavior previously defined as normal, or if there are deviations that raise suspicions about the normality of the action in the network. It seems that the future of network defense systems continues in this direction, not only by increasing amount of traffic, but also by the diversity of actions, services and entities that reflect different patterns, thus contributing to the detection of anomalous activities on the network. The methodologies propose the collection of metadata, up to the transport layer of the osi model, which will then be processed by the machien learning algorithms in order to classify the underlying action. Intending to contribute beyond denial-of-service attacks and the network domain, the methodologies were described in a generic way, in order to be applied in other scenarios of greater or less complexity. The third chapter presents a proof of concept with attack vectors that marked the history and a few evaluation metrics that allows to compare the different classifiers as to their success rate, given the various activities in the network and inherent dynamics. The various tests show flexibility, speed and accuracy of the various classification algorithms, setting the bar between 90 and 99 percent.De ano para ano são estabelecidos novos recordes de quantidade de tráfego num ataque, que demonstram não só a presença constante de ataques de negação de serviço distribuídos, como também a sua evolução, demarcando-se das outras ameaças de rede. A crescente importância da disponibilidade de recursos a par do debate sobre a segurança nos dispositivos e infraestruturas de rede é contínuo, dado o papel preponderante tanto no dominio doméstico como no corporativo. Face à constante ameaça, os sistemas de segurança de rede mais recentes têm vindo a aplicar técnicas de reconhecimento de padrões para inferir, detetar e reagir de forma mais rápida e assertiva. Esta dissertação propõe metodologias para inferir padrões de atividades na rede, tendo por base o seu tráfego: se segue um comportamento previamente definido como normal, ou se existem desvios que levantam suspeitas sobre normalidade da ação na rede. Tudo indica que o futuro dos sistemas de defesa de rede continuará neste sentido, servindo-se não só do crescente aumento da quantidade de tráfego, como também da diversidade de ações, serviços e entidades que refletem padrões distintos contribuindo assim para a deteção de atividades anómalas na rede. As metodologias propõem a recolha de metadados, até á camada de transporte, que seguidamente serão processados pelos algoritmos de aprendizagem automática com o objectivo de classificar a ação subjacente. Pretendendo que o contributo fosse além dos ataques de negação de serviço e do dominio de rede, as metodologias foram descritas de forma tendencialmente genérica, de forma a serem aplicadas noutros cenários de maior ou menos complexidade. No quarto capítulo é apresentada uma prova de conceito com vetores de ataques que marcaram a história e, algumas métricas de avaliação que permitem comparar os diferentes classificadores quanto à sua taxa de sucesso, face às várias atividades na rede e inerentes dinâmicas. Os vários testes mostram flexibilidade, rapidez e precisão dos vários algoritmos de classificação, estabelecendo a fasquia entre os 90 e os 99 por cento.Mestrado em Engenharia de Computadores e Telemátic

Tear feature extraction with spatial analysis: a thangka case study

This paper on Conservation of Cultural Heritage explores the use of spatial analysis functions for feature extraction. The study evaluates the performance of neighbourhood functions for the delimitation of a tear in a thangka painting. The pathology area was documented with a non-conventional technique in painting conservation.Este estudio en Conservación de Patrimonio Cultural explora el uso de las funciones del análisis espacial para la identificación de características de la superficie. El artículo evalúa el comportamiento de las funciones de proximidad en la delimitación de un desgarro en una pintura thangka. La zona de la patología ha sido documentada con una técnica no convencional de diagnóstico en conservación de pintura.Este artigo em Conservação de Património Cultural explora a utilização de funções de análise espacial para extracção de características da superfície. O estudo avalia o comportamento das funções de vizinhança na determinação de um rasgão numa pintura thangka. A patologia foi documentada por intermédio de uma técnica de diagnóstico em conservação de pintura não convencional

A critical review of measuring and mapping urban typologies in Portugal

UIDB/04647/2020 UIDP/04647/2020 UIDB/04008/2020The concept of urban area is complex and has been discussed for many years by several authors and organisations through different perspectives and methodological approaches. For administrative and comparison purposes statistical institutions, both at the national and international levels, classify territories according to a certain degree of urbanisation defining typologies from which indicators and certain public policies are applied. The purpose of this study is to discuss the relevance and suitability of different urban typologies. Through mapping and measuring the data of official documents, the urban dimension of Mainland Portuguese territory is discussed and its usefulness concerning the allocation of resources for promoting territorial cohesion is stressed. Results show the inadequacy of these classifications to inform planning actions, decision making, and to promote territorial policies. It also provides evidence of inaccuracies that distort the reading of the territorial reality of the case study.publishersversionpublishe