Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease

The Almeida lab has been supported by FCTJPCOFUND/0004/2015; Alzheimer’s Association Research Grant (AARG-19-618007); Maratona da Saúde; H2020 Spreading Excellence and Widening Participation, H2020-WIDESPREAD01-2016-2017-TeamingPhase2-GA739572; iNOVA4Health (UID/Multi/04462/2019), a program financially supported by Fundação para a Ciencia e Tecnologia (FCT)/Ministério da Educação e Ciencia, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. CG’s salary is supported by FCT-CEECIND/00410/2017. FM has been the recipient of an FCT doctoral fellowship (PD/BD/128344/2017). CP has been the recipient of an FCT doctoral fellowship (SFRH/BD/128374/2017).Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by β-amyloid (Aβ) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aβ-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aβ oligomers, highlighting the dysfunction of endocytic trafficking as an Aβ-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo- and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aβ, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aβ and by LOAD genes to disrupt synapses.publishersversionpublishe

Tailoring cutinase activity towards polyethylene terephthalate and polyamide 6,6 fibers

Cutinase from Fusarium solani pisi was genetically modified near the active site, by site-directed mutagenesis, to enhance its activity towards polyethylene terephthalate (PET) and polyamide 6,6 (PA 6,6) fibers. The mutations L81A, N84A, L182A, V184A and L189A were done to enlarge the active site in order to better fit a larger polymer chain. Modeling studies have shown enhanced free energy stabilization of model substrate tetrahedral intermediate (TI) bound at the enzyme active site for all mutants, for both model polymers. L81A and L182A showed an activity increase of four- and five-fold, respectively, when compared with the wild type, for PET fibers. L182A showed the one- and two-fold higher ability to biodegrade aliphatic polyamide substrates. Further studies in aliphatic polyesters seem to indicate that cutinase has higher ability to recognize aliphatic substrates.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BD/22490/2005, SFRH/BD/22149/2005European Community - Biosyntex Project, no. G5RD-CT-2000-30110 “Competitive and Sustainable Growth

Structure of Hierridin C, Synthesis of Hierridins B and C, and Evidence for Prevalent Alkylresorcinol Biosynthesis in Picocyanobacteria

Small, single-celled planktonic cyanobacteria are ubiquitous in the world's oceans yet tend not to be perceived as secondary metabolite-rich organisms. Here we report the isolation and structure elucidation of hierridin C, a minor metabolite obtained from the cultured picocyanobacterium Cyanobium sp. LEGE 06113. We describe a simple, straightforward synthetic route to the scarcely produced hierridins that relies on a key regioselective halogenation step. In addition, we show that these compounds originate from a type III PKS pathway and that similar biosynthetic gene clusters are found in a variety of bacterial genomes, most notably those of the globally distributed picocyanobacteria genera Prochlorococcus, Cyanobium and Synechococcus.info:eu-repo/semantics/publishedVersio

A prediction rule to stratify mortality risk of patients with pulmonary tuberculosis

Tuberculosis imposes high human and economic tolls, including in Europe. This study was conducted to develop a severity assessment tool for stratifying mortality risk in pulmonary tuberculosis (PTB) patients. A derivation cohort of 681 PTB cases was retrospectively reviewed to generate a model based on multiple logistic regression analysis of prognostic variables with 6-month mortality as the outcome measure. A clinical scoring system was developed and tested against a validation cohort of 103 patients. Five risk features were selected for the prediction model: hypoxemic respiratory failure (OR 4.7, 95% CI 2.8-7.9), age >= 50 years (OR 2.9, 95% CI 1.7-4.8), bilateral lung involvement (OR 2.5, 95% CI 1.44.4), >= 1 significant comorbidity-HIV infection, diabetes mellitus, liver failure or cirrhosis, congestive heart failure and chronic respiratory disease-(OR 2.3, 95% CI 1.3-3.8), and hemoglobin = 6) mortality risk. The mortality associated with each group was 2.9%, 22.9% and 53.9%, respectively. The model performed equally well in the validation cohort. We provide a new, easy-to-use clinical scoring system to identify PTB patients with high-mortality risk in settings with good healthcare access, helping clinicians to decide which patients are in need of closer medical care during treatment.This work was supported by Fundacao Amelia de Mello/Jose de Mello Saude and Sociedade Portuguesa de Pneumologia (SPP). This work was developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). NSO is a FCT (Fundacao para a Ciencia e Tecnologia) investigator. MS is an Associate FCT Investigator. The fundershad no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation

O valor da consciência fonológica nas crianças com Português língua estrangeira

Como resultado do grande movimento migratório, Portugal assistiu a uma nova problemática: a diversidade linguística. Esta realidade trouxe às escolas o desafio de gerir, por um lado, as diferentes relações linguísticas entre os alunos e a língua portuguesa; por outro, as novas medidas de escolarização que pressupõem a adoção de metodologias de aprendizagem do Português como Língua Não Materna, a criação de grupos de proficiência e a avaliação das aprendizagens. O desenvolvimento colaborativo de novas metas, conjuntamente com as bibliotecas escolares, permitem uma melhor viabilização da construção do saber destes alunos. O presente estudo pretende avaliar o desenvolvimento da consciência fonológica e suas correlações com a aprendizagem da leitura e escrita e verificar se há diferenças na manifestação da consciência fonológica em alunos com Português Língua Não Materna, posicionados em diferentes níveis de proficiência linguística. A centralização deste estudo baseou-se fundamentalmente na audição dos sons e respetiva produção escrita, pois representam os elementos essenciais no uso das várias funcionalidades da língua. Em contexto de Português Língua Não Materna é importante evocar, nos alunos, no que respeita ao processo de ensino-aprendizagem da escrita, uma consciência / competência que se deseja fonológica e metalinguística

Avaliação do módulo de queda de folhada em eucaliptais no modelo 3PG

A subvalorização das estimativas de biomassa de folhada obtidas com a utilização do modelo 3-PG na análise do ensaio de fertilização e rega, para todos os tratamentos (Testemunha, Fertilização, Rega e Fertilização+Rega) conduziu à instalação de cestos de recolha de folhada em três parcelas, localizadas na Quinta do Furadouro, em Óbidos, em povoamentos de Eucalyptus globulus de origem seminal, em alto fuste e com diferentes idades e localizados em zonas com diferentes índices de qualidade de estação para confirmar as tendências observadas no referido ensaio. As parcelas 1 e 2 foram instaladas num eucaliptal de 4,5 anos, diferindo apenas no índice de qualidade de estação, enquanto a parcela 3 num de 8,5 anos de idade. As recolhas de folhada foram efectuadas com intervalos de 15 dias. Respectivamente, obtiveram-se valores de biomassa seca de folhada acumulada no período de 15 Março a 26 Outubro de 2011 de 1,12 Mg ha-1, 1,86 Mg ha-1 e 2,82 Mg ha-1. A melhor qualidade de estação diferenciou os resultados das parcelas da mesma idade, enquanto que a parcela de 8,5 anos apresentou valores superiores a ambas. Embora o número de recolhas seja reduzido, as estimativas obtidas pelo modelo 3-PG para as parcelas indiciam também a mesma subestimação, parecendo confirmar os resultados do ensaio que justificou este estudo. Embora estejam indiciadas conclusões, é necessário este estudo completar, pelo menos, um ano de recolhas de folhada e/ou possivelmente instalar novas parcelas para confirmar a necessidade de melhorar o submodelo de queda de folhada do modelo 3-PG para Eucalyptus globulus em Portugalinfo:eu-repo/semantics/publishedVersio