Browsing by Author "Lopes, Joao"
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- Exogenous WNT5A and WNT11 proteins rescue CITED2 dysfunction in mouse embryonic stem cells and zebrafish morphantsPublication . Santos, João; Mendes-Silva, Leonardo; Afonso,Vanessa; Martins, Gil; Machado, Rui; Lopes, Joao; Cancela, M. Leonor; Futschik, Matthias; Sachinidis, Agapios; Gavaia, Paulo; Bragança, JoséMutations and inadequate methylation profiles of CITED2 are associated with human congenital heart disease (CHD). In mouse, Cited2 is necessary for embryogenesis, particularly for heart development, and its depletion in embryonic stem cells (ESC) impairs cardiac differentiation. We have now determined that Cited2 depletion in ESC affects the expression of transcription factors and cardiopoietic genes involved in early mesoderm and cardiac specification. Interestingly, the supplementation of the secretome prepared from ESC overexpressing CITED2, during the onset of differentiation, rescued the cardiogenic defects of Cited2-depleted ESC. In addition, we demonstrate that the proteins WNT5A and WNT11 held the potential for rescue. We also validated the zebrafish as a model to investigate cited2 function during development. Indeed, the microinjection of morpholinos targeting cited2 transcripts caused developmental defects recapitulating those of mice knockout models, including the increased propensity for cardiac defects and severe death rate. Importantly, the co-injection of anti-cited2 morpholinos with either CITED2 or WNT5A and WNT11 recombinant proteins corrected the developmental defects of Cited2-morphants. This study argues that defects caused by the dysfunction of Cited2 at early stages of development, including heart anomalies, may be remediable by supplementation of exogenous molecules, offering the opportunity to develop novel therapeutic strategies aiming to prevent CHD.
- Insights into the demographic history of african pygmies from complete mitochondrial genomesPublication . Batini, Chiara; Lopes, Joao; Behar, Doron M.; Calafell, Francesc; Jorde, Lynn B.; van der Veen, Lolke; Quintana-Murci, Lluis; Spedini, Gabriella; Destro Bisol, Giovanni; Comas, DavidPygmy populations are among the few hunter-gatherers currently living in sub-Saharan Africa and are mainly represented by two groups, Eastern and Western, according to their current geographical distribution. They are scattered across the Central African belt and surrounded by Bantu-speaking farmers, with whom they have complex social and economic interactions. To investigate the demographic history of Pygmy groups, a population approach was applied to the analysis of 205 complete mitochondrial DNA (mtDNA) sequences from ten central African populations. No sharing of maternal lineages was observed between the two Pygmy groups, with haplogroup L1c being characteristic of the Western group but most of Eastern Pygmy lineages falling into subclades of L0a, L2a, and L5. Demographic inferences based on Bayesian coalescent simulations point to an early split among the maternal ancestors of Pygmies and those of Bantu-speaking farmers (similar to 70,000 years ago [ya]). Evidence for population growth in the ancestors of Bantu-speaking farmers has been observed, starting similar to 65,000 ya, well before the diffusion of Bantu languages. Subsequently, the effective population size of the ancestors of Pygmies remained constant over time and similar to 27,000 ya, coincident with the Last Glacial Maximum, Eastern and Western Pygmies diverged, with evidence of subsequent migration only among the Western group and the Bantu-speaking farmers. Western Pygmies show signs of a recent bottleneck 4,000-650 ya, coincident with the diffusion of Bantu Languages, whereas Eastern Pygmies seem to have experienced a more ancient decrease in population size (20,000-4,000 ya). In conclusion, the results of this first attempt at analyzing complete mtDNA sequences at the population level in sub-Saharan Africa not only support previous findings but also offer new insights into the demographic history of Pygmy populations, shedding new light on the ancient peopling of the African continent.
- Intranasal drug delivery for treatment of Alzheimer's diseasePublication . Fonseca, Leonor Cancela; Lopes, Joao; Vieira, Joao; Viegas, Claudia; Oliveira, Claudia S.; Hartmann, Rafael P.; Fonte, PedroThe Alzheimer's disease is a neurodegenerative condition with severe consequences interfering with patient quality of life. It is characterized as a progressive and irreversible brain disorder hampering memory and thinking, affecting the capacity to perform daily tasks leading to physical and cognitive incapacitation. The conventional treatment occurs by the oral route, but it presents relevant drawbacks such as low bioavailability, fast metabolism, limited brain exposure, and undesirable side effects. The intranasal route has been proposed as a promising alternative to deliver drugs and improve the Alzheimer's disease treatment. Still, there is not a clear alternative delivery system available in the market with advantageous bioavailability and safety. The aim of this review is to perform an overview on the strategies for drug intranasal delivery for Alzheimer's disease treatment. The advantages and disadvantages of this delivery route and the delivery systems developed so far are discussed. A special focus is given on the use of permeation enhancers, the types of intranasal drug delivery devices, as well as possible toxicity concerns.
- Late hospital arrival for thrombolysis after stroke in Southern Portugal: Who is at risk?Publication . Sobral, Sofia; Taveira, Isabel; Seixas, Rui; Vicente, Ana Claudia; Duarte, Josiana; Goes, Ana Teresa; Duran, David; Lopes, Joao; Rita, Henrique; Nzwalo, HipólitoBackground: Delayed hospital arrival remains the main reason for the low rates of thrombolysis in eligible acute ischemic stroke (AIS) patients. The role of socioeconomic and clinical factors for the prehospital delay of AIS remains poor and has never been studied in Portugal. Objectives: Describe the socioeconomic and clinical factors leading to delayed hospital admission of AIS patients eligible to thrombolysis. Methods: A case-control study with a consecutive thrombolyzed AIS patients from 2010 to 2015. Controls were patients who did not receive thrombolysis because of late hospital arrival. Logistic regression with stepwise forward regression analysis was used to identify independent predictors of delayed admission to receive thrombolysis with intravenous tissue-type plasminogen activator (rtPA). Results: Of the 1247 patients admitted with AIS, 76 (6%) arrived on-time and received intravenous rtPA. Controls were 65.8% (146/222) of the total number of patients included in the study. Overall, the mean age was 73 years (+/- 11, 61), a minority were below 60 years, and 43.7% were women. Being beneficiary of social insertion income (odds ratio [OR]: .286; .124-.662, P = .003), not having any telephone contact (OR: .145; .039-.536, .004) or having exclusive landline (.055; .014-.210, < .001) and posterior circulation stroke (OR: .266; .087-.811, P = .020) decreased the likelihood of hospital arrive on-time rtPA. The use of prehospital ambulance services increased (OR: 6.478; 2.751-15.254, P < .001) the odds of ER on-time arrival for thrombolysis. Conclusions: Poverty, lack of stroke awareness, or difficulties in requesting immediate medical help are the main factors implicated in late-hospital admission for thrombolysis in AIS. Stroke awareness campaigns, promotion of activation of national emergency number and stroke code can increase the rate of thrombolysis.